Commentary: Node irradiation, HER2+ treatment, and diet in BC, August 2023

Multiple previous trials have demonstrated the benefits of regional nodal irradiation (RNI) among patients with node-positive breast cancer, including postmastectomy and after breast-conserving surgery (BCS). The NCIC MA.20 trial, which included primarily patients with one to three involved nodes, demonstrated disease-free survival (DFS) improvement with the addition of RNI to whole-breast radiotherapy (DFS of 82.0% in the RNI group vs 77.0% in the control group; hazard ratio for DFS 0.76; P = .01).¹ However, the selection of patients for RNI is variable and may depend on patient and tumor characteristics as well as surgery and the systemic therapies applied. In the NCIC MA.20 trial, nodal-irradiation was associated with better overall survival among those with estrogen receptor (ER)–negative breast cancer but not among those with ER-positive disease. A secondary analysis of the SWOG S1007 trial, which randomly assigned patients with hormone receptor (HR)–positive/human epidermal growth factor receptor 2 (HER2)–negative breast cancer with one to three involved nodes and a 21-gene recurrence score ≤ 25 to endocrine therapy alone or chemotherapy plus endocrine therapy, investigated the use of radiotherapy and patterns of locoregional recurrence (Jagsi et al). Of those patients who received radiotherapy with complete information on targets (N = 3852), 59% (N = 2274) received RNI. At median follow-up of 6.1 years, the cumulative incidence of locoregional recurrence was low among all groups: 0.85% after BCS and radiotherapy with RNI, 0.55% after BCS with radiotherapy without RNI, 0.11% after mastectomy with postmastectomy radiation therapy (PMRT), and 1.7% after mastectomy without radiotherapy. Receiving RNI was not associated with invasive DFS for pre- or postmenopausal patients. These data support the importance of prospective studies, including the NCIC MA.39 trial,² designed to identify optimal locoregional therapy in patients with limited nodal burden and favorable disease biology.

The addition of pertuzumab to trastuzumab plus chemotherapy has demonstrated improvement in pathologic complete response (pCR) rates compared with trastuzumab plus chemotherapy in early-stage HER2-positive breast cancer.³ The framework of oncology is built on clinical trials through their rigorous design, enrollment, and synthesis of data; however, real-world studies are an integral component of cancer research because they provide a more representative sample of the general population treated in routine clinical practice. Neopearl was a retrospective, observational, real-world study that evaluated the efficacy and safety of trastuzumab plus chemotherapy with or without pertuzumab among 271 patients with stage II-III HER2-positive breast cancer (Fabbri et al). The addition of pertuzumab led to an increase in pCR rate (49% vs 62%; odds ratio 1.74; P = .032) and improvement in 5-year event-free survival (81% vs 93%; hazard ratio 2.22; P = .041), and the benefit on univariate analysis was restricted to patients with positive axillary nodes. Furthermore, there were no significant differences in adverse events, including cardiac, between the two groups. These results serve to strengthen the available data regarding the clinical efficacy and favorable safety profile of dual HER2-targeted therapy combined with neoadjuvant chemotherapy.

Lifestyle factors, including physical activity and diet, are becoming increasingly recognized as important determinants of various cancer-specific outcomes and overall health. Furthermore, because these are modifiable, there is often motivation on behalf of an individual to change behaviors that can affect their outcome. Adherence to the Mediterranean diet (MD) has been associated with reduced risk for breast cancer development and lower mortality among women with breast cancer.^4,5 Data from a prospective multicenter European cohort including 13,270 breast cancer survivors demonstrated that low compared with medium adherence to a MD before a breast cancer diagnosis was associated with a 13% higher risk for all-cause mortality (hazard ratio 1.13; 95% CI 1.01-1.26). A three-unit increase in the adapted relative MD score was associated with an 8% reduced risk for overall mortality (hazard ratio_3-unit 0.92; 95% CI 0.87-0.97); this result was sustained in the postmenopausal population and strengthened in metastatic disease (Castro-Espin et al). The connection between diet and cancer outcomes is complex, and future research evaluating specific dietary interventions and the underlying biologic pathways by which nutrition exerts its effects will be important to inform our counseling for patients with breast cancer in the survivorship setting.

