Commentary: Looking at Treatment Regimens for HR+ Breast Cancer and Triple-Negative Breast Cancer, March 2023

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