Yara Abdou, MD

Prior studies show inconsistent outcomes in patients with invasive lobular carcinoma (ILC) and data in premenopausal women is limited. The retrospective cohort study by Yoon and colleagues analyzed the data from three databases and included 225,938 premenopausal women with stage I-III ILC or invasive ductal carcinoma (IDC) in their study to evaluate survival trends in young women with ILC. In the Surveillance, Epidemiology, and End Results (SEER) database, patients with ILC vs IDC showed superior breast cancer severity score (BCSS) outcomes during the first 10 years after diagnosis (HR 0.73; P < .001); similar results were seen in the Asan Medical Center Research (AMCR) database (HR 0.50; 95% CI 0.29-0.86; P = .01). After 10 years, the trend reversed, and BCSS outcomes worsened by 80% in patients with ILC in the SEER database (HR 1.80; P < .001). This was also seen in both the Korean Breast Cancer Registry (HR 2.79; 95% CI 1.32-5.88; P = .007) and AMCR database (HR 2.23; 95% CI 1.04-4.79; P = .04). These findings remained consistent after adjusting for tumor characteristics including age, stage, tumor grade, hormone receptor status, and after controlling for treatment with chemotherapy and radiation. In addition, in the SEER database, the histologic type exerted a statistically significant time-dependent association with BCSS, with ILC showing decreasing BCSS over time (time interaction HR 1.93; 95% CI 1.78-2.10; P < .001). Furthermore, on annual hazard function analysis, the ILC annual peak event of BCSS occurred 5 years after diagnosis, whereas the IDC recurrence events peaked at 5 years before diagnosis, suggesting a higher late recurrence rate for ILC. These findings may have implications on the duration of endocrine therapy used in these patients given concern for worse long-term outcomes in premenopausal patients with ILC.

Oral selective estrogen receptor degraders (SERD) have recently emerged as a new therapeutic mechanism for patients with hormone receptor–positive breast cancer who have developed resistance to other endocrine therapies. Two of these agents, elacestrant and camizestrant, have demonstrated statistically significant progression-free survival benefit in these populations, particularly in tumors with ESR1 mutations. The efficacy of these agents in tumors with ESR1 wild-type subgroup remains uncertain. A meta-analysis by Wong and colleagues of individual patient data from four randomized clinical trials (ACELERA, AMEERA-3, EMERALD, and SERENA-2) included 1290 patients with hormone receptor–positive/human epidermal growth factor receptor 2–negative metastatic breast cancer who received oral SERD or endocrine therapies (ET) of the physician's choice. In the overall cohort, oral SERD showed improved progression-free survival (PFS) outcomes compared with ET of the physician's choice (HR 0.783; 95% CI 0.681-0.900; P < .001). This was also noted in the subgroup of patients with ESR1 mutations (HR 0.557; 95% CI 0.440-0.705; P < .001); although no significant PFS benefit was observed with oral SERD in the ESR1 wild-type subgroup (HR 0.944; 95% CI 0.783-1.138; P = .543). These results suggest that the PFS benefit observed with oral SERD is mainly seen in patients with ESR1-mutated tumors, and, therefore, these drugs should be prescribed accordingly.

Additional Reference

1. Cold S, Cold F, Jensen M-B, et al. Systemic or vaginal hormone therapy after early breast cancer: A Danish observational cohort study. J Natl Cancer Inst. 2022;114:1347–1354. doi: 10.1093/jnci/djac112

Prior studies show inconsistent outcomes in patients with invasive lobular carcinoma (ILC) and data in premenopausal women is limited. The retrospective cohort study by Yoon and colleagues analyzed the data from three databases and included 225,938 premenopausal women with stage I-III ILC or invasive ductal carcinoma (IDC) in their study to evaluate survival trends in young women with ILC. In the Surveillance, Epidemiology, and End Results (SEER) database, patients with ILC vs IDC showed superior breast cancer severity score (BCSS) outcomes during the first 10 years after diagnosis (HR 0.73; P < .001); similar results were seen in the Asan Medical Center Research (AMCR) database (HR 0.50; 95% CI 0.29-0.86; P = .01). After 10 years, the trend reversed, and BCSS outcomes worsened by 80% in patients with ILC in the SEER database (HR 1.80; P < .001). This was also seen in both the Korean Breast Cancer Registry (HR 2.79; 95% CI 1.32-5.88; P = .007) and AMCR database (HR 2.23; 95% CI 1.04-4.79; P = .04). These findings remained consistent after adjusting for tumor characteristics including age, stage, tumor grade, hormone receptor status, and after controlling for treatment with chemotherapy and radiation. In addition, in the SEER database, the histologic type exerted a statistically significant time-dependent association with BCSS, with ILC showing decreasing BCSS over time (time interaction HR 1.93; 95% CI 1.78-2.10; P < .001). Furthermore, on annual hazard function analysis, the ILC annual peak event of BCSS occurred 5 years after diagnosis, whereas the IDC recurrence events peaked at 5 years before diagnosis, suggesting a higher late recurrence rate for ILC. These findings may have implications on the duration of endocrine therapy used in these patients given concern for worse long-term outcomes in premenopausal patients with ILC.

Oral selective estrogen receptor degraders (SERD) have recently emerged as a new therapeutic mechanism for patients with hormone receptor–positive breast cancer who have developed resistance to other endocrine therapies. Two of these agents, elacestrant and camizestrant, have demonstrated statistically significant progression-free survival benefit in these populations, particularly in tumors with ESR1 mutations. The efficacy of these agents in tumors with ESR1 wild-type subgroup remains uncertain. A meta-analysis by Wong and colleagues of individual patient data from four randomized clinical trials (ACELERA, AMEERA-3, EMERALD, and SERENA-2) included 1290 patients with hormone receptor–positive/human epidermal growth factor receptor 2–negative metastatic breast cancer who received oral SERD or endocrine therapies (ET) of the physician's choice. In the overall cohort, oral SERD showed improved progression-free survival (PFS) outcomes compared with ET of the physician's choice (HR 0.783; 95% CI 0.681-0.900; P < .001). This was also noted in the subgroup of patients with ESR1 mutations (HR 0.557; 95% CI 0.440-0.705; P < .001); although no significant PFS benefit was observed with oral SERD in the ESR1 wild-type subgroup (HR 0.944; 95% CI 0.783-1.138; P = .543). These results suggest that the PFS benefit observed with oral SERD is mainly seen in patients with ESR1-mutated tumors, and, therefore, these drugs should be prescribed accordingly.

Additional Reference

1. Cold S, Cold F, Jensen M-B, et al. Systemic or vaginal hormone therapy after early breast cancer: A Danish observational cohort study. J Natl Cancer Inst. 2022;114:1347–1354. doi: 10.1093/jnci/djac112

Prior studies show inconsistent outcomes in patients with invasive lobular carcinoma (ILC) and data in premenopausal women is limited. The retrospective cohort study by Yoon and colleagues analyzed the data from three databases and included 225,938 premenopausal women with stage I-III ILC or invasive ductal carcinoma (IDC) in their study to evaluate survival trends in young women with ILC. In the Surveillance, Epidemiology, and End Results (SEER) database, patients with ILC vs IDC showed superior breast cancer severity score (BCSS) outcomes during the first 10 years after diagnosis (HR 0.73; P < .001); similar results were seen in the Asan Medical Center Research (AMCR) database (HR 0.50; 95% CI 0.29-0.86; P = .01). After 10 years, the trend reversed, and BCSS outcomes worsened by 80% in patients with ILC in the SEER database (HR 1.80; P < .001). This was also seen in both the Korean Breast Cancer Registry (HR 2.79; 95% CI 1.32-5.88; P = .007) and AMCR database (HR 2.23; 95% CI 1.04-4.79; P = .04). These findings remained consistent after adjusting for tumor characteristics including age, stage, tumor grade, hormone receptor status, and after controlling for treatment with chemotherapy and radiation. In addition, in the SEER database, the histologic type exerted a statistically significant time-dependent association with BCSS, with ILC showing decreasing BCSS over time (time interaction HR 1.93; 95% CI 1.78-2.10; P < .001). Furthermore, on annual hazard function analysis, the ILC annual peak event of BCSS occurred 5 years after diagnosis, whereas the IDC recurrence events peaked at 5 years before diagnosis, suggesting a higher late recurrence rate for ILC. These findings may have implications on the duration of endocrine therapy used in these patients given concern for worse long-term outcomes in premenopausal patients with ILC.

Oral selective estrogen receptor degraders (SERD) have recently emerged as a new therapeutic mechanism for patients with hormone receptor–positive breast cancer who have developed resistance to other endocrine therapies. Two of these agents, elacestrant and camizestrant, have demonstrated statistically significant progression-free survival benefit in these populations, particularly in tumors with ESR1 mutations. The efficacy of these agents in tumors with ESR1 wild-type subgroup remains uncertain. A meta-analysis by Wong and colleagues of individual patient data from four randomized clinical trials (ACELERA, AMEERA-3, EMERALD, and SERENA-2) included 1290 patients with hormone receptor–positive/human epidermal growth factor receptor 2–negative metastatic breast cancer who received oral SERD or endocrine therapies (ET) of the physician's choice. In the overall cohort, oral SERD showed improved progression-free survival (PFS) outcomes compared with ET of the physician's choice (HR 0.783; 95% CI 0.681-0.900; P < .001). This was also noted in the subgroup of patients with ESR1 mutations (HR 0.557; 95% CI 0.440-0.705; P < .001); although no significant PFS benefit was observed with oral SERD in the ESR1 wild-type subgroup (HR 0.944; 95% CI 0.783-1.138; P = .543). These results suggest that the PFS benefit observed with oral SERD is mainly seen in patients with ESR1-mutated tumors, and, therefore, these drugs should be prescribed accordingly.

Additional Reference

1. Cold S, Cold F, Jensen M-B, et al. Systemic or vaginal hormone therapy after early breast cancer: A Danish observational cohort study. J Natl Cancer Inst. 2022;114:1347–1354. doi: 10.1093/jnci/djac112

In patients with node-positive and locally advanced breast cancer (BC), postmastectomy radiation therapy (PMRT) decreases risk for recurrence and improves survival (Mutter et al). Proton therapy is an attractive newer way to deliver PMRT compared with photon-based methods and allows improved sparing of cardiopulmonary and other normal tissue. The phase 2 MC1631 trial included 82 patients with BC who underwent mastectomy with or without immediate breast reconstruction and who were randomly assigned to receive either conventional fractionated (50 Gy in 25 fractions of 2 Gy) or hypofractionated (40.05 Gy in 15 fractions of 2.67 Gy) proton PMRT. At a median follow-up of 39.3 months, both conventional fractionated and hypofractionated proton PMRT had similar complication rates (15% vs 20%; absolute difference 4.9%; one-sided 95% CI 18.5; P = .27), with most complications occurring in patients with immediate expander or implant-based reconstruction. Noninferiority of the hypofractionation group could not be determined after a median follow-up of 39 months. However, no isolated local regional recurrences in either treatment arm were seen. This study provides the first prospective, randomized data of hypofractionated proton PMRT. Further data are awaited to support this approach. 

In patients with metastatic hormone receptor (HR)–positive, PIK3CA-mutant BC, the combination of fulvestrant with alpelisib improves progression-free survival per the SOLAR-1 study.1 Higher rates of hyperglycemia observed among patients treated with alpelisib have led to alpelisib dose reductions, treatment delays, and discontinuation of the drug. In a retrospective cohort study of 247 patients with metastatic BC who received alpelisib either as standard care (n = 147) or in a clinical trial setting (n = 100), 61.5% of patients developed any-grade hyperglycemia (Shen et al). The rate of hyperglycemia was considerably higher in patients who received alpelisib as part of standard care vs clinical trial (80.3% vs 34.0%). Baseline body mass index ≥ 25 (P = .036) and A1c levels in the prediabetes and diabetes range were significantly associated with the development of any-grade hyperglycemia (P = .036 and P < .001, respectively) and grade 3-4 hyperglycemia (P < .001 for both). A total of 4.5% of patients discontinued alpelisib owing to hyperglycemia, 17% of patients required dose reductions, and in 27% of patients alpelisib was held until resolution of hyperglycemia. This study highlights the importance of the management of comorbidities before alpelisib treatment to ensure lower rates of adverse events. 

Patritumab deruxtecan (HER3-DXd) is a novel HER3-targeted antibody-drug conjugate that is being evaluated in HER3-expressing metastatic BC. The U31402-A-J101 study is a phase 1/2 trial including 182 heavily pretreated patients (median of five prior therapies) with HER3-expressing advanced BC who received HER3-DXd (Krop et al). The objective response rate was 30.1% (95% CI 21.8%-39.4%) in HR-positive, human epidermal growth factor receptor 2 (HER2)–negative BC, 22.6% (95% CI 12.3%-36.2%) in triple-negative BC, and 42.9% (95% CI 17.1%-71.1%) in HER2-positive BC. Although 71.4% of patients reported grade ≥ 3 treatment-emergent adverse events (TEAE), the overall rate of treatment discontinuation due to TEAE was low (9.9%). These findings demonstrate an encouraging efficacy and a manageable safety profile for patritumab deruxtecan in previously treated patients with BC across all subtypes. Further studies are awaited to confirm these findings and whether prior treatment with antibody-drug conjugate will affect the activity of this drug.

A retrospective analysis of a cohort including 149 patients with metastatic BC looked at predictors of prognosis in patients who had brain metastases and underwent stereotactic radiosurgery (Depner et al). The median overall survival was 14.8 months for the entire cohort. Receptor profiles and the presence of extracranial visceral metastases were significant predictors of prognosis. Overall survival outcomes worsened in patients with estrogen receptor (ER)–negative, HER2-negative BC (hazard ratio 2.00; 95% CI 1.09-3.67) but were better in those with ER-positive, HER2-positive BC (hazard ratio 0.43; 95% CI 0.19-0.96). Furthermore, the presence of extracranial visceral metastases was associated with poor survival outcomes (hazard ratio 2.90; 95% CI 1.53-5.50)

Additional Reference
1.    André F et al, for the SOLAR-1 Study Group. Alpelisib for PIK3CA-mutated, hormone receptor–positive advanced breast cancer. N Engl J Med. 2019;380:1929-1940. doi: 10.1056/NEJMoa1813904
 

In patients with node-positive and locally advanced breast cancer (BC), postmastectomy radiation therapy (PMRT) decreases risk for recurrence and improves survival (Mutter et al). Proton therapy is an attractive newer way to deliver PMRT compared with photon-based methods and allows improved sparing of cardiopulmonary and other normal tissue. The phase 2 MC1631 trial included 82 patients with BC who underwent mastectomy with or without immediate breast reconstruction and who were randomly assigned to receive either conventional fractionated (50 Gy in 25 fractions of 2 Gy) or hypofractionated (40.05 Gy in 15 fractions of 2.67 Gy) proton PMRT. At a median follow-up of 39.3 months, both conventional fractionated and hypofractionated proton PMRT had similar complication rates (15% vs 20%; absolute difference 4.9%; one-sided 95% CI 18.5; P = .27), with most complications occurring in patients with immediate expander or implant-based reconstruction. Noninferiority of the hypofractionation group could not be determined after a median follow-up of 39 months. However, no isolated local regional recurrences in either treatment arm were seen. This study provides the first prospective, randomized data of hypofractionated proton PMRT. Further data are awaited to support this approach. 