Additional References

1. Whelan TJ, Olivotto IA, Parulekar WR, et al, for the MA.20 Study Investigators. Regional nodal irradiation in early-stage breast cancer. N Engl J Med. 2015;373:307-16. doi:10.1056/NEJMoa1415340
2. ClinicalTrials.gov. Regional radiotherapy in biomarker low-risk node positive and T3N0 breast cancer (TAILOR RT). National Library of Medicine. Last updated November 23, 2022. https://www.clinicaltrials.gov/study/NCT03488693
3. Gianni L, Pienkowski T, Im YH, et al. Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): A randomised multicentre, open-label, phase 2 trial. Lancet Oncol. 2012;13:25-32. doi:10.1016/S1470-2045(11)70336-9
4. Buckland G, Travier N, Cottet V, et al. Adherence to the mediterranean diet and risk of breast cancer in the European prospective investigation into cancer and nutrition cohort study. Int J Cancer. 2013;132:2918-27. doi:10.1002/ijc.27958
5. Haslam DE, John EM, Knight JA, et al. Diet quality and all-cause mortality in women with breast cancer from the Breast Cancer Family Registry. Cancer Epidemiol Biomarkers Prev. 2023;32:678-686. doi:10.1158/1055-9965.EPI-22-1198

Multiple previous trials have demonstrated the benefits of regional nodal irradiation (RNI) among patients with node-positive breast cancer, including postmastectomy and after breast-conserving surgery (BCS). The NCIC MA.20 trial, which included primarily patients with one to three involved nodes, demonstrated disease-free survival (DFS) improvement with the addition of RNI to whole-breast radiotherapy (DFS of 82.0% in the RNI group vs 77.0% in the control group; hazard ratio for DFS 0.76; P = .01).¹ However, the selection of patients for RNI is variable and may depend on patient and tumor characteristics as well as surgery and the systemic therapies applied. In the NCIC MA.20 trial, nodal-irradiation was associated with better overall survival among those with estrogen receptor (ER)–negative breast cancer but not among those with ER-positive disease. A secondary analysis of the SWOG S1007 trial, which randomly assigned patients with hormone receptor (HR)–positive/human epidermal growth factor receptor 2 (HER2)–negative breast cancer with one to three involved nodes and a 21-gene recurrence score ≤ 25 to endocrine therapy alone or chemotherapy plus endocrine therapy, investigated the use of radiotherapy and patterns of locoregional recurrence (Jagsi et al). Of those patients who received radiotherapy with complete information on targets (N = 3852), 59% (N = 2274) received RNI. At median follow-up of 6.1 years, the cumulative incidence of locoregional recurrence was low among all groups: 0.85% after BCS and radiotherapy with RNI, 0.55% after BCS with radiotherapy without RNI, 0.11% after mastectomy with postmastectomy radiation therapy (PMRT), and 1.7% after mastectomy without radiotherapy. Receiving RNI was not associated with invasive DFS for pre- or postmenopausal patients. These data support the importance of prospective studies, including the NCIC MA.39 trial,² designed to identify optimal locoregional therapy in patients with limited nodal burden and favorable disease biology.

The addition of pertuzumab to trastuzumab plus chemotherapy has demonstrated improvement in pathologic complete response (pCR) rates compared with trastuzumab plus chemotherapy in early-stage HER2-positive breast cancer.³ The framework of oncology is built on clinical trials through their rigorous design, enrollment, and synthesis of data; however, real-world studies are an integral component of cancer research because they provide a more representative sample of the general population treated in routine clinical practice. Neopearl was a retrospective, observational, real-world study that evaluated the efficacy and safety of trastuzumab plus chemotherapy with or without pertuzumab among 271 patients with stage II-III HER2-positive breast cancer (Fabbri et al). The addition of pertuzumab led to an increase in pCR rate (49% vs 62%; odds ratio 1.74; P = .032) and improvement in 5-year event-free survival (81% vs 93%; hazard ratio 2.22; P = .041), and the benefit on univariate analysis was restricted to patients with positive axillary nodes. Furthermore, there were no significant differences in adverse events, including cardiac, between the two groups. These results serve to strengthen the available data regarding the clinical efficacy and favorable safety profile of dual HER2-targeted therapy combined with neoadjuvant chemotherapy.

