Commentary: Alisertib, trastuzumab, and treatment timing, April 2023

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.