In patients with metastatic hormone receptor (HR)–positive, PIK3CA-mutant BC, the combination of fulvestrant with alpelisib improves progression-free survival per the SOLAR-1 study.1 Higher rates of hyperglycemia observed among patients treated with alpelisib have led to alpelisib dose reductions, treatment delays, and discontinuation of the drug. In a retrospective cohort study of 247 patients with metastatic BC who received alpelisib either as standard care (n = 147) or in a clinical trial setting (n = 100), 61.5% of patients developed any-grade hyperglycemia (Shen et al). The rate of hyperglycemia was considerably higher in patients who received alpelisib as part of standard care vs clinical trial (80.3% vs 34.0%). Baseline body mass index ≥ 25 (P = .036) and A1c levels in the prediabetes and diabetes range were significantly associated with the development of any-grade hyperglycemia (P = .036 and P < .001, respectively) and grade 3-4 hyperglycemia (P < .001 for both). A total of 4.5% of patients discontinued alpelisib owing to hyperglycemia, 17% of patients required dose reductions, and in 27% of patients alpelisib was held until resolution of hyperglycemia. This study highlights the importance of the management of comorbidities before alpelisib treatment to ensure lower rates of adverse events. 

Patritumab deruxtecan (HER3-DXd) is a novel HER3-targeted antibody-drug conjugate that is being evaluated in HER3-expressing metastatic BC. The U31402-A-J101 study is a phase 1/2 trial including 182 heavily pretreated patients (median of five prior therapies) with HER3-expressing advanced BC who received HER3-DXd (Krop et al). The objective response rate was 30.1% (95% CI 21.8%-39.4%) in HR-positive, human epidermal growth factor receptor 2 (HER2)–negative BC, 22.6% (95% CI 12.3%-36.2%) in triple-negative BC, and 42.9% (95% CI 17.1%-71.1%) in HER2-positive BC. Although 71.4% of patients reported grade ≥ 3 treatment-emergent adverse events (TEAE), the overall rate of treatment discontinuation due to TEAE was low (9.9%). These findings demonstrate an encouraging efficacy and a manageable safety profile for patritumab deruxtecan in previously treated patients with BC across all subtypes. Further studies are awaited to confirm these findings and whether prior treatment with antibody-drug conjugate will affect the activity of this drug.

A retrospective analysis of a cohort including 149 patients with metastatic BC looked at predictors of prognosis in patients who had brain metastases and underwent stereotactic radiosurgery (Depner et al). The median overall survival was 14.8 months for the entire cohort. Receptor profiles and the presence of extracranial visceral metastases were significant predictors of prognosis. Overall survival outcomes worsened in patients with estrogen receptor (ER)–negative, HER2-negative BC (hazard ratio 2.00; 95% CI 1.09-3.67) but were better in those with ER-positive, HER2-positive BC (hazard ratio 0.43; 95% CI 0.19-0.96). Furthermore, the presence of extracranial visceral metastases was associated with poor survival outcomes (hazard ratio 2.90; 95% CI 1.53-5.50)

Additional Reference
1.    André F et al, for the SOLAR-1 Study Group. Alpelisib for PIK3CA-mutated, hormone receptor–positive advanced breast cancer. N Engl J Med. 2019;380:1929-1940. doi: 10.1056/NEJMoa1813904
 

In patients with node-positive and locally advanced breast cancer (BC), postmastectomy radiation therapy (PMRT) decreases risk for recurrence and improves survival (Mutter et al). Proton therapy is an attractive newer way to deliver PMRT compared with photon-based methods and allows improved sparing of cardiopulmonary and other normal tissue. The phase 2 MC1631 trial included 82 patients with BC who underwent mastectomy with or without immediate breast reconstruction and who were randomly assigned to receive either conventional fractionated (50 Gy in 25 fractions of 2 Gy) or hypofractionated (40.05 Gy in 15 fractions of 2.67 Gy) proton PMRT. At a median follow-up of 39.3 months, both conventional fractionated and hypofractionated proton PMRT had similar complication rates (15% vs 20%; absolute difference 4.9%; one-sided 95% CI 18.5; P = .27), with most complications occurring in patients with immediate expander or implant-based reconstruction. Noninferiority of the hypofractionation group could not be determined after a median follow-up of 39 months. However, no isolated local regional recurrences in either treatment arm were seen. This study provides the first prospective, randomized data of hypofractionated proton PMRT. Further data are awaited to support this approach. 

In patients with metastatic hormone receptor (HR)–positive, PIK3CA-mutant BC, the combination of fulvestrant with alpelisib improves progression-free survival per the SOLAR-1 study.1 Higher rates of hyperglycemia observed among patients treated with alpelisib have led to alpelisib dose reductions, treatment delays, and discontinuation of the drug. In a retrospective cohort study of 247 patients with metastatic BC who received alpelisib either as standard care (n = 147) or in a clinical trial setting (n = 100), 61.5% of patients developed any-grade hyperglycemia (Shen et al). The rate of hyperglycemia was considerably higher in patients who received alpelisib as part of standard care vs clinical trial (80.3% vs 34.0%). Baseline body mass index ≥ 25 (P = .036) and A1c levels in the prediabetes and diabetes range were significantly associated with the development of any-grade hyperglycemia (P = .036 and P < .001, respectively) and grade 3-4 hyperglycemia (P < .001 for both). A total of 4.5% of patients discontinued alpelisib owing to hyperglycemia, 17% of patients required dose reductions, and in 27% of patients alpelisib was held until resolution of hyperglycemia. This study highlights the importance of the management of comorbidities before alpelisib treatment to ensure lower rates of adverse events. 

Patritumab deruxtecan (HER3-DXd) is a novel HER3-targeted antibody-drug conjugate that is being evaluated in HER3-expressing metastatic BC. The U31402-A-J101 study is a phase 1/2 trial including 182 heavily pretreated patients (median of five prior therapies) with HER3-expressing advanced BC who received HER3-DXd (Krop et al). The objective response rate was 30.1% (95% CI 21.8%-39.4%) in HR-positive, human epidermal growth factor receptor 2 (HER2)–negative BC, 22.6% (95% CI 12.3%-36.2%) in triple-negative BC, and 42.9% (95% CI 17.1%-71.1%) in HER2-positive BC. Although 71.4% of patients reported grade ≥ 3 treatment-emergent adverse events (TEAE), the overall rate of treatment discontinuation due to TEAE was low (9.9%). These findings demonstrate an encouraging efficacy and a manageable safety profile for patritumab deruxtecan in previously treated patients with BC across all subtypes. Further studies are awaited to confirm these findings and whether prior treatment with antibody-drug conjugate will affect the activity of this drug.

A retrospective analysis of a cohort including 149 patients with metastatic BC looked at predictors of prognosis in patients who had brain metastases and underwent stereotactic radiosurgery (Depner et al). The median overall survival was 14.8 months for the entire cohort. Receptor profiles and the presence of extracranial visceral metastases were significant predictors of prognosis. Overall survival outcomes worsened in patients with estrogen receptor (ER)–negative, HER2-negative BC (hazard ratio 2.00; 95% CI 1.09-3.67) but were better in those with ER-positive, HER2-positive BC (hazard ratio 0.43; 95% CI 0.19-0.96). Furthermore, the presence of extracranial visceral metastases was associated with poor survival outcomes (hazard ratio 2.90; 95% CI 1.53-5.50)

Additional Reference
1.    André F et al, for the SOLAR-1 Study Group. Alpelisib for PIK3CA-mutated, hormone receptor–positive advanced breast cancer. N Engl J Med. 2019;380:1929-1940. doi: 10.1056/NEJMoa1813904
 

A recently published study by Rugo and colleagues presented the final analysis of overall survival and endpoints by trophoblast cell surface antigen 2 (Trop-2) expression. Results showed that at the 12.5-month median follow-up, sacituzumab govitecan vs chemotherapy improved overall survival by 3.2 months (hazard ratio 0.79; P = .020). The survival benefit was consistent across different levels of Trop-2 expression. No new adverse events were reported; however, one fatal adverse event (septic shock caused by neutropenic colitis) was determined to be related to sacituzumab govitecan treatment. These updated data continue to support the use of sacituzumab govitecan as a new treatment option for patients with endocrine-resistant HR+ and HER2- MBC.

It remains unclear whether anti-HER2 therapy alone (without chemotherapy) is an effective treatment approach for patients with ERBB2-positive MBC in the first-line setting. Huober and the Swiss Group for Clinical Cancer Research, the Unicancer Breast Group, and the Dutch Breast Cancer Research Group report a phase 2 trial that included 210 patients with ERBB2+ MBC who were randomly assigned to receive pertuzumab plus trastuzumab with or without chemotherapy followed by trastuzumab-emtansine as the second-line therapy in both groups. Despite worse progression-free survival in the nonchemotherapy vs the chemotherapy group (8.4 months [95% CI 7.9-12.0] vs 23.3 months [95% CI 18.9-33.1]), overall survival rates were comparable at 2 years of follow-up (79.0% [90% CI 71.4%-85.4%] vs 78.1% [90% CI 70.4%-84.5%]). Furthermore, adverse events were more frequent in the chemotherapy cohort, with small quality-of-life improvements from baseline in the nonchemotherapy cohort. Further prospective data are needed to confirm whether a chemotherapy-free approach is an acceptable treatment approach in certain population of patients, without unfavorable effects on overall survival.

Prior results from the SOFT and TEXT trials have shown improved survival with the addition of ovarian function suppression (OFS) in premenopausal women after chemotherapy. The ASTRRA trial is a similar phase 3 study that included 1282 premenopausal women with estrogen receptor–positive BC who remained premenopausal or regained ovarian function after chemotherapy and were randomly assigned to receive tamoxifen with or without OFS. The results showed a consistent disease-free survival benefit in women who received tamoxifen plus OFS vs tamoxifen alone (85.4% vs 80.2%; hazard ratio 0.67; P = .003) after a median follow-up of 8 years. There were no significant differences in 8-year OS rates between the two groups (P = .305), although both cohorts had high OS rates overall (> 95%). This trial highlights the overall excellent prognosis in this patient population and underscores the importance of OFS in the subgroup of patients who remain in a premenopausal state or resume ovarian function after chemotherapy.

The ICE study (Ibandronate with or without Capecitabine in Elderly patients with early breast cancer) was a phase 3 trial looking at 1358 patients age ≥ 65 years with node-positive or high-risk node-negative early BC who were randomly assigned to receive 2 years of ibandronate with or without capecitabine for six cycles in the adjuvant setting. At a median follow-up of 61 months, the 5-year invasive disease-free survival rates were similar amongst patients treated with adjuvant ibandronate plus capecitabine and ibandronate alone (hazard ratio 0.96; 95% CI 0.78-1.19). Outcomes were independent of age, nodal status, and hormone receptor status. The incidences of high-grade gastrointestinal disorders (6.7% vs 1.0%; P < .001) and skin toxicity (14.6% vs 0.6%; P < .01) were significantly higher in the capecitabine plus ibandronate arm vs the ibandronate alone arm.

Adjuvant capecitabine plus ibandronate failed to show improved survival outcomes compared with ibandronate alone in older patients with node-positive/high-risk node-negative BC. This was similar to results of the CALGB 49907 trial, which showed inferior survival for adjuvant capecitabine compared with standard adjuvant chemotherapy in patients ≥ 65 years of age.¹ Therefore, although oral capecitabine may be more tolerable than intravenous polychemotherapy in older patients with high-risk BC, this should be weighed against lower efficacy.

Additional Reference

1. Muss HB, Berry DA, Cirrincione CT, et al, for the CALGB Investigators. Adjuvant chemotherapy in older women with early-stage breast cancer. N Engl J Med. 2009;360:2055-2065. doi: 10.1056/NEJMoa0810266

A recently published study by Rugo and colleagues presented the final analysis of overall survival and endpoints by trophoblast cell surface antigen 2 (Trop-2) expression. Results showed that at the 12.5-month median follow-up, sacituzumab govitecan vs chemotherapy improved overall survival by 3.2 months (hazard ratio 0.79; P = .020). The survival benefit was consistent across different levels of Trop-2 expression. No new adverse events were reported; however, one fatal adverse event (septic shock caused by neutropenic colitis) was determined to be related to sacituzumab govitecan treatment. These updated data continue to support the use of sacituzumab govitecan as a new treatment option for patients with endocrine-resistant HR+ and HER2- MBC.

It remains unclear whether anti-HER2 therapy alone (without chemotherapy) is an effective treatment approach for patients with ERBB2-positive MBC in the first-line setting. Huober and the Swiss Group for Clinical Cancer Research, the Unicancer Breast Group, and the Dutch Breast Cancer Research Group report a phase 2 trial that included 210 patients with ERBB2+ MBC who were randomly assigned to receive pertuzumab plus trastuzumab with or without chemotherapy followed by trastuzumab-emtansine as the second-line therapy in both groups. Despite worse progression-free survival in the nonchemotherapy vs the chemotherapy group (8.4 months [95% CI 7.9-12.0] vs 23.3 months [95% CI 18.9-33.1]), overall survival rates were comparable at 2 years of follow-up (79.0% [90% CI 71.4%-85.4%] vs 78.1% [90% CI 70.4%-84.5%]). Furthermore, adverse events were more frequent in the chemotherapy cohort, with small quality-of-life improvements from baseline in the nonchemotherapy cohort. Further prospective data are needed to confirm whether a chemotherapy-free approach is an acceptable treatment approach in certain population of patients, without unfavorable effects on overall survival.