Lifestyle factors, including physical activity and diet, are becoming increasingly recognized as important determinants of various cancer-specific outcomes and overall health. Furthermore, because these are modifiable, there is often motivation on behalf of an individual to change behaviors that can affect their outcome. Adherence to the Mediterranean diet (MD) has been associated with reduced risk for breast cancer development and lower mortality among women with breast cancer.^4,5 Data from a prospective multicenter European cohort including 13,270 breast cancer survivors demonstrated that low compared with medium adherence to a MD before a breast cancer diagnosis was associated with a 13% higher risk for all-cause mortality (hazard ratio 1.13; 95% CI 1.01-1.26). A three-unit increase in the adapted relative MD score was associated with an 8% reduced risk for overall mortality (hazard ratio_3-unit 0.92; 95% CI 0.87-0.97); this result was sustained in the postmenopausal population and strengthened in metastatic disease (Castro-Espin et al). The connection between diet and cancer outcomes is complex, and future research evaluating specific dietary interventions and the underlying biologic pathways by which nutrition exerts its effects will be important to inform our counseling for patients with breast cancer in the survivorship setting.

Additional References

1. Whelan TJ, Olivotto IA, Parulekar WR, et al, for the MA.20 Study Investigators. Regional nodal irradiation in early-stage breast cancer. N Engl J Med. 2015;373:307-16. doi:10.1056/NEJMoa1415340
2. ClinicalTrials.gov. Regional radiotherapy in biomarker low-risk node positive and T3N0 breast cancer (TAILOR RT). National Library of Medicine. Last updated November 23, 2022. https://www.clinicaltrials.gov/study/NCT03488693
3. Gianni L, Pienkowski T, Im YH, et al. Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): A randomised multicentre, open-label, phase 2 trial. Lancet Oncol. 2012;13:25-32. doi:10.1016/S1470-2045(11)70336-9
4. Buckland G, Travier N, Cottet V, et al. Adherence to the mediterranean diet and risk of breast cancer in the European prospective investigation into cancer and nutrition cohort study. Int J Cancer. 2013;132:2918-27. doi:10.1002/ijc.27958
5. Haslam DE, John EM, Knight JA, et al. Diet quality and all-cause mortality in women with breast cancer from the Breast Cancer Family Registry. Cancer Epidemiol Biomarkers Prev. 2023;32:678-686. doi:10.1158/1055-9965.EPI-22-1198

Multiple previous trials have demonstrated the benefits of regional nodal irradiation (RNI) among patients with node-positive breast cancer, including postmastectomy and after breast-conserving surgery (BCS). The NCIC MA.20 trial, which included primarily patients with one to three involved nodes, demonstrated disease-free survival (DFS) improvement with the addition of RNI to whole-breast radiotherapy (DFS of 82.0% in the RNI group vs 77.0% in the control group; hazard ratio for DFS 0.76; P = .01).¹ However, the selection of patients for RNI is variable and may depend on patient and tumor characteristics as well as surgery and the systemic therapies applied. In the NCIC MA.20 trial, nodal-irradiation was associated with better overall survival among those with estrogen receptor (ER)–negative breast cancer but not among those with ER-positive disease. A secondary analysis of the SWOG S1007 trial, which randomly assigned patients with hormone receptor (HR)–positive/human epidermal growth factor receptor 2 (HER2)–negative breast cancer with one to three involved nodes and a 21-gene recurrence score ≤ 25 to endocrine therapy alone or chemotherapy plus endocrine therapy, investigated the use of radiotherapy and patterns of locoregional recurrence (Jagsi et al). Of those patients who received radiotherapy with complete information on targets (N = 3852), 59% (N = 2274) received RNI. At median follow-up of 6.1 years, the cumulative incidence of locoregional recurrence was low among all groups: 0.85% after BCS and radiotherapy with RNI, 0.55% after BCS with radiotherapy without RNI, 0.11% after mastectomy with postmastectomy radiation therapy (PMRT), and 1.7% after mastectomy without radiotherapy. Receiving RNI was not associated with invasive DFS for pre- or postmenopausal patients. These data support the importance of prospective studies, including the NCIC MA.39 trial,² designed to identify optimal locoregional therapy in patients with limited nodal burden and favorable disease biology.

