Erin Roesch, MD

The role of adjuvant olaparib was investigated in the phase 3 OlympiA trial, which included 1,836 patients with high-risk HER2-negative gBRCAm early breast cancer who received local treatment and adjuvant or neoadjuvant chemotherapy. One year of adjuvant olaparib was associated with a significant improvement in invasive disease-free survival (hazard ratio [HR] 0.58, P < .001) and distant disease-free survival (HR 0.57, P < .001). The 3-year invasive disease-free survival (iDFS) was 85.9% in the olaparib group and 77.1% in the placebo group (absolute benefit of 8.8%), and 3-year distant disease-free survival (dDFS) was 87.5% and 80.4%, respectively (difference of 7.1%). These results are considered practice changing and lead to questions regarding the expansion of germline testing in early stage breast cancer. Furthermore, PARP inhibitors have shown exciting results in the neoadjuvant setting. Among 61 patients with gBRCAm HER2-negative early breast cancer, neoadjuvant talazoparib produced a pathologic complete response (pCR) in 49.2%, and there may be a subgroup of patients for whom this approach is relevant.

The presence of residual disease after neoadjuvant chemotherapy has prognostic implications and can help tailor adjuvant treatment recommendations. The CREATE-X trial has established the role of adjuvant capecitabine for patients with triple-negative breast cancer with residual disease after pre-operative chemotherapy. The phase 3 EA1131 trial randomized 415 patients with stage II-III triple-negative breast cancer and residual disease post-neoadjuvant chemotherapy to platinum agent or capecitabine. There was no significant difference in 3-year iDFS (42% for platinum vs 49% for capecitabine; HR 1.06, 95% CI 0.62-1.81), and higher hematologic toxicity and dose reductions in the platinum arm. These data support the continued use of capecitabine in this population, and the high event rate highlights the need for more effective therapies in this setting.

The majority of patients with HR+/HER2- MBC will receive a CDK 4/6 inhibitor at some point during their treatment course. In an updated analysis of the phase 3 MONALEESA-3 trial which included postmenopausal patients with HR+HER2- MBC, with median follow-up of 56.3 months, ribociclib plus fulvestrant continued to show an overall survival (OS) benefit of greater than 1 year compared with fulvestrant alone (median OS 53.7 months vs 41.5 months in the ribociclib vs placebo arm, respectively; HR 0.726, 95% CI 0.59-0.90). Additionally, extended follow-up of the PALOMA-3 trial demonstrated OS benefit with palbociclib plus fulvestrant compared to fulvestrant alone in patients with HR+/HER2- MBC; at median follow-up of 73.3 months, median OS was 34.8 months in the palbociclib arm vs 28.0 months in the placebo arm (HR 0.81, P = .0221). Sequencing of other targeted therapies (such as PI3K inhibitors), predictors of CDK 4/6 inhibitor response in different intrinsic subtypes, and the role of CDK 4/6 inhibitor use beyond progression are areas where further research is warranted.

References:

Robson M, Im SA, Senkus E, et al. Olaparib for Metastatic Breast Cancer in Patients with a Germline BRCA Mutation. N Engl J Med. 2017;377(6):523-533.

Litton JK, Beck JT, Jones JM, et al. Neoadjuvant talazoparib in patients with germline BRCA1/2 (gBRCA1/2) mutation-positive, early HER2-negative breast cancer (BC): Results of a phase 2 study. J Clin Oncol 39, 2021 (suppl 15; abstr 505).

Symmans WF, Wei C, Gould R, et al. Long-Term Prognostic Risk After Neoadjuvant Chemotherapy Associated With Residual Cancer Burden and Breast Cancer Subtype. J Clin Oncol. 2017;35:1049-1060.

Masuda N, Lee SJ, Ohtani S, et al. Adjuvant Capecitabine for Breast Cancer after Preoperative Chemotherapy. N Engl J Med. 2017;376:2147-2159.

Cristofanilli M, Rugo H, Im SA, et al. Overall survival (OS) with palbociclib (PAL) + fulvestrant (FUL) in women with hormone receptor–positive (HR+), human epidermal growth factor receptor 2–negative (HER2–) advanced breast cancer (ABC): Updated analyses from PALOMA-3. J Clin Oncol. 2021; 39:15_suppl, 1000-1000.

The role of adjuvant olaparib was investigated in the phase 3 OlympiA trial, which included 1,836 patients with high-risk HER2-negative gBRCAm early breast cancer who received local treatment and adjuvant or neoadjuvant chemotherapy. One year of adjuvant olaparib was associated with a significant improvement in invasive disease-free survival (hazard ratio [HR] 0.58, P < .001) and distant disease-free survival (HR 0.57, P < .001). The 3-year invasive disease-free survival (iDFS) was 85.9% in the olaparib group and 77.1% in the placebo group (absolute benefit of 8.8%), and 3-year distant disease-free survival (dDFS) was 87.5% and 80.4%, respectively (difference of 7.1%). These results are considered practice changing and lead to questions regarding the expansion of germline testing in early stage breast cancer. Furthermore, PARP inhibitors have shown exciting results in the neoadjuvant setting. Among 61 patients with gBRCAm HER2-negative early breast cancer, neoadjuvant talazoparib produced a pathologic complete response (pCR) in 49.2%, and there may be a subgroup of patients for whom this approach is relevant.