Prior results from the SOFT and TEXT trials have shown improved survival with the addition of ovarian function suppression (OFS) in premenopausal women after chemotherapy. The ASTRRA trial is a similar phase 3 study that included 1282 premenopausal women with estrogen receptor–positive BC who remained premenopausal or regained ovarian function after chemotherapy and were randomly assigned to receive tamoxifen with or without OFS. The results showed a consistent disease-free survival benefit in women who received tamoxifen plus OFS vs tamoxifen alone (85.4% vs 80.2%; hazard ratio 0.67; P = .003) after a median follow-up of 8 years. There were no significant differences in 8-year OS rates between the two groups (P = .305), although both cohorts had high OS rates overall (> 95%). This trial highlights the overall excellent prognosis in this patient population and underscores the importance of OFS in the subgroup of patients who remain in a premenopausal state or resume ovarian function after chemotherapy.

The ICE study (Ibandronate with or without Capecitabine in Elderly patients with early breast cancer) was a phase 3 trial looking at 1358 patients age ≥ 65 years with node-positive or high-risk node-negative early BC who were randomly assigned to receive 2 years of ibandronate with or without capecitabine for six cycles in the adjuvant setting. At a median follow-up of 61 months, the 5-year invasive disease-free survival rates were similar amongst patients treated with adjuvant ibandronate plus capecitabine and ibandronate alone (hazard ratio 0.96; 95% CI 0.78-1.19). Outcomes were independent of age, nodal status, and hormone receptor status. The incidences of high-grade gastrointestinal disorders (6.7% vs 1.0%; P < .001) and skin toxicity (14.6% vs 0.6%; P < .01) were significantly higher in the capecitabine plus ibandronate arm vs the ibandronate alone arm.

Adjuvant capecitabine plus ibandronate failed to show improved survival outcomes compared with ibandronate alone in older patients with node-positive/high-risk node-negative BC. This was similar to results of the CALGB 49907 trial, which showed inferior survival for adjuvant capecitabine compared with standard adjuvant chemotherapy in patients ≥ 65 years of age.¹ Therefore, although oral capecitabine may be more tolerable than intravenous polychemotherapy in older patients with high-risk BC, this should be weighed against lower efficacy.

Additional Reference

1. Muss HB, Berry DA, Cirrincione CT, et al, for the CALGB Investigators. Adjuvant chemotherapy in older women with early-stage breast cancer. N Engl J Med. 2009;360:2055-2065. doi: 10.1056/NEJMoa0810266

A recently published study by Rugo and colleagues presented the final analysis of overall survival and endpoints by trophoblast cell surface antigen 2 (Trop-2) expression. Results showed that at the 12.5-month median follow-up, sacituzumab govitecan vs chemotherapy improved overall survival by 3.2 months (hazard ratio 0.79; P = .020). The survival benefit was consistent across different levels of Trop-2 expression. No new adverse events were reported; however, one fatal adverse event (septic shock caused by neutropenic colitis) was determined to be related to sacituzumab govitecan treatment. These updated data continue to support the use of sacituzumab govitecan as a new treatment option for patients with endocrine-resistant HR+ and HER2- MBC.

It remains unclear whether anti-HER2 therapy alone (without chemotherapy) is an effective treatment approach for patients with ERBB2-positive MBC in the first-line setting. Huober and the Swiss Group for Clinical Cancer Research, the Unicancer Breast Group, and the Dutch Breast Cancer Research Group report a phase 2 trial that included 210 patients with ERBB2+ MBC who were randomly assigned to receive pertuzumab plus trastuzumab with or without chemotherapy followed by trastuzumab-emtansine as the second-line therapy in both groups. Despite worse progression-free survival in the nonchemotherapy vs the chemotherapy group (8.4 months [95% CI 7.9-12.0] vs 23.3 months [95% CI 18.9-33.1]), overall survival rates were comparable at 2 years of follow-up (79.0% [90% CI 71.4%-85.4%] vs 78.1% [90% CI 70.4%-84.5%]). Furthermore, adverse events were more frequent in the chemotherapy cohort, with small quality-of-life improvements from baseline in the nonchemotherapy cohort. Further prospective data are needed to confirm whether a chemotherapy-free approach is an acceptable treatment approach in certain population of patients, without unfavorable effects on overall survival.

Prior results from the SOFT and TEXT trials have shown improved survival with the addition of ovarian function suppression (OFS) in premenopausal women after chemotherapy. The ASTRRA trial is a similar phase 3 study that included 1282 premenopausal women with estrogen receptor–positive BC who remained premenopausal or regained ovarian function after chemotherapy and were randomly assigned to receive tamoxifen with or without OFS. The results showed a consistent disease-free survival benefit in women who received tamoxifen plus OFS vs tamoxifen alone (85.4% vs 80.2%; hazard ratio 0.67; P = .003) after a median follow-up of 8 years. There were no significant differences in 8-year OS rates between the two groups (P = .305), although both cohorts had high OS rates overall (> 95%). This trial highlights the overall excellent prognosis in this patient population and underscores the importance of OFS in the subgroup of patients who remain in a premenopausal state or resume ovarian function after chemotherapy.

The ICE study (Ibandronate with or without Capecitabine in Elderly patients with early breast cancer) was a phase 3 trial looking at 1358 patients age ≥ 65 years with node-positive or high-risk node-negative early BC who were randomly assigned to receive 2 years of ibandronate with or without capecitabine for six cycles in the adjuvant setting. At a median follow-up of 61 months, the 5-year invasive disease-free survival rates were similar amongst patients treated with adjuvant ibandronate plus capecitabine and ibandronate alone (hazard ratio 0.96; 95% CI 0.78-1.19). Outcomes were independent of age, nodal status, and hormone receptor status. The incidences of high-grade gastrointestinal disorders (6.7% vs 1.0%; P < .001) and skin toxicity (14.6% vs 0.6%; P < .01) were significantly higher in the capecitabine plus ibandronate arm vs the ibandronate alone arm.

Adjuvant capecitabine plus ibandronate failed to show improved survival outcomes compared with ibandronate alone in older patients with node-positive/high-risk node-negative BC. This was similar to results of the CALGB 49907 trial, which showed inferior survival for adjuvant capecitabine compared with standard adjuvant chemotherapy in patients ≥ 65 years of age.¹ Therefore, although oral capecitabine may be more tolerable than intravenous polychemotherapy in older patients with high-risk BC, this should be weighed against lower efficacy.

Additional Reference

1. Muss HB, Berry DA, Cirrincione CT, et al, for the CALGB Investigators. Adjuvant chemotherapy in older women with early-stage breast cancer. N Engl J Med. 2009;360:2055-2065. doi: 10.1056/NEJMoa0810266

The use of proton pump inhibitors (PPI) can affect the bioavailability and effectiveness of concomitant medications, including cancer therapies. A retrospective study by Lee and colleagues aimed to identify the clinical outcomes of patients with hormone receptor–positive (HR+) and human epidermal growth factor receptor 2–negative advanced or metastatic BC who were concomitantly using PPI and palbociclib. The study included 1310 patients, of which 344 received concomitant PPI plus palbociclib and 966 patients received palbociclib alone. Results showed that patients who received concomitant PPI plus palbociclib had significantly shorter progression-free survival (hazard ratio 1.76; 95% CI 1.46-2.13) and overall survival (hazard ratio 2.72; 95% CI 2.07-3.53) rates compared with those who received palbociclib alone. These results suggest that the concomitant use of PPI with palbociclib may alter the therapeutic efficacy of the drug. More research studies are needed to confirm these findings.

Pfeiler and colleagues examined the association of BMI with side effects, treatment discontinuation, and efficacy of palbociclib. This study looked at 5698 patients with early-stage HR+ BC who received palbociclib plus endocrine therapy as part of a preplanned analysis of the PALLAS trial. Results showed that in women who received adjuvant palbociclib, higher BMI was associated with a significantly lower rate of neutropenia (odds ratio for a 1-unit change in BMI 0.93; 95% CI 0.92-0.95) and a lower rate of treatment discontinuation (adjusted hazard ratio for a 10-unit change in BMI 0.75; 95% CI 0.67-0.83) compared with normal-weight patients. No effect of BMI on palbociclib efficacy was observed at 31 months of follow-up. Further studies are needed to validate these findings in different cohorts.

In cases of early-stage breast cancer (clinical T1, T2) where patients undergo upfront breast-conserving therapy and sentinel lymph node biopsy (SLNB), completion of axillary lymph node dissection (CLND) is often omitted if only one or two positive sentinel lymph nodes are detected. A study by Zaveri and colleagues looked at outcomes among 548 patients with cT1-2 N0 BC who were treated with upfront mastectomy and had one or two positive lymph nodes on SLNB. The 5-year cumulative incidence rate of overall locoregional recurrence was comparable between patients who underwent vs those who did not undergo CLND (1.8% vs 1.3%; P = .93); receipt of post-mastectomy radiation therapy did not affect the locoregional recurrence rate in both categories of patients who underwent SLNB alone and SLNB with CLND (P = .1638). These results suggest that CLND may not necessarily improve outcomes in this patient population. Larger prospective studies are needed to confirm these findings.

The use of proton pump inhibitors (PPI) can affect the bioavailability and effectiveness of concomitant medications, including cancer therapies. A retrospective study by Lee and colleagues aimed to identify the clinical outcomes of patients with hormone receptor–positive (HR+) and human epidermal growth factor receptor 2–negative advanced or metastatic BC who were concomitantly using PPI and palbociclib. The study included 1310 patients, of which 344 received concomitant PPI plus palbociclib and 966 patients received palbociclib alone. Results showed that patients who received concomitant PPI plus palbociclib had significantly shorter progression-free survival (hazard ratio 1.76; 95% CI 1.46-2.13) and overall survival (hazard ratio 2.72; 95% CI 2.07-3.53) rates compared with those who received palbociclib alone. These results suggest that the concomitant use of PPI with palbociclib may alter the therapeutic efficacy of the drug. More research studies are needed to confirm these findings.

Pfeiler and colleagues examined the association of BMI with side effects, treatment discontinuation, and efficacy of palbociclib. This study looked at 5698 patients with early-stage HR+ BC who received palbociclib plus endocrine therapy as part of a preplanned analysis of the PALLAS trial. Results showed that in women who received adjuvant palbociclib, higher BMI was associated with a significantly lower rate of neutropenia (odds ratio for a 1-unit change in BMI 0.93; 95% CI 0.92-0.95) and a lower rate of treatment discontinuation (adjusted hazard ratio for a 10-unit change in BMI 0.75; 95% CI 0.67-0.83) compared with normal-weight patients. No effect of BMI on palbociclib efficacy was observed at 31 months of follow-up. Further studies are needed to validate these findings in different cohorts.

In cases of early-stage breast cancer (clinical T1, T2) where patients undergo upfront breast-conserving therapy and sentinel lymph node biopsy (SLNB), completion of axillary lymph node dissection (CLND) is often omitted if only one or two positive sentinel lymph nodes are detected. A study by Zaveri and colleagues looked at outcomes among 548 patients with cT1-2 N0 BC who were treated with upfront mastectomy and had one or two positive lymph nodes on SLNB. The 5-year cumulative incidence rate of overall locoregional recurrence was comparable between patients who underwent vs those who did not undergo CLND (1.8% vs 1.3%; P = .93); receipt of post-mastectomy radiation therapy did not affect the locoregional recurrence rate in both categories of patients who underwent SLNB alone and SLNB with CLND (P = .1638). These results suggest that CLND may not necessarily improve outcomes in this patient population. Larger prospective studies are needed to confirm these findings.

The use of proton pump inhibitors (PPI) can affect the bioavailability and effectiveness of concomitant medications, including cancer therapies. A retrospective study by Lee and colleagues aimed to identify the clinical outcomes of patients with hormone receptor–positive (HR+) and human epidermal growth factor receptor 2–negative advanced or metastatic BC who were concomitantly using PPI and palbociclib. The study included 1310 patients, of which 344 received concomitant PPI plus palbociclib and 966 patients received palbociclib alone. Results showed that patients who received concomitant PPI plus palbociclib had significantly shorter progression-free survival (hazard ratio 1.76; 95% CI 1.46-2.13) and overall survival (hazard ratio 2.72; 95% CI 2.07-3.53) rates compared with those who received palbociclib alone. These results suggest that the concomitant use of PPI with palbociclib may alter the therapeutic efficacy of the drug. More research studies are needed to confirm these findings.

Pfeiler and colleagues examined the association of BMI with side effects, treatment discontinuation, and efficacy of palbociclib. This study looked at 5698 patients with early-stage HR+ BC who received palbociclib plus endocrine therapy as part of a preplanned analysis of the PALLAS trial. Results showed that in women who received adjuvant palbociclib, higher BMI was associated with a significantly lower rate of neutropenia (odds ratio for a 1-unit change in BMI 0.93; 95% CI 0.92-0.95) and a lower rate of treatment discontinuation (adjusted hazard ratio for a 10-unit change in BMI 0.75; 95% CI 0.67-0.83) compared with normal-weight patients. No effect of BMI on palbociclib efficacy was observed at 31 months of follow-up. Further studies are needed to validate these findings in different cohorts.

In cases of early-stage breast cancer (clinical T1, T2) where patients undergo upfront breast-conserving therapy and sentinel lymph node biopsy (SLNB), completion of axillary lymph node dissection (CLND) is often omitted if only one or two positive sentinel lymph nodes are detected. A study by Zaveri and colleagues looked at outcomes among 548 patients with cT1-2 N0 BC who were treated with upfront mastectomy and had one or two positive lymph nodes on SLNB. The 5-year cumulative incidence rate of overall locoregional recurrence was comparable between patients who underwent vs those who did not undergo CLND (1.8% vs 1.3%; P = .93); receipt of post-mastectomy radiation therapy did not affect the locoregional recurrence rate in both categories of patients who underwent SLNB alone and SLNB with CLND (P = .1638). These results suggest that CLND may not necessarily improve outcomes in this patient population. Larger prospective studies are needed to confirm these findings.

Data are limited regarding the effect of interrupting radiation therapy for patients with BC. A retrospective study by Chow and colleagues looked at 35,845 patients with nonmetastatic triple-negative BC from the National Cancer Database who had received external beam radiation therapy as part of the management of their BC. The analysis showed inferior overall survival in patients with a longer duration of radiation treatment (hazard ratio 1.023; 95% CI 1.015-1.031) The more days of interruption, the higher the likelihood of mortality seen. In reference to 0-1 days of interruption, patients with 2-5 interrupted days (hazard ratio 1.069; 95% CI 1.002-1.140), 6-10 interrupted days (hazard ratio 1.239; 95% CI 1.140-1.348), and 11-15 interrupted days (hazard ratio 1.265; 95% CI 1.126-1.431) did worse. These findings should encourage further studies to explore ways to minimize treatment interruptions among patients with BC.