The addition of pertuzumab to trastuzumab plus chemotherapy has demonstrated improvement in pathologic complete response (pCR) rates compared with trastuzumab plus chemotherapy in early-stage HER2-positive breast cancer.³ The framework of oncology is built on clinical trials through their rigorous design, enrollment, and synthesis of data; however, real-world studies are an integral component of cancer research because they provide a more representative sample of the general population treated in routine clinical practice. Neopearl was a retrospective, observational, real-world study that evaluated the efficacy and safety of trastuzumab plus chemotherapy with or without pertuzumab among 271 patients with stage II-III HER2-positive breast cancer (Fabbri et al). The addition of pertuzumab led to an increase in pCR rate (49% vs 62%; odds ratio 1.74; P = .032) and improvement in 5-year event-free survival (81% vs 93%; hazard ratio 2.22; P = .041), and the benefit on univariate analysis was restricted to patients with positive axillary nodes. Furthermore, there were no significant differences in adverse events, including cardiac, between the two groups. These results serve to strengthen the available data regarding the clinical efficacy and favorable safety profile of dual HER2-targeted therapy combined with neoadjuvant chemotherapy.

Lifestyle factors, including physical activity and diet, are becoming increasingly recognized as important determinants of various cancer-specific outcomes and overall health. Furthermore, because these are modifiable, there is often motivation on behalf of an individual to change behaviors that can affect their outcome. Adherence to the Mediterranean diet (MD) has been associated with reduced risk for breast cancer development and lower mortality among women with breast cancer.^4,5 Data from a prospective multicenter European cohort including 13,270 breast cancer survivors demonstrated that low compared with medium adherence to a MD before a breast cancer diagnosis was associated with a 13% higher risk for all-cause mortality (hazard ratio 1.13; 95% CI 1.01-1.26). A three-unit increase in the adapted relative MD score was associated with an 8% reduced risk for overall mortality (hazard ratio_3-unit 0.92; 95% CI 0.87-0.97); this result was sustained in the postmenopausal population and strengthened in metastatic disease (Castro-Espin et al). The connection between diet and cancer outcomes is complex, and future research evaluating specific dietary interventions and the underlying biologic pathways by which nutrition exerts its effects will be important to inform our counseling for patients with breast cancer in the survivorship setting.

Additional References

1. Whelan TJ, Olivotto IA, Parulekar WR, et al, for the MA.20 Study Investigators. Regional nodal irradiation in early-stage breast cancer. N Engl J Med. 2015;373:307-16. doi:10.1056/NEJMoa1415340
2. ClinicalTrials.gov. Regional radiotherapy in biomarker low-risk node positive and T3N0 breast cancer (TAILOR RT). National Library of Medicine. Last updated November 23, 2022. https://www.clinicaltrials.gov/study/NCT03488693
3. Gianni L, Pienkowski T, Im YH, et al. Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): A randomised multicentre, open-label, phase 2 trial. Lancet Oncol. 2012;13:25-32. doi:10.1016/S1470-2045(11)70336-9
4. Buckland G, Travier N, Cottet V, et al. Adherence to the mediterranean diet and risk of breast cancer in the European prospective investigation into cancer and nutrition cohort study. Int J Cancer. 2013;132:2918-27. doi:10.1002/ijc.27958
5. Haslam DE, John EM, Knight JA, et al. Diet quality and all-cause mortality in women with breast cancer from the Breast Cancer Family Registry. Cancer Epidemiol Biomarkers Prev. 2023;32:678-686. doi:10.1158/1055-9965.EPI-22-1198