A lack of adherence to adjuvant endocrine therapy has been associated with increased mortality among women with BC. The retrospective study by Zheng and Thomas  included 25,796 older women (> 65 years old) diagnosed with stage I-III hormone receptor–positive BC and looked at associations between adherence to and persistence with adjuvant endocrine therapy and mortality in this cohort. Their findings showed that the risk for all-cause mortality was reduced by 25% in patients with vs without cumulative adherence to endocrine therapy (hazard ratio 0.75; P < .001), although no association was seen with BC-specific mortality. Persistence with endocrine therapy, which was defined as having taken the treatment for ≥ 180 continuous days, was associated with 11% reduction in all-cause mortality and 37% reduction in BC-specific mortality. This study supports prior studies in highlighting the importance of endocrine therapy adherence among women with hormone-positive BC.

Tumor-infiltrating lymphocytes (TIL) are considered significant prognostic markers in patients with BC, although the prognostic effect of TIL in human epidermal growth factor reception 2 (HER2)–low BC has not been identified. A large-cohort, single-institution retrospective analysis by Sun and colleagues investigated the prognostic role of TIL in HER2-low early-stage BC. The analysis included 1763 patients with early-stage BC who underwent surgery, of whom 429 patients were HER2+, 739 were HER2-low, and 595 were HER2-0. No differences in disease-free survival (DFS) were seen between the three cohorts. However, in patients with HER2-low BC, high (>10%) vs low (≤10%) TIL levels were associated with a 53% improvement in DFS overall (hazard ratio 0.47; P = .035), and a 58% improvement in DFS was seen for the hormone receptor–positive/HER2-low cohort (hazard ratio 0.42; P = .032).

Data are limited regarding the effect of interrupting radiation therapy for patients with BC. A retrospective study by Chow and colleagues looked at 35,845 patients with nonmetastatic triple-negative BC from the National Cancer Database who had received external beam radiation therapy as part of the management of their BC. The analysis showed inferior overall survival in patients with a longer duration of radiation treatment (hazard ratio 1.023; 95% CI 1.015-1.031) The more days of interruption, the higher the likelihood of mortality seen. In reference to 0-1 days of interruption, patients with 2-5 interrupted days (hazard ratio 1.069; 95% CI 1.002-1.140), 6-10 interrupted days (hazard ratio 1.239; 95% CI 1.140-1.348), and 11-15 interrupted days (hazard ratio 1.265; 95% CI 1.126-1.431) did worse. These findings should encourage further studies to explore ways to minimize treatment interruptions among patients with BC.

A lack of adherence to adjuvant endocrine therapy has been associated with increased mortality among women with BC. The retrospective study by Zheng and Thomas  included 25,796 older women (> 65 years old) diagnosed with stage I-III hormone receptor–positive BC and looked at associations between adherence to and persistence with adjuvant endocrine therapy and mortality in this cohort. Their findings showed that the risk for all-cause mortality was reduced by 25% in patients with vs without cumulative adherence to endocrine therapy (hazard ratio 0.75; P < .001), although no association was seen with BC-specific mortality. Persistence with endocrine therapy, which was defined as having taken the treatment for ≥ 180 continuous days, was associated with 11% reduction in all-cause mortality and 37% reduction in BC-specific mortality. This study supports prior studies in highlighting the importance of endocrine therapy adherence among women with hormone-positive BC.

Tumor-infiltrating lymphocytes (TIL) are considered significant prognostic markers in patients with BC, although the prognostic effect of TIL in human epidermal growth factor reception 2 (HER2)–low BC has not been identified. A large-cohort, single-institution retrospective analysis by Sun and colleagues investigated the prognostic role of TIL in HER2-low early-stage BC. The analysis included 1763 patients with early-stage BC who underwent surgery, of whom 429 patients were HER2+, 739 were HER2-low, and 595 were HER2-0. No differences in disease-free survival (DFS) were seen between the three cohorts. However, in patients with HER2-low BC, high (>10%) vs low (≤10%) TIL levels were associated with a 53% improvement in DFS overall (hazard ratio 0.47; P = .035), and a 58% improvement in DFS was seen for the hormone receptor–positive/HER2-low cohort (hazard ratio 0.42; P = .032).

Data are limited regarding the effect of interrupting radiation therapy for patients with BC. A retrospective study by Chow and colleagues looked at 35,845 patients with nonmetastatic triple-negative BC from the National Cancer Database who had received external beam radiation therapy as part of the management of their BC. The analysis showed inferior overall survival in patients with a longer duration of radiation treatment (hazard ratio 1.023; 95% CI 1.015-1.031) The more days of interruption, the higher the likelihood of mortality seen. In reference to 0-1 days of interruption, patients with 2-5 interrupted days (hazard ratio 1.069; 95% CI 1.002-1.140), 6-10 interrupted days (hazard ratio 1.239; 95% CI 1.140-1.348), and 11-15 interrupted days (hazard ratio 1.265; 95% CI 1.126-1.431) did worse. These findings should encourage further studies to explore ways to minimize treatment interruptions among patients with BC.

A lack of adherence to adjuvant endocrine therapy has been associated with increased mortality among women with BC. The retrospective study by Zheng and Thomas  included 25,796 older women (> 65 years old) diagnosed with stage I-III hormone receptor–positive BC and looked at associations between adherence to and persistence with adjuvant endocrine therapy and mortality in this cohort. Their findings showed that the risk for all-cause mortality was reduced by 25% in patients with vs without cumulative adherence to endocrine therapy (hazard ratio 0.75; P < .001), although no association was seen with BC-specific mortality. Persistence with endocrine therapy, which was defined as having taken the treatment for ≥ 180 continuous days, was associated with 11% reduction in all-cause mortality and 37% reduction in BC-specific mortality. This study supports prior studies in highlighting the importance of endocrine therapy adherence among women with hormone-positive BC.

Tumor-infiltrating lymphocytes (TIL) are considered significant prognostic markers in patients with BC, although the prognostic effect of TIL in human epidermal growth factor reception 2 (HER2)–low BC has not been identified. A large-cohort, single-institution retrospective analysis by Sun and colleagues investigated the prognostic role of TIL in HER2-low early-stage BC. The analysis included 1763 patients with early-stage BC who underwent surgery, of whom 429 patients were HER2+, 739 were HER2-low, and 595 were HER2-0. No differences in disease-free survival (DFS) were seen between the three cohorts. However, in patients with HER2-low BC, high (>10%) vs low (≤10%) TIL levels were associated with a 53% improvement in DFS overall (hazard ratio 0.47; P = .035), and a 58% improvement in DFS was seen for the hormone receptor–positive/HER2-low cohort (hazard ratio 0.42; P = .032).

After a median follow-up of 21.6 mo, the dalpiciclib group demonstrated a significantly longer median progression-free survival (PFS) compared with the placebo group (30.6 mo vs 18.2 mo; stratified hazard ratio [HR] 0.51; 95% CI 0.38-0.69; P < .0001). Overall, the dalpiciclib group demonstrated a manageable safety profile, although a higher percentage of grade 3/4 adverse events was noted with dalpiciclib than with placebo (90% vs 12%), as expected. Overall survival data for this CDK4/6 inhibitor are yet to come. These results suggest that dalpiciclib in combination with endocrine therapy is an alternative treatment for this group of patients, especially in countries where the traditionally approved CDK4/6 inhibitors (palbociclib, ribociclib, and abemaciclib) are not available.

The optimal sequencing of endocrine therapy (ET) after progression on CDK4/6 inhibitor–based therapy remains a challenge. In the phase 2 MAINTAIN trial, 119 patients (all of whom had HR+/HER2- metastatic breast cancer and who progressed on ET and CDK4/6 inhibitors) were randomly assigned to receive a different ET (fulvestrant or exemestane) from the previous ET they had received plus either the CDK4/6 inhibitor ribociclib or placebo. In the study by Kalinksky and colleagues, at a median follow-up of 18.2 mo, a significant improvement in PFS was observed in the switched ET-plus-ribociclib group compared with the switched ET-plus-placebo group (HR 0.57; P = .006). The phase 2 MAINTAIN trial is the first randomized trial to show the benefit of a CDK4/6 inhibitor after progression on another CDK4/6 inhibitor. It is important to note that the majority of patients in the MAINTAIN study previously received palbociclib in the first-line setting, which in recent studies has been demonstrated to be inferior to other CDK4/6 inhibitors. Therefore, it is important to confirm whether this will hold true upon progression from ribociclib or abemaciclib in the first-line setting. In addition, more data are needed to compare this approach with other ET treatment options, such as phosphoinositide 3-kinases inhibitors and oral selective estrogen receptor degraders.

There are several options for adjuvant radiation therapy for early-stage breast cancer. A meta-analysis of 14 randomized controlled trials and six comparative observational studies assessed the efficacy of whole breast irradiation (WBI) compared with partial breast irradiation (PBI) in 17,234 adults with early-stage breast cancer. Results of this meta-analysis showed that PBI was not significantly different from WBI, with similar rates of ipsilateral breast recurrence  at 5 years (relative risk [RR] 1.34; 95% CI 0.83-2.18) and 10 years (RR 1.29; 95% CI 0.87-1.91), although patients undergoing PBI reported fewer acute adverse events  compared with patients undergoing WBI (incidence rate ratio [IRR] 0.53; 95% CI 0.31-0.92) and acute grade ≥2 adverse events (IRR 0.21; 95% CI 0.07-0.62). These findings support using PBI as the adjuvant radiotherapy modality for select patients with favorable-risk early-stage breast cancer.

Another meta-analysis looked at assessing the survival benefit of adding CDK4/6 inhibitors to standard ET in older patients with advanced breast cancer. The study included 10 trials with 1985 older patients with advanced ER+ breast cancer who received ET with or without CDK4/6 inhibitors. The findings showed that adding CDK4/6 inhibitors to ET (letrozole or fulvestrant) significantly reduced the mortality risk by 21% (HR 0.79; 95% CI 0.69-0.91) and progression risk by 41% (HR 0.59; 95% CI 0.51-0.69) in older patients (age ≥ 65 years) with advanced breast cancer. Grade 3-4 neutropenia and diarrhea were similar in older patients. This study supports the use of CDK4/6 inhibitors as a reasonable treatment modality for older patients. More studies dedicated to the geriatric population are needed to help elaborate on the efficacy and tolerability of such agents in this population.

The phase 3 National Surgical Adjuvant Breast and Bowel Project B-42 (NSABP B-42) trial evaluated the role of extended letrozole therapy in postmenopausal breast cancer patients who were disease-free after 5 years of aromatase inhibitor–based therapy. The study included 3966 postmenopausal women with stage I-IIIA HR+ breast cancer who were randomly assigned to receive letrozole or placebo for 5 more years. After a median follow-up of 10.3 years, letrozole significantly improved disease-free survival (10-year absolute benefit 3.4%; HR 0.85; P = .01) compared with placebo, although there were no differences noted in overall survival between the groups (HR 0.97, P = .74). Furthermore, letrozole significantly reduced the breast cancer–free interval (HR 0.75, ,P = .003) and distant recurrence (HR 0.72, P = .01). There were no notable differences in toxicity, particularly rates of osteoporotic fractures and arterial thrombotic events, between the groups. Extended therapy with aromatase inhibitors beyond 5 years can be considered for select patients with early-stage breast cancer. Careful consideration of risks and benefits is needed to make these recommendations. 

After a median follow-up of 21.6 mo, the dalpiciclib group demonstrated a significantly longer median progression-free survival (PFS) compared with the placebo group (30.6 mo vs 18.2 mo; stratified hazard ratio [HR] 0.51; 95% CI 0.38-0.69; P < .0001). Overall, the dalpiciclib group demonstrated a manageable safety profile, although a higher percentage of grade 3/4 adverse events was noted with dalpiciclib than with placebo (90% vs 12%), as expected. Overall survival data for this CDK4/6 inhibitor are yet to come. These results suggest that dalpiciclib in combination with endocrine therapy is an alternative treatment for this group of patients, especially in countries where the traditionally approved CDK4/6 inhibitors (palbociclib, ribociclib, and abemaciclib) are not available.

The optimal sequencing of endocrine therapy (ET) after progression on CDK4/6 inhibitor–based therapy remains a challenge. In the phase 2 MAINTAIN trial, 119 patients (all of whom had HR+/HER2- metastatic breast cancer and who progressed on ET and CDK4/6 inhibitors) were randomly assigned to receive a different ET (fulvestrant or exemestane) from the previous ET they had received plus either the CDK4/6 inhibitor ribociclib or placebo. In the study by Kalinksky and colleagues, at a median follow-up of 18.2 mo, a significant improvement in PFS was observed in the switched ET-plus-ribociclib group compared with the switched ET-plus-placebo group (HR 0.57; P = .006). The phase 2 MAINTAIN trial is the first randomized trial to show the benefit of a CDK4/6 inhibitor after progression on another CDK4/6 inhibitor. It is important to note that the majority of patients in the MAINTAIN study previously received palbociclib in the first-line setting, which in recent studies has been demonstrated to be inferior to other CDK4/6 inhibitors. Therefore, it is important to confirm whether this will hold true upon progression from ribociclib or abemaciclib in the first-line setting. In addition, more data are needed to compare this approach with other ET treatment options, such as phosphoinositide 3-kinases inhibitors and oral selective estrogen receptor degraders.

There are several options for adjuvant radiation therapy for early-stage breast cancer. A meta-analysis of 14 randomized controlled trials and six comparative observational studies assessed the efficacy of whole breast irradiation (WBI) compared with partial breast irradiation (PBI) in 17,234 adults with early-stage breast cancer. Results of this meta-analysis showed that PBI was not significantly different from WBI, with similar rates of ipsilateral breast recurrence  at 5 years (relative risk [RR] 1.34; 95% CI 0.83-2.18) and 10 years (RR 1.29; 95% CI 0.87-1.91), although patients undergoing PBI reported fewer acute adverse events  compared with patients undergoing WBI (incidence rate ratio [IRR] 0.53; 95% CI 0.31-0.92) and acute grade ≥2 adverse events (IRR 0.21; 95% CI 0.07-0.62). These findings support using PBI as the adjuvant radiotherapy modality for select patients with favorable-risk early-stage breast cancer.

Another meta-analysis looked at assessing the survival benefit of adding CDK4/6 inhibitors to standard ET in older patients with advanced breast cancer. The study included 10 trials with 1985 older patients with advanced ER+ breast cancer who received ET with or without CDK4/6 inhibitors. The findings showed that adding CDK4/6 inhibitors to ET (letrozole or fulvestrant) significantly reduced the mortality risk by 21% (HR 0.79; 95% CI 0.69-0.91) and progression risk by 41% (HR 0.59; 95% CI 0.51-0.69) in older patients (age ≥ 65 years) with advanced breast cancer. Grade 3-4 neutropenia and diarrhea were similar in older patients. This study supports the use of CDK4/6 inhibitors as a reasonable treatment modality for older patients. More studies dedicated to the geriatric population are needed to help elaborate on the efficacy and tolerability of such agents in this population.

The phase 3 National Surgical Adjuvant Breast and Bowel Project B-42 (NSABP B-42) trial evaluated the role of extended letrozole therapy in postmenopausal breast cancer patients who were disease-free after 5 years of aromatase inhibitor–based therapy. The study included 3966 postmenopausal women with stage I-IIIA HR+ breast cancer who were randomly assigned to receive letrozole or placebo for 5 more years. After a median follow-up of 10.3 years, letrozole significantly improved disease-free survival (10-year absolute benefit 3.4%; HR 0.85; P = .01) compared with placebo, although there were no differences noted in overall survival between the groups (HR 0.97, P = .74). Furthermore, letrozole significantly reduced the breast cancer–free interval (HR 0.75, ,P = .003) and distant recurrence (HR 0.72, P = .01). There were no notable differences in toxicity, particularly rates of osteoporotic fractures and arterial thrombotic events, between the groups. Extended therapy with aromatase inhibitors beyond 5 years can be considered for select patients with early-stage breast cancer. Careful consideration of risks and benefits is needed to make these recommendations. 

After a median follow-up of 21.6 mo, the dalpiciclib group demonstrated a significantly longer median progression-free survival (PFS) compared with the placebo group (30.6 mo vs 18.2 mo; stratified hazard ratio [HR] 0.51; 95% CI 0.38-0.69; P < .0001). Overall, the dalpiciclib group demonstrated a manageable safety profile, although a higher percentage of grade 3/4 adverse events was noted with dalpiciclib than with placebo (90% vs 12%), as expected. Overall survival data for this CDK4/6 inhibitor are yet to come. These results suggest that dalpiciclib in combination with endocrine therapy is an alternative treatment for this group of patients, especially in countries where the traditionally approved CDK4/6 inhibitors (palbociclib, ribociclib, and abemaciclib) are not available.

The optimal sequencing of endocrine therapy (ET) after progression on CDK4/6 inhibitor–based therapy remains a challenge. In the phase 2 MAINTAIN trial, 119 patients (all of whom had HR+/HER2- metastatic breast cancer and who progressed on ET and CDK4/6 inhibitors) were randomly assigned to receive a different ET (fulvestrant or exemestane) from the previous ET they had received plus either the CDK4/6 inhibitor ribociclib or placebo. In the study by Kalinksky and colleagues, at a median follow-up of 18.2 mo, a significant improvement in PFS was observed in the switched ET-plus-ribociclib group compared with the switched ET-plus-placebo group (HR 0.57; P = .006). The phase 2 MAINTAIN trial is the first randomized trial to show the benefit of a CDK4/6 inhibitor after progression on another CDK4/6 inhibitor. It is important to note that the majority of patients in the MAINTAIN study previously received palbociclib in the first-line setting, which in recent studies has been demonstrated to be inferior to other CDK4/6 inhibitors. Therefore, it is important to confirm whether this will hold true upon progression from ribociclib or abemaciclib in the first-line setting. In addition, more data are needed to compare this approach with other ET treatment options, such as phosphoinositide 3-kinases inhibitors and oral selective estrogen receptor degraders.

There are several options for adjuvant radiation therapy for early-stage breast cancer. A meta-analysis of 14 randomized controlled trials and six comparative observational studies assessed the efficacy of whole breast irradiation (WBI) compared with partial breast irradiation (PBI) in 17,234 adults with early-stage breast cancer. Results of this meta-analysis showed that PBI was not significantly different from WBI, with similar rates of ipsilateral breast recurrence  at 5 years (relative risk [RR] 1.34; 95% CI 0.83-2.18) and 10 years (RR 1.29; 95% CI 0.87-1.91), although patients undergoing PBI reported fewer acute adverse events  compared with patients undergoing WBI (incidence rate ratio [IRR] 0.53; 95% CI 0.31-0.92) and acute grade ≥2 adverse events (IRR 0.21; 95% CI 0.07-0.62). These findings support using PBI as the adjuvant radiotherapy modality for select patients with favorable-risk early-stage breast cancer.

Another meta-analysis looked at assessing the survival benefit of adding CDK4/6 inhibitors to standard ET in older patients with advanced breast cancer. The study included 10 trials with 1985 older patients with advanced ER+ breast cancer who received ET with or without CDK4/6 inhibitors. The findings showed that adding CDK4/6 inhibitors to ET (letrozole or fulvestrant) significantly reduced the mortality risk by 21% (HR 0.79; 95% CI 0.69-0.91) and progression risk by 41% (HR 0.59; 95% CI 0.51-0.69) in older patients (age ≥ 65 years) with advanced breast cancer. Grade 3-4 neutropenia and diarrhea were similar in older patients. This study supports the use of CDK4/6 inhibitors as a reasonable treatment modality for older patients. More studies dedicated to the geriatric population are needed to help elaborate on the efficacy and tolerability of such agents in this population.

The phase 3 National Surgical Adjuvant Breast and Bowel Project B-42 (NSABP B-42) trial evaluated the role of extended letrozole therapy in postmenopausal breast cancer patients who were disease-free after 5 years of aromatase inhibitor–based therapy. The study included 3966 postmenopausal women with stage I-IIIA HR+ breast cancer who were randomly assigned to receive letrozole or placebo for 5 more years. After a median follow-up of 10.3 years, letrozole significantly improved disease-free survival (10-year absolute benefit 3.4%; HR 0.85; P = .01) compared with placebo, although there were no differences noted in overall survival between the groups (HR 0.97, P = .74). Furthermore, letrozole significantly reduced the breast cancer–free interval (HR 0.75, ,P = .003) and distant recurrence (HR 0.72, P = .01). There were no notable differences in toxicity, particularly rates of osteoporotic fractures and arterial thrombotic events, between the groups. Extended therapy with aromatase inhibitors beyond 5 years can be considered for select patients with early-stage breast cancer. Careful consideration of risks and benefits is needed to make these recommendations. 

Among the patients treated with trastuzumab deruxtecan, median progression-free survival was significantly prolonged compared with the physician's choice treatment group (17.8 vs 6.9 months; hazard ratio 0.36; P < .0001). There were no new safety signals reported for trastuzumab deruxtecan. Of interest, drug-related interstitial lung disease occurred in 10% of patients treated with trastuzumab deruxtecan (including two grade 5 death events) compared with < 1% in the physician's-choice treatment group.

Overall, trastuzumab deruxtecan demonstrated a favorable benefit-risk profile in patients with HER2+ BC previously treated with trastuzumab emtansine. This is the first randomized study to show efficacy with an antibody-drug conjugate after a previous antibody-drug conjugate.

Breast density is a known independent risk factor for BC, furthermore, dense breast tissue can make identifying BC on screening mammograms more challenging. The nested case-control cohort study by Jiang and colleagues observed women with no history of any cancer for 10 years, with screening mammograms every 1-2 years. Subsequently, 289 women who developed BC were identified and analyzed along with 658 matched control individuals. BC risk factors were also collected via questionnaires at the time of enrollment. Of note, the BC cases cohort had an overall higher mean body mass index, a higher percentage of Black women, and of women with a family history of BC. The results showed that though women's breast density decreased over time in both cases and controls, the rate of change in breast density was significantly slower in the breast that later developed cancer compared with the cancer-free breast in control individuals (estimate 0.027; P = .04). Enhancing screening modalities to enable assessing for longitudinal changes in breast density may provide an additional tool for evaluating the risk for BC.

Reducing the late BC recurrence risk beyond 5 years is a significant issue in patients with hormone receptor–positive (HR+) BC. This prospective, randomized, phase 3, AERAS trial included 1593 postmenopausal women with HR+ early-stage invasive BC who were disease-free at 5 years after postoperative endocrine therapy. Patients were randomly assigned 1:1 to stop or continue receiving anastrozole for an additional 5 years. Results showed that continuation of anastrozole treatment for an additional 5 years significantly improved 5-year disease-free survival (DFS) (hazard ratio 0.61; 95% CI 0.46-0.82; P < .0010). Furthermore, extended anastrozole treatment reduced the incidence of local recurrence and second primary cancers. However, there was no significant difference in distant DFS. The incidence of grade 3 or higher adverse events was < 1% in both groups, although menopausal or bone-related all-grade adverse events were more frequent among patients in the group that continued with anastrozole, as expected. Results from this study help inform the risks and benefits of extending hormone therapy beyond 5 years.

The RxPONDER trial comparing endocrine therapy (ET) alone to chemotherapy plus endocrine therapy (CET) in patients with one to three positive axillary lymph nodes and recurrence score (RS) ≤ 25 showed that CET did not improve survival outcomes compared with ET alone in postmenopausal women with HR+/HER2- BC. This retrospective cohort study of real-world data from the National Cancer Database included 28,427 women with stage I-III HR+/HER2- BC and one to three positive axillary lymph nodes, of which 26.3% and 73.7% of patients received CET and ET, respectively. Results showed that in patients with RS of 20-25, CET was associated with a significant improvement in overall survival compared with ET alone, in both premenopausal (age ≤ 50 years: hazard ratio 0.334, P = .002) and postmenopausal patients (age > 50 years: hazard ratio 0.521, P = .019). Though these results are inconsistent with the RxPONDER trial results regarding the postmenopausal cohort, they do raise an important finding that is supported by prior published data.¹ More studies are needed to validate these findings. At this time, guidelines recommend omitting chemotherapy in patients with HR+/HER2- BC, one to three positive axillary lymph nodes, and an RS of 20-25 per RxPONDER.

Additional Reference

1. Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Comparisons between different polychemotherapy regimens for early breast cancer: Meta-analyses of long-term outcome among 100,000 women in 123 randomised trials. Lancet. 2012;379:432-444. doi: 10.1016/S0140-6736(11)61625-5

Among the patients treated with trastuzumab deruxtecan, median progression-free survival was significantly prolonged compared with the physician's choice treatment group (17.8 vs 6.9 months; hazard ratio 0.36; P < .0001). There were no new safety signals reported for trastuzumab deruxtecan. Of interest, drug-related interstitial lung disease occurred in 10% of patients treated with trastuzumab deruxtecan (including two grade 5 death events) compared with < 1% in the physician's-choice treatment group.

Overall, trastuzumab deruxtecan demonstrated a favorable benefit-risk profile in patients with HER2+ BC previously treated with trastuzumab emtansine. This is the first randomized study to show efficacy with an antibody-drug conjugate after a previous antibody-drug conjugate.

Breast density is a known independent risk factor for BC, furthermore, dense breast tissue can make identifying BC on screening mammograms more challenging. The nested case-control cohort study by Jiang and colleagues observed women with no history of any cancer for 10 years, with screening mammograms every 1-2 years. Subsequently, 289 women who developed BC were identified and analyzed along with 658 matched control individuals. BC risk factors were also collected via questionnaires at the time of enrollment. Of note, the BC cases cohort had an overall higher mean body mass index, a higher percentage of Black women, and of women with a family history of BC. The results showed that though women's breast density decreased over time in both cases and controls, the rate of change in breast density was significantly slower in the breast that later developed cancer compared with the cancer-free breast in control individuals (estimate 0.027; P = .04). Enhancing screening modalities to enable assessing for longitudinal changes in breast density may provide an additional tool for evaluating the risk for BC.

Reducing the late BC recurrence risk beyond 5 years is a significant issue in patients with hormone receptor–positive (HR+) BC. This prospective, randomized, phase 3, AERAS trial included 1593 postmenopausal women with HR+ early-stage invasive BC who were disease-free at 5 years after postoperative endocrine therapy. Patients were randomly assigned 1:1 to stop or continue receiving anastrozole for an additional 5 years. Results showed that continuation of anastrozole treatment for an additional 5 years significantly improved 5-year disease-free survival (DFS) (hazard ratio 0.61; 95% CI 0.46-0.82; P < .0010). Furthermore, extended anastrozole treatment reduced the incidence of local recurrence and second primary cancers. However, there was no significant difference in distant DFS. The incidence of grade 3 or higher adverse events was < 1% in both groups, although menopausal or bone-related all-grade adverse events were more frequent among patients in the group that continued with anastrozole, as expected. Results from this study help inform the risks and benefits of extending hormone therapy beyond 5 years.

The RxPONDER trial comparing endocrine therapy (ET) alone to chemotherapy plus endocrine therapy (CET) in patients with one to three positive axillary lymph nodes and recurrence score (RS) ≤ 25 showed that CET did not improve survival outcomes compared with ET alone in postmenopausal women with HR+/HER2- BC. This retrospective cohort study of real-world data from the National Cancer Database included 28,427 women with stage I-III HR+/HER2- BC and one to three positive axillary lymph nodes, of which 26.3% and 73.7% of patients received CET and ET, respectively. Results showed that in patients with RS of 20-25, CET was associated with a significant improvement in overall survival compared with ET alone, in both premenopausal (age ≤ 50 years: hazard ratio 0.334, P = .002) and postmenopausal patients (age > 50 years: hazard ratio 0.521, P = .019). Though these results are inconsistent with the RxPONDER trial results regarding the postmenopausal cohort, they do raise an important finding that is supported by prior published data.¹ More studies are needed to validate these findings. At this time, guidelines recommend omitting chemotherapy in patients with HR+/HER2- BC, one to three positive axillary lymph nodes, and an RS of 20-25 per RxPONDER.

Additional Reference

1. Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Comparisons between different polychemotherapy regimens for early breast cancer: Meta-analyses of long-term outcome among 100,000 women in 123 randomised trials. Lancet. 2012;379:432-444. doi: 10.1016/S0140-6736(11)61625-5

Among the patients treated with trastuzumab deruxtecan, median progression-free survival was significantly prolonged compared with the physician's choice treatment group (17.8 vs 6.9 months; hazard ratio 0.36; P < .0001). There were no new safety signals reported for trastuzumab deruxtecan. Of interest, drug-related interstitial lung disease occurred in 10% of patients treated with trastuzumab deruxtecan (including two grade 5 death events) compared with < 1% in the physician's-choice treatment group.

Overall, trastuzumab deruxtecan demonstrated a favorable benefit-risk profile in patients with HER2+ BC previously treated with trastuzumab emtansine. This is the first randomized study to show efficacy with an antibody-drug conjugate after a previous antibody-drug conjugate.

Breast density is a known independent risk factor for BC, furthermore, dense breast tissue can make identifying BC on screening mammograms more challenging. The nested case-control cohort study by Jiang and colleagues observed women with no history of any cancer for 10 years, with screening mammograms every 1-2 years. Subsequently, 289 women who developed BC were identified and analyzed along with 658 matched control individuals. BC risk factors were also collected via questionnaires at the time of enrollment. Of note, the BC cases cohort had an overall higher mean body mass index, a higher percentage of Black women, and of women with a family history of BC. The results showed that though women's breast density decreased over time in both cases and controls, the rate of change in breast density was significantly slower in the breast that later developed cancer compared with the cancer-free breast in control individuals (estimate 0.027; P = .04). Enhancing screening modalities to enable assessing for longitudinal changes in breast density may provide an additional tool for evaluating the risk for BC.

Reducing the late BC recurrence risk beyond 5 years is a significant issue in patients with hormone receptor–positive (HR+) BC. This prospective, randomized, phase 3, AERAS trial included 1593 postmenopausal women with HR+ early-stage invasive BC who were disease-free at 5 years after postoperative endocrine therapy. Patients were randomly assigned 1:1 to stop or continue receiving anastrozole for an additional 5 years. Results showed that continuation of anastrozole treatment for an additional 5 years significantly improved 5-year disease-free survival (DFS) (hazard ratio 0.61; 95% CI 0.46-0.82; P < .0010). Furthermore, extended anastrozole treatment reduced the incidence of local recurrence and second primary cancers. However, there was no significant difference in distant DFS. The incidence of grade 3 or higher adverse events was < 1% in both groups, although menopausal or bone-related all-grade adverse events were more frequent among patients in the group that continued with anastrozole, as expected. Results from this study help inform the risks and benefits of extending hormone therapy beyond 5 years.

The RxPONDER trial comparing endocrine therapy (ET) alone to chemotherapy plus endocrine therapy (CET) in patients with one to three positive axillary lymph nodes and recurrence score (RS) ≤ 25 showed that CET did not improve survival outcomes compared with ET alone in postmenopausal women with HR+/HER2- BC. This retrospective cohort study of real-world data from the National Cancer Database included 28,427 women with stage I-III HR+/HER2- BC and one to three positive axillary lymph nodes, of which 26.3% and 73.7% of patients received CET and ET, respectively. Results showed that in patients with RS of 20-25, CET was associated with a significant improvement in overall survival compared with ET alone, in both premenopausal (age ≤ 50 years: hazard ratio 0.334, P = .002) and postmenopausal patients (age > 50 years: hazard ratio 0.521, P = .019). Though these results are inconsistent with the RxPONDER trial results regarding the postmenopausal cohort, they do raise an important finding that is supported by prior published data.¹ More studies are needed to validate these findings. At this time, guidelines recommend omitting chemotherapy in patients with HR+/HER2- BC, one to three positive axillary lymph nodes, and an RS of 20-25 per RxPONDER.

Additional Reference

1. Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Comparisons between different polychemotherapy regimens for early breast cancer: Meta-analyses of long-term outcome among 100,000 women in 123 randomised trials. Lancet. 2012;379:432-444. doi: 10.1016/S0140-6736(11)61625-5

A cohort study by Minami and colleagues assessed the association between surgery type (lumpectomy vs mastectomy) and change in frailty status in older patients with early-stage breast cancer (BC) undergoing locoregional therapy. The study included 31,084 women, age ≥ 65 years, with ductal carcinoma in situ (n = 9962) or stage I hormone receptor–positive (HR+) and ERBB2+ (human epidermal growth factor receptor 2 positive [HER2+]) BC (n = 21,122), of which 22.6% and 77.4% of patients underwent mastectomy and lumpectomy, respectively. The study showed that older patients who underwent mastectomy vs lumpectomy were more likely to experience worse frailty (adjusted odds ratio 1.31; 95% CI 1.23-1.39). Additionally, women who were robust vs having moderate to severe frailty at baseline, ≥ 75 years vs 65-69 years, or African American/Black vs non-Hispanic White, had significantly higher odds of decline. Given that prior data have shown comparable survival between lumpectomy and mastectomy, careful and thoughtful treatment considerations are needed before deciding to intensify surgical management in this population, even in women who do not appear frail at baseline.

Low-dose tamoxifen continues to prevent BC recurrence in breast noninvasive neoplasia

Low-dose tamoxifen is a treatment option for women with noninvasive BC, especially if the patient was not able to tolerate the standard dose of 20 mg daily. The phase 3 TAM-01 trial included 500 women with intraepithelial neoplasia of the breast who were randomly assigned to receive low-dose tamoxifen (5 mg once daily) or placebo. The 10-year follow-up analysis by Lazzeroni and colleagues showed that treatment with low-dose tamoxifen for 3 years continued to prevent a BC recurrence for at least 7 years after treatment cessation. After a median follow-up of 9.7 years, fewer cases of both invasive and in situ BC (hazard ratio 0.58; log-rank P = .03) and contralateral BC (hazard ratio 0.36; P = .025) were reported in the tamoxifen vs placebo group. These results are meaningful, especially in a setting of an optimal safety profile, where patients on low-dose tamoxifen were experiencing similar menopausal symptoms to placebo, and serious adverse events, such as deep vein thrombosis and pulmonary embolism, were not increased during low-dose tamoxifen therapy. This is different from the threefold increased risk reported with standard dosing.

Worse survival in BRCA1/2 germline mutation carriers receiving ET in HR+/HER2− BC

Inconsistent data have been reported on the prognostic impact of BRCA1/2 mutation in HR+ BC. A retrospective study by Frenel and colleagues included 13,776 patients with metastatic BC (MBC) from the Epidemiological Strategy and Medical Economics (ESME) MBC database, of which 676 and 170 patients were germline BRCA wild-type (gBRCAwt) and germline BRCA mutation (gBRCAm) carriers, respectively. They looked at outcomes and first-line endocrine treatment efficacy in patients with HR+/HER2- MBC, treated in a pre–cyclin-dependent kinase (CDK) 4/6 inhibitors era. The results showed that gBRCAm carriers had shorter overall survival (OS; adjusted hazard ratio [aHR] 1.26; P = .024) and progression-free survival (PFS; aHR 1.21; P = .017) compared with gBRCAwt carriers. Furthermore, among those treated with front-line endocrine therapy, gBRCAm patients had lower adjusted OS (aHR [95% CI] 1.54 [1.03-2.32]) and PFS (aHR [95% CI] 1.58 [1.17-2.12]) compared with gBRCAwt patients. Outcomes were similar for gBRCAm patients who received first-line chemotherapy compared with the gBRCAwt group (OS: aHR [95% CI] 1.12 [0.88-1.41]; first-line PFS: aHR [95% CI] 1.09 [0.90-1.31]). A previous retrospective study by Lambertini and colleagues, focusing on young patients with gBRCAm, also showed a tendency for a worse distant recurrence-free interval (aHR 1.39; 95% CI  0.94-2.05) in patients with HR+ BC. Additional studies are needed, especially in the setting of an evolving treatment landscape that includes CDK4/6 inhibitors and poly-ADP ribose polymerase (PARP) inhibitors.

A cohort study by Minami and colleagues assessed the association between surgery type (lumpectomy vs mastectomy) and change in frailty status in older patients with early-stage breast cancer (BC) undergoing locoregional therapy. The study included 31,084 women, age ≥ 65 years, with ductal carcinoma in situ (n = 9962) or stage I hormone receptor–positive (HR+) and ERBB2+ (human epidermal growth factor receptor 2 positive [HER2+]) BC (n = 21,122), of which 22.6% and 77.4% of patients underwent mastectomy and lumpectomy, respectively. The study showed that older patients who underwent mastectomy vs lumpectomy were more likely to experience worse frailty (adjusted odds ratio 1.31; 95% CI 1.23-1.39). Additionally, women who were robust vs having moderate to severe frailty at baseline, ≥ 75 years vs 65-69 years, or African American/Black vs non-Hispanic White, had significantly higher odds of decline. Given that prior data have shown comparable survival between lumpectomy and mastectomy, careful and thoughtful treatment considerations are needed before deciding to intensify surgical management in this population, even in women who do not appear frail at baseline.

Low-dose tamoxifen continues to prevent BC recurrence in breast noninvasive neoplasia

Low-dose tamoxifen is a treatment option for women with noninvasive BC, especially if the patient was not able to tolerate the standard dose of 20 mg daily. The phase 3 TAM-01 trial included 500 women with intraepithelial neoplasia of the breast who were randomly assigned to receive low-dose tamoxifen (5 mg once daily) or placebo. The 10-year follow-up analysis by Lazzeroni and colleagues showed that treatment with low-dose tamoxifen for 3 years continued to prevent a BC recurrence for at least 7 years after treatment cessation. After a median follow-up of 9.7 years, fewer cases of both invasive and in situ BC (hazard ratio 0.58; log-rank P = .03) and contralateral BC (hazard ratio 0.36; P = .025) were reported in the tamoxifen vs placebo group. These results are meaningful, especially in a setting of an optimal safety profile, where patients on low-dose tamoxifen were experiencing similar menopausal symptoms to placebo, and serious adverse events, such as deep vein thrombosis and pulmonary embolism, were not increased during low-dose tamoxifen therapy. This is different from the threefold increased risk reported with standard dosing.

Worse survival in BRCA1/2 germline mutation carriers receiving ET in HR+/HER2− BC

Inconsistent data have been reported on the prognostic impact of BRCA1/2 mutation in HR+ BC. A retrospective study by Frenel and colleagues included 13,776 patients with metastatic BC (MBC) from the Epidemiological Strategy and Medical Economics (ESME) MBC database, of which 676 and 170 patients were germline BRCA wild-type (gBRCAwt) and germline BRCA mutation (gBRCAm) carriers, respectively. They looked at outcomes and first-line endocrine treatment efficacy in patients with HR+/HER2- MBC, treated in a pre–cyclin-dependent kinase (CDK) 4/6 inhibitors era. The results showed that gBRCAm carriers had shorter overall survival (OS; adjusted hazard ratio [aHR] 1.26; P = .024) and progression-free survival (PFS; aHR 1.21; P = .017) compared with gBRCAwt carriers. Furthermore, among those treated with front-line endocrine therapy, gBRCAm patients had lower adjusted OS (aHR [95% CI] 1.54 [1.03-2.32]) and PFS (aHR [95% CI] 1.58 [1.17-2.12]) compared with gBRCAwt patients. Outcomes were similar for gBRCAm patients who received first-line chemotherapy compared with the gBRCAwt group (OS: aHR [95% CI] 1.12 [0.88-1.41]; first-line PFS: aHR [95% CI] 1.09 [0.90-1.31]). A previous retrospective study by Lambertini and colleagues, focusing on young patients with gBRCAm, also showed a tendency for a worse distant recurrence-free interval (aHR 1.39; 95% CI  0.94-2.05) in patients with HR+ BC. Additional studies are needed, especially in the setting of an evolving treatment landscape that includes CDK4/6 inhibitors and poly-ADP ribose polymerase (PARP) inhibitors.

A cohort study by Minami and colleagues assessed the association between surgery type (lumpectomy vs mastectomy) and change in frailty status in older patients with early-stage breast cancer (BC) undergoing locoregional therapy. The study included 31,084 women, age ≥ 65 years, with ductal carcinoma in situ (n = 9962) or stage I hormone receptor–positive (HR+) and ERBB2+ (human epidermal growth factor receptor 2 positive [HER2+]) BC (n = 21,122), of which 22.6% and 77.4% of patients underwent mastectomy and lumpectomy, respectively. The study showed that older patients who underwent mastectomy vs lumpectomy were more likely to experience worse frailty (adjusted odds ratio 1.31; 95% CI 1.23-1.39). Additionally, women who were robust vs having moderate to severe frailty at baseline, ≥ 75 years vs 65-69 years, or African American/Black vs non-Hispanic White, had significantly higher odds of decline. Given that prior data have shown comparable survival between lumpectomy and mastectomy, careful and thoughtful treatment considerations are needed before deciding to intensify surgical management in this population, even in women who do not appear frail at baseline.

Low-dose tamoxifen continues to prevent BC recurrence in breast noninvasive neoplasia

Low-dose tamoxifen is a treatment option for women with noninvasive BC, especially if the patient was not able to tolerate the standard dose of 20 mg daily. The phase 3 TAM-01 trial included 500 women with intraepithelial neoplasia of the breast who were randomly assigned to receive low-dose tamoxifen (5 mg once daily) or placebo. The 10-year follow-up analysis by Lazzeroni and colleagues showed that treatment with low-dose tamoxifen for 3 years continued to prevent a BC recurrence for at least 7 years after treatment cessation. After a median follow-up of 9.7 years, fewer cases of both invasive and in situ BC (hazard ratio 0.58; log-rank P = .03) and contralateral BC (hazard ratio 0.36; P = .025) were reported in the tamoxifen vs placebo group. These results are meaningful, especially in a setting of an optimal safety profile, where patients on low-dose tamoxifen were experiencing similar menopausal symptoms to placebo, and serious adverse events, such as deep vein thrombosis and pulmonary embolism, were not increased during low-dose tamoxifen therapy. This is different from the threefold increased risk reported with standard dosing.

Worse survival in BRCA1/2 germline mutation carriers receiving ET in HR+/HER2− BC

Inconsistent data have been reported on the prognostic impact of BRCA1/2 mutation in HR+ BC. A retrospective study by Frenel and colleagues included 13,776 patients with metastatic BC (MBC) from the Epidemiological Strategy and Medical Economics (ESME) MBC database, of which 676 and 170 patients were germline BRCA wild-type (gBRCAwt) and germline BRCA mutation (gBRCAm) carriers, respectively. They looked at outcomes and first-line endocrine treatment efficacy in patients with HR+/HER2- MBC, treated in a pre–cyclin-dependent kinase (CDK) 4/6 inhibitors era. The results showed that gBRCAm carriers had shorter overall survival (OS; adjusted hazard ratio [aHR] 1.26; P = .024) and progression-free survival (PFS; aHR 1.21; P = .017) compared with gBRCAwt carriers. Furthermore, among those treated with front-line endocrine therapy, gBRCAm patients had lower adjusted OS (aHR [95% CI] 1.54 [1.03-2.32]) and PFS (aHR [95% CI] 1.58 [1.17-2.12]) compared with gBRCAwt patients. Outcomes were similar for gBRCAm patients who received first-line chemotherapy compared with the gBRCAwt group (OS: aHR [95% CI] 1.12 [0.88-1.41]; first-line PFS: aHR [95% CI] 1.09 [0.90-1.31]). A previous retrospective study by Lambertini and colleagues, focusing on young patients with gBRCAm, also showed a tendency for a worse distant recurrence-free interval (aHR 1.39; 95% CI  0.94-2.05) in patients with HR+ BC. Additional studies are needed, especially in the setting of an evolving treatment landscape that includes CDK4/6 inhibitors and poly-ADP ribose polymerase (PARP) inhibitors.

HER2-positive (HER2+) BC was associated with poor outcomes compared with other BC subtypes. However, the introduction of trastuzumab has drastically changed the treatment paradigm for these patients afflicted with HER2+ BC. The pivotal trials with trastuzumab included only a few patients with lower-risk HER2+ tumors; therefore, it was not clear whether these lower-risk patients can benefit from a de-escalated adjuvant regimen. The phase 2 APT trial prospectively investigated the safety and efficacy of 12 weeks of paclitaxel with trastuzumab, followed by 9 months of trastuzumab monotherapy, in patients with small (≤ 3 cm), node-negative, HER2+ BC. After a median follow-up of 10.8 years, the 10-year invasive disease-free survival was 91.3%, the recurrence-free interval was 96.3%, the overall survival rate was 94.3%, and the BC-specific survival rate was 98.8%.

The researchers also conducted an exploratory analysis in 284 patients using the HER2DX genomic test. This is a single 27-gene expression and clinical feature-based classifier developed for early-stage, HER2+ BC. The tool identified a subset of patients with a high HER2DX score (HERDX score ≥ 32) who might harbor an increased risk for long-term recurrence.

These excellent long-term outcomes from the APT trial support the use of the currently endorsed adjuvant regimen of paclitaxel and trastuzumab in patients with stage I HER2+ BC. Furthermore, the HER2DX risk score, if validated, may provide a promising genomic tool to identify a subset of these patients who are at increased risk for recurrence and therefore may benefit from additional therapy.

Prior studies have noted worse survival outcomes with longer times from BC diagnosis to surgical treatment; however, the specific time interval that is acceptable to wait between diagnosis and surgery is still unclear. A case series study by Weiner and colleagues looked at the association between time from BC diagnosis to primary breast surgery and overall survival. The study looked at 373,334 female patients from the National Cancer Database with stage I-III BC who underwent primary breast surgery. Results showed worse overall survival outcomes when time to surgery was 9 or more weeks compared with surgery between 0 and 4 weeks (hazard ratio 1.15; P < .001). Factors associated with longer times to surgery included younger age, uninsured or Medicaid status, and lower neighborhood household income. On the basis of these findings, surgery before 8 weeks from BC diagnosis appears to be an acceptable time frame to avoid unfavorable survival outcomes and allow for appropriate multidisciplinary care. Furthermore, it is critical to identify potential barriers in a timely manner to prevent prolonged delays in care.

In hormone receptor-positive (HR+) BC, adjuvant endocrine therapy (ET) is usually delayed until after adjuvant radiotherapy, although, the optimal sequence of both therapies is still unknown. The aim of the study by Sutton and colleagues was to assess the association between time from surgery to ET initiation and cancer outcomes in high-risk HR+ patients, particularly those with residual disease after neoadjuvant chemotherapy. The study analysed 179 patients with HR+ BC from a multi-institutional database who received adjuvant radiotherapy, of which 68 patients received adjuvant ET before or during radiotherapy and 111 patients received ET after cessation of radiotherapy. Results showed that an interval of >14 weeks between surgery and the receipt of ET was independently associated with worse recurrence-free survival compared with an interval of 14 or less weeks (hazard ratio 3.20; P = .02). Of interest, the study also showed that patients receiving ET before or during radiation were more likely to experience skin and soft tissue late radiation morbidity, and this was nonsignificantly associated with worse radiation-associated complication-free survival (hazard ratio 1.87; P = .06). Although prior studies have reported that the interval from surgery to ET does not affect cancer outcomes, this was not studied in a high-risk cohort who have received neoadjuvant chemotherapy. Further studies in larger prospective cohorts are needed to validate these findings. At this time, the risks and benefits of concurrent ET with radiation need to be assessed prior to making any treatment recommendations.

HER2-positive (HER2+) BC was associated with poor outcomes compared with other BC subtypes. However, the introduction of trastuzumab has drastically changed the treatment paradigm for these patients afflicted with HER2+ BC. The pivotal trials with trastuzumab included only a few patients with lower-risk HER2+ tumors; therefore, it was not clear whether these lower-risk patients can benefit from a de-escalated adjuvant regimen. The phase 2 APT trial prospectively investigated the safety and efficacy of 12 weeks of paclitaxel with trastuzumab, followed by 9 months of trastuzumab monotherapy, in patients with small (≤ 3 cm), node-negative, HER2+ BC. After a median follow-up of 10.8 years, the 10-year invasive disease-free survival was 91.3%, the recurrence-free interval was 96.3%, the overall survival rate was 94.3%, and the BC-specific survival rate was 98.8%.

The researchers also conducted an exploratory analysis in 284 patients using the HER2DX genomic test. This is a single 27-gene expression and clinical feature-based classifier developed for early-stage, HER2+ BC. The tool identified a subset of patients with a high HER2DX score (HERDX score ≥ 32) who might harbor an increased risk for long-term recurrence.

These excellent long-term outcomes from the APT trial support the use of the currently endorsed adjuvant regimen of paclitaxel and trastuzumab in patients with stage I HER2+ BC. Furthermore, the HER2DX risk score, if validated, may provide a promising genomic tool to identify a subset of these patients who are at increased risk for recurrence and therefore may benefit from additional therapy.

Prior studies have noted worse survival outcomes with longer times from BC diagnosis to surgical treatment; however, the specific time interval that is acceptable to wait between diagnosis and surgery is still unclear. A case series study by Weiner and colleagues looked at the association between time from BC diagnosis to primary breast surgery and overall survival. The study looked at 373,334 female patients from the National Cancer Database with stage I-III BC who underwent primary breast surgery. Results showed worse overall survival outcomes when time to surgery was 9 or more weeks compared with surgery between 0 and 4 weeks (hazard ratio 1.15; P < .001). Factors associated with longer times to surgery included younger age, uninsured or Medicaid status, and lower neighborhood household income. On the basis of these findings, surgery before 8 weeks from BC diagnosis appears to be an acceptable time frame to avoid unfavorable survival outcomes and allow for appropriate multidisciplinary care. Furthermore, it is critical to identify potential barriers in a timely manner to prevent prolonged delays in care.

In hormone receptor-positive (HR+) BC, adjuvant endocrine therapy (ET) is usually delayed until after adjuvant radiotherapy, although, the optimal sequence of both therapies is still unknown. The aim of the study by Sutton and colleagues was to assess the association between time from surgery to ET initiation and cancer outcomes in high-risk HR+ patients, particularly those with residual disease after neoadjuvant chemotherapy. The study analysed 179 patients with HR+ BC from a multi-institutional database who received adjuvant radiotherapy, of which 68 patients received adjuvant ET before or during radiotherapy and 111 patients received ET after cessation of radiotherapy. Results showed that an interval of >14 weeks between surgery and the receipt of ET was independently associated with worse recurrence-free survival compared with an interval of 14 or less weeks (hazard ratio 3.20; P = .02). Of interest, the study also showed that patients receiving ET before or during radiation were more likely to experience skin and soft tissue late radiation morbidity, and this was nonsignificantly associated with worse radiation-associated complication-free survival (hazard ratio 1.87; P = .06). Although prior studies have reported that the interval from surgery to ET does not affect cancer outcomes, this was not studied in a high-risk cohort who have received neoadjuvant chemotherapy. Further studies in larger prospective cohorts are needed to validate these findings. At this time, the risks and benefits of concurrent ET with radiation need to be assessed prior to making any treatment recommendations.

HER2-positive (HER2+) BC was associated with poor outcomes compared with other BC subtypes. However, the introduction of trastuzumab has drastically changed the treatment paradigm for these patients afflicted with HER2+ BC. The pivotal trials with trastuzumab included only a few patients with lower-risk HER2+ tumors; therefore, it was not clear whether these lower-risk patients can benefit from a de-escalated adjuvant regimen. The phase 2 APT trial prospectively investigated the safety and efficacy of 12 weeks of paclitaxel with trastuzumab, followed by 9 months of trastuzumab monotherapy, in patients with small (≤ 3 cm), node-negative, HER2+ BC. After a median follow-up of 10.8 years, the 10-year invasive disease-free survival was 91.3%, the recurrence-free interval was 96.3%, the overall survival rate was 94.3%, and the BC-specific survival rate was 98.8%.

The researchers also conducted an exploratory analysis in 284 patients using the HER2DX genomic test. This is a single 27-gene expression and clinical feature-based classifier developed for early-stage, HER2+ BC. The tool identified a subset of patients with a high HER2DX score (HERDX score ≥ 32) who might harbor an increased risk for long-term recurrence.

These excellent long-term outcomes from the APT trial support the use of the currently endorsed adjuvant regimen of paclitaxel and trastuzumab in patients with stage I HER2+ BC. Furthermore, the HER2DX risk score, if validated, may provide a promising genomic tool to identify a subset of these patients who are at increased risk for recurrence and therefore may benefit from additional therapy.

Prior studies have noted worse survival outcomes with longer times from BC diagnosis to surgical treatment; however, the specific time interval that is acceptable to wait between diagnosis and surgery is still unclear. A case series study by Weiner and colleagues looked at the association between time from BC diagnosis to primary breast surgery and overall survival. The study looked at 373,334 female patients from the National Cancer Database with stage I-III BC who underwent primary breast surgery. Results showed worse overall survival outcomes when time to surgery was 9 or more weeks compared with surgery between 0 and 4 weeks (hazard ratio 1.15; P < .001). Factors associated with longer times to surgery included younger age, uninsured or Medicaid status, and lower neighborhood household income. On the basis of these findings, surgery before 8 weeks from BC diagnosis appears to be an acceptable time frame to avoid unfavorable survival outcomes and allow for appropriate multidisciplinary care. Furthermore, it is critical to identify potential barriers in a timely manner to prevent prolonged delays in care.

In hormone receptor-positive (HR+) BC, adjuvant endocrine therapy (ET) is usually delayed until after adjuvant radiotherapy, although, the optimal sequence of both therapies is still unknown. The aim of the study by Sutton and colleagues was to assess the association between time from surgery to ET initiation and cancer outcomes in high-risk HR+ patients, particularly those with residual disease after neoadjuvant chemotherapy. The study analysed 179 patients with HR+ BC from a multi-institutional database who received adjuvant radiotherapy, of which 68 patients received adjuvant ET before or during radiotherapy and 111 patients received ET after cessation of radiotherapy. Results showed that an interval of >14 weeks between surgery and the receipt of ET was independently associated with worse recurrence-free survival compared with an interval of 14 or less weeks (hazard ratio 3.20; P = .02). Of interest, the study also showed that patients receiving ET before or during radiation were more likely to experience skin and soft tissue late radiation morbidity, and this was nonsignificantly associated with worse radiation-associated complication-free survival (hazard ratio 1.87; P = .06). Although prior studies have reported that the interval from surgery to ET does not affect cancer outcomes, this was not studied in a high-risk cohort who have received neoadjuvant chemotherapy. Further studies in larger prospective cohorts are needed to validate these findings. At this time, the risks and benefits of concurrent ET with radiation need to be assessed prior to making any treatment recommendations.

A post hoc analysis of the ShortHER trial, including 784 patients with hormone-positive (HR+) and human epidermal growth factor receptor 2–positive (HER2+) early breast cancer who received adjuvant trastuzumab plus chemotherapy, showed that adjuvant endocrine therapy (ET) with an aromatase inhibitor (AI) was associated with better outcomes than tamoxifen (TAM) or TAM and AI (TAM-AI) in this population. Disease-free survival rates at 8 years were 86.4% for AI vs 79.7% for the TAM/TAM-AI groups, with an absolute difference of 6.7% (log-rank P = .013). This effect was seen independently of menopausal status in a multivariate analysis.

In the exploratory analysis focusing on the premenopausal patients, the addition of gonadotropin-releasing hormone to ET was associated with a significantly better disease-free survival. This was also noted in an exploratory subgroup analysis of the SOFT trial,^[1] which showed greater benefit from the addition of ovarian suppression to TAM, as compared with TAM alone, among women with HER2+ disease (hazard ratio 0.41; 95% CI 0.22-0.75).

It is important to note that not all patients in the ShortHER trial received the standard-of-care duration of adjuvant trastuzumab; half of them received only 9-week treatment as opposed to the standard 12 months of adjuvant therapy. It is unclear whether this difference in adjuvant therapy could have affected the results, although the disease-free survival multivariate analysis showed no significant effect of the treatment arm on the role of ET. More studies are needed to verify the optimal adjuvant ET for patients with HR+/HER2+ breast cancer, especially in premenopausal patients.

Contralateral Prophylactic Mastectomy Offers No Survival Advantage in Triple-Negative Breast Cancer

There is insufficient evidence that contralateral prophylactic mastectomy (CPM) improves survival in patients with unilateral triple-negative breast cancer (TNBC). A multi-institutional database study, including 796 patients with TNBC, of which 15.5% underwent CPM, showed that CPM did not offer survival benefit to patients with unilateral TNBC. Women who underwent CPM were more likely to be White (P < .001), younger (P < .001), and had had genetic testing performed (P < .001). While there was a borderline improvement in 5-year unadjusted overall survival for patients undergoing CPM compared with no CPM overall (95.1% vs 85.0%; P = .05), no significant improvement was observed for local recurrence-free survival (P = .40) or distant recurrence-free survival (P = .37). Very few (n = 15/673, 2.2%) of the no-CPM patients developed a new primary breast cancer; 3 of the 15 patients were known BRCA1 or BRCA2 mutation carriers. Among the genetic mutation carriers, 5-year overall survival was 97.2% for CPM vs 84.1% for no CPM (P = .35). This study did not demonstrate any statistically significant survival difference between CPM compared with no CPM, regardless of the presence of a BRCA mutation, although prior studies have shown improved outcomes for CPM in BRCA mutation carriers.^[2] Larger prospective studies are needed to evaluate the potential benefit of CPM among patients with TNBC, especially patients with BRCA1/2 mutations.

Adding Endocrine Therapy to Dual Anti-HER2 Targeted Therapy Beneficial in HER2+/HR+ Metastatic Breast Cancer

The current first-line standard of care for HER2+ metastatic breast cancer is dual anti-HER2 targeted therapy plus chemotherapy, with consideration for maintenance treatment with anti-HER2 therapy and ET for patients with HR+ and HER2+ metastatic breast cancer. The potential benefit of adding ET for patients with HR+/HER2+ metastatic breast cancer has been reported previously, but data overall are limited. This study analyzed the real-world data of 147 patients with HR+/HER2+ metastatic breast cancer from a prospective registry and who received first-line chemotherapy plus trastuzumab and pertuzumab with (n = 91) or without (n = 56) concurrent ET. The findings showed that adding ET resulted in a significant improvement in 5-year progression-free survival (PFS) (hazard ratio 0.59; P = .031) and overall survival (hazard ratio 0.52; P = .018) compared with not adding ET. No new safety concerns were identified when combining HER2+ targeted therapy and ET. While this is a small retrospective analysis, results are certainly encouraging and support the addition of ET to dual anti-HER2 therapy as maintenance therapy post chemotherapy in this subset of patients.

High PD-L2 Levels May Predict Worse Clinical Outcomes in ER+ Breast Cancer

Programmed cell death-1 ligand-2 (PD-L2) is a second ligand for programmed cell death-1 (PD-1) and inhibits T-cell activation. A retrospective study including patients with estrogen receptor–positive (ER+) breast cancer looked at PD-L2 protein levels in cancer cells and stromal cells of therapy-naive, locoregional ER+ breast cancer in the main study cohort (n = 684) and in an independent validation cohort (n = 273), and correlated findings with PFS. High levels of PD-L2 protein were present in up to one third (33%) of ER+ tumors and were associated with shorter PFS in the entire cohort of patients with ER+ breast cancer (hazard ratio 2.0; P < .001) and in the subgroup of patients treated with adjuvant chemotherapy (hazard ratio 3.4; P < .001). A multivariable analysis showed that high levels of PD-L2 were an independent prognostic marker in ER+ patients. These findings suggest that high PD-L2 is associated with unfavorable prognosis in ER+ breast cancer and may be a potential biomarker of response to checkpoint inhibitors.

Additional References

1. Francis PA, Pagani O, Fleming GF, et al for the SOFT and TEXT Investigators and the International Breast Cancer Study Group. Tailoring adjuvant endocrine therapy for premenopausal breast cancer. N Engl J Med. 2018;379:122-137. Doi: 10.1056/NEJMoa1803164
2. Li X, You R, Wang X, et al. Effectiveness of prophylactic surgeries in BRCA1 or BRCA2 mutation carriers: A meta-analysis and systematic review. Clin Cancer Res. 2016;22:3971-3981. Doi: 10.1158/1078-0432.CCR-15-1465

A post hoc analysis of the ShortHER trial, including 784 patients with hormone-positive (HR+) and human epidermal growth factor receptor 2–positive (HER2+) early breast cancer who received adjuvant trastuzumab plus chemotherapy, showed that adjuvant endocrine therapy (ET) with an aromatase inhibitor (AI) was associated with better outcomes than tamoxifen (TAM) or TAM and AI (TAM-AI) in this population. Disease-free survival rates at 8 years were 86.4% for AI vs 79.7% for the TAM/TAM-AI groups, with an absolute difference of 6.7% (log-rank P = .013). This effect was seen independently of menopausal status in a multivariate analysis.

In the exploratory analysis focusing on the premenopausal patients, the addition of gonadotropin-releasing hormone to ET was associated with a significantly better disease-free survival. This was also noted in an exploratory subgroup analysis of the SOFT trial,^[1] which showed greater benefit from the addition of ovarian suppression to TAM, as compared with TAM alone, among women with HER2+ disease (hazard ratio 0.41; 95% CI 0.22-0.75).

It is important to note that not all patients in the ShortHER trial received the standard-of-care duration of adjuvant trastuzumab; half of them received only 9-week treatment as opposed to the standard 12 months of adjuvant therapy. It is unclear whether this difference in adjuvant therapy could have affected the results, although the disease-free survival multivariate analysis showed no significant effect of the treatment arm on the role of ET. More studies are needed to verify the optimal adjuvant ET for patients with HR+/HER2+ breast cancer, especially in premenopausal patients.

Contralateral Prophylactic Mastectomy Offers No Survival Advantage in Triple-Negative Breast Cancer

There is insufficient evidence that contralateral prophylactic mastectomy (CPM) improves survival in patients with unilateral triple-negative breast cancer (TNBC). A multi-institutional database study, including 796 patients with TNBC, of which 15.5% underwent CPM, showed that CPM did not offer survival benefit to patients with unilateral TNBC. Women who underwent CPM were more likely to be White (P < .001), younger (P < .001), and had had genetic testing performed (P < .001). While there was a borderline improvement in 5-year unadjusted overall survival for patients undergoing CPM compared with no CPM overall (95.1% vs 85.0%; P = .05), no significant improvement was observed for local recurrence-free survival (P = .40) or distant recurrence-free survival (P = .37). Very few (n = 15/673, 2.2%) of the no-CPM patients developed a new primary breast cancer; 3 of the 15 patients were known BRCA1 or BRCA2 mutation carriers. Among the genetic mutation carriers, 5-year overall survival was 97.2% for CPM vs 84.1% for no CPM (P = .35). This study did not demonstrate any statistically significant survival difference between CPM compared with no CPM, regardless of the presence of a BRCA mutation, although prior studies have shown improved outcomes for CPM in BRCA mutation carriers.^[2] Larger prospective studies are needed to evaluate the potential benefit of CPM among patients with TNBC, especially patients with BRCA1/2 mutations.

Adding Endocrine Therapy to Dual Anti-HER2 Targeted Therapy Beneficial in HER2+/HR+ Metastatic Breast Cancer

The current first-line standard of care for HER2+ metastatic breast cancer is dual anti-HER2 targeted therapy plus chemotherapy, with consideration for maintenance treatment with anti-HER2 therapy and ET for patients with HR+ and HER2+ metastatic breast cancer. The potential benefit of adding ET for patients with HR+/HER2+ metastatic breast cancer has been reported previously, but data overall are limited. This study analyzed the real-world data of 147 patients with HR+/HER2+ metastatic breast cancer from a prospective registry and who received first-line chemotherapy plus trastuzumab and pertuzumab with (n = 91) or without (n = 56) concurrent ET. The findings showed that adding ET resulted in a significant improvement in 5-year progression-free survival (PFS) (hazard ratio 0.59; P = .031) and overall survival (hazard ratio 0.52; P = .018) compared with not adding ET. No new safety concerns were identified when combining HER2+ targeted therapy and ET. While this is a small retrospective analysis, results are certainly encouraging and support the addition of ET to dual anti-HER2 therapy as maintenance therapy post chemotherapy in this subset of patients.

High PD-L2 Levels May Predict Worse Clinical Outcomes in ER+ Breast Cancer

Programmed cell death-1 ligand-2 (PD-L2) is a second ligand for programmed cell death-1 (PD-1) and inhibits T-cell activation. A retrospective study including patients with estrogen receptor–positive (ER+) breast cancer looked at PD-L2 protein levels in cancer cells and stromal cells of therapy-naive, locoregional ER+ breast cancer in the main study cohort (n = 684) and in an independent validation cohort (n = 273), and correlated findings with PFS. High levels of PD-L2 protein were present in up to one third (33%) of ER+ tumors and were associated with shorter PFS in the entire cohort of patients with ER+ breast cancer (hazard ratio 2.0; P < .001) and in the subgroup of patients treated with adjuvant chemotherapy (hazard ratio 3.4; P < .001). A multivariable analysis showed that high levels of PD-L2 were an independent prognostic marker in ER+ patients. These findings suggest that high PD-L2 is associated with unfavorable prognosis in ER+ breast cancer and may be a potential biomarker of response to checkpoint inhibitors.

Additional References

1. Francis PA, Pagani O, Fleming GF, et al for the SOFT and TEXT Investigators and the International Breast Cancer Study Group. Tailoring adjuvant endocrine therapy for premenopausal breast cancer. N Engl J Med. 2018;379:122-137. Doi: 10.1056/NEJMoa1803164
2. Li X, You R, Wang X, et al. Effectiveness of prophylactic surgeries in BRCA1 or BRCA2 mutation carriers: A meta-analysis and systematic review. Clin Cancer Res. 2016;22:3971-3981. Doi: 10.1158/1078-0432.CCR-15-1465

A post hoc analysis of the ShortHER trial, including 784 patients with hormone-positive (HR+) and human epidermal growth factor receptor 2–positive (HER2+) early breast cancer who received adjuvant trastuzumab plus chemotherapy, showed that adjuvant endocrine therapy (ET) with an aromatase inhibitor (AI) was associated with better outcomes than tamoxifen (TAM) or TAM and AI (TAM-AI) in this population. Disease-free survival rates at 8 years were 86.4% for AI vs 79.7% for the TAM/TAM-AI groups, with an absolute difference of 6.7% (log-rank P = .013). This effect was seen independently of menopausal status in a multivariate analysis.

In the exploratory analysis focusing on the premenopausal patients, the addition of gonadotropin-releasing hormone to ET was associated with a significantly better disease-free survival. This was also noted in an exploratory subgroup analysis of the SOFT trial,^[1] which showed greater benefit from the addition of ovarian suppression to TAM, as compared with TAM alone, among women with HER2+ disease (hazard ratio 0.41; 95% CI 0.22-0.75).

It is important to note that not all patients in the ShortHER trial received the standard-of-care duration of adjuvant trastuzumab; half of them received only 9-week treatment as opposed to the standard 12 months of adjuvant therapy. It is unclear whether this difference in adjuvant therapy could have affected the results, although the disease-free survival multivariate analysis showed no significant effect of the treatment arm on the role of ET. More studies are needed to verify the optimal adjuvant ET for patients with HR+/HER2+ breast cancer, especially in premenopausal patients.

Contralateral Prophylactic Mastectomy Offers No Survival Advantage in Triple-Negative Breast Cancer

There is insufficient evidence that contralateral prophylactic mastectomy (CPM) improves survival in patients with unilateral triple-negative breast cancer (TNBC). A multi-institutional database study, including 796 patients with TNBC, of which 15.5% underwent CPM, showed that CPM did not offer survival benefit to patients with unilateral TNBC. Women who underwent CPM were more likely to be White (P < .001), younger (P < .001), and had had genetic testing performed (P < .001). While there was a borderline improvement in 5-year unadjusted overall survival for patients undergoing CPM compared with no CPM overall (95.1% vs 85.0%; P = .05), no significant improvement was observed for local recurrence-free survival (P = .40) or distant recurrence-free survival (P = .37). Very few (n = 15/673, 2.2%) of the no-CPM patients developed a new primary breast cancer; 3 of the 15 patients were known BRCA1 or BRCA2 mutation carriers. Among the genetic mutation carriers, 5-year overall survival was 97.2% for CPM vs 84.1% for no CPM (P = .35). This study did not demonstrate any statistically significant survival difference between CPM compared with no CPM, regardless of the presence of a BRCA mutation, although prior studies have shown improved outcomes for CPM in BRCA mutation carriers.^[2] Larger prospective studies are needed to evaluate the potential benefit of CPM among patients with TNBC, especially patients with BRCA1/2 mutations.

Adding Endocrine Therapy to Dual Anti-HER2 Targeted Therapy Beneficial in HER2+/HR+ Metastatic Breast Cancer

The current first-line standard of care for HER2+ metastatic breast cancer is dual anti-HER2 targeted therapy plus chemotherapy, with consideration for maintenance treatment with anti-HER2 therapy and ET for patients with HR+ and HER2+ metastatic breast cancer. The potential benefit of adding ET for patients with HR+/HER2+ metastatic breast cancer has been reported previously, but data overall are limited. This study analyzed the real-world data of 147 patients with HR+/HER2+ metastatic breast cancer from a prospective registry and who received first-line chemotherapy plus trastuzumab and pertuzumab with (n = 91) or without (n = 56) concurrent ET. The findings showed that adding ET resulted in a significant improvement in 5-year progression-free survival (PFS) (hazard ratio 0.59; P = .031) and overall survival (hazard ratio 0.52; P = .018) compared with not adding ET. No new safety concerns were identified when combining HER2+ targeted therapy and ET. While this is a small retrospective analysis, results are certainly encouraging and support the addition of ET to dual anti-HER2 therapy as maintenance therapy post chemotherapy in this subset of patients.

High PD-L2 Levels May Predict Worse Clinical Outcomes in ER+ Breast Cancer

Programmed cell death-1 ligand-2 (PD-L2) is a second ligand for programmed cell death-1 (PD-1) and inhibits T-cell activation. A retrospective study including patients with estrogen receptor–positive (ER+) breast cancer looked at PD-L2 protein levels in cancer cells and stromal cells of therapy-naive, locoregional ER+ breast cancer in the main study cohort (n = 684) and in an independent validation cohort (n = 273), and correlated findings with PFS. High levels of PD-L2 protein were present in up to one third (33%) of ER+ tumors and were associated with shorter PFS in the entire cohort of patients with ER+ breast cancer (hazard ratio 2.0; P < .001) and in the subgroup of patients treated with adjuvant chemotherapy (hazard ratio 3.4; P < .001). A multivariable analysis showed that high levels of PD-L2 were an independent prognostic marker in ER+ patients. These findings suggest that high PD-L2 is associated with unfavorable prognosis in ER+ breast cancer and may be a potential biomarker of response to checkpoint inhibitors.

Additional References

1. Francis PA, Pagani O, Fleming GF, et al for the SOFT and TEXT Investigators and the International Breast Cancer Study Group. Tailoring adjuvant endocrine therapy for premenopausal breast cancer. N Engl J Med. 2018;379:122-137. Doi: 10.1056/NEJMoa1803164
2. Li X, You R, Wang X, et al. Effectiveness of prophylactic surgeries in BRCA1 or BRCA2 mutation carriers: A meta-analysis and systematic review. Clin Cancer Res. 2016;22:3971-3981. Doi: 10.1158/1078-0432.CCR-15-1465