The presence of residual disease after neoadjuvant chemotherapy has prognostic implications and can help tailor adjuvant treatment recommendations. The CREATE-X trial has established the role of adjuvant capecitabine for patients with triple-negative breast cancer with residual disease after pre-operative chemotherapy. The phase 3 EA1131 trial randomized 415 patients with stage II-III triple-negative breast cancer and residual disease post-neoadjuvant chemotherapy to platinum agent or capecitabine. There was no significant difference in 3-year iDFS (42% for platinum vs 49% for capecitabine; HR 1.06, 95% CI 0.62-1.81), and higher hematologic toxicity and dose reductions in the platinum arm. These data support the continued use of capecitabine in this population, and the high event rate highlights the need for more effective therapies in this setting.

The majority of patients with HR+/HER2- MBC will receive a CDK 4/6 inhibitor at some point during their treatment course. In an updated analysis of the phase 3 MONALEESA-3 trial which included postmenopausal patients with HR+HER2- MBC, with median follow-up of 56.3 months, ribociclib plus fulvestrant continued to show an overall survival (OS) benefit of greater than 1 year compared with fulvestrant alone (median OS 53.7 months vs 41.5 months in the ribociclib vs placebo arm, respectively; HR 0.726, 95% CI 0.59-0.90). Additionally, extended follow-up of the PALOMA-3 trial demonstrated OS benefit with palbociclib plus fulvestrant compared to fulvestrant alone in patients with HR+/HER2- MBC; at median follow-up of 73.3 months, median OS was 34.8 months in the palbociclib arm vs 28.0 months in the placebo arm (HR 0.81, P = .0221). Sequencing of other targeted therapies (such as PI3K inhibitors), predictors of CDK 4/6 inhibitor response in different intrinsic subtypes, and the role of CDK 4/6 inhibitor use beyond progression are areas where further research is warranted.

References:

Robson M, Im SA, Senkus E, et al. Olaparib for Metastatic Breast Cancer in Patients with a Germline BRCA Mutation. N Engl J Med. 2017;377(6):523-533.

Litton JK, Beck JT, Jones JM, et al. Neoadjuvant talazoparib in patients with germline BRCA1/2 (gBRCA1/2) mutation-positive, early HER2-negative breast cancer (BC): Results of a phase 2 study. J Clin Oncol 39, 2021 (suppl 15; abstr 505).

Symmans WF, Wei C, Gould R, et al. Long-Term Prognostic Risk After Neoadjuvant Chemotherapy Associated With Residual Cancer Burden and Breast Cancer Subtype. J Clin Oncol. 2017;35:1049-1060.

Masuda N, Lee SJ, Ohtani S, et al. Adjuvant Capecitabine for Breast Cancer after Preoperative Chemotherapy. N Engl J Med. 2017;376:2147-2159.

Cristofanilli M, Rugo H, Im SA, et al. Overall survival (OS) with palbociclib (PAL) + fulvestrant (FUL) in women with hormone receptor–positive (HR+), human epidermal growth factor receptor 2–negative (HER2–) advanced breast cancer (ABC): Updated analyses from PALOMA-3. J Clin Oncol. 2021; 39:15_suppl, 1000-1000.

The role of adjuvant olaparib was investigated in the phase 3 OlympiA trial, which included 1,836 patients with high-risk HER2-negative gBRCAm early breast cancer who received local treatment and adjuvant or neoadjuvant chemotherapy. One year of adjuvant olaparib was associated with a significant improvement in invasive disease-free survival (hazard ratio [HR] 0.58, P < .001) and distant disease-free survival (HR 0.57, P < .001). The 3-year invasive disease-free survival (iDFS) was 85.9% in the olaparib group and 77.1% in the placebo group (absolute benefit of 8.8%), and 3-year distant disease-free survival (dDFS) was 87.5% and 80.4%, respectively (difference of 7.1%). These results are considered practice changing and lead to questions regarding the expansion of germline testing in early stage breast cancer. Furthermore, PARP inhibitors have shown exciting results in the neoadjuvant setting. Among 61 patients with gBRCAm HER2-negative early breast cancer, neoadjuvant talazoparib produced a pathologic complete response (pCR) in 49.2%, and there may be a subgroup of patients for whom this approach is relevant.

The presence of residual disease after neoadjuvant chemotherapy has prognostic implications and can help tailor adjuvant treatment recommendations. The CREATE-X trial has established the role of adjuvant capecitabine for patients with triple-negative breast cancer with residual disease after pre-operative chemotherapy. The phase 3 EA1131 trial randomized 415 patients with stage II-III triple-negative breast cancer and residual disease post-neoadjuvant chemotherapy to platinum agent or capecitabine. There was no significant difference in 3-year iDFS (42% for platinum vs 49% for capecitabine; HR 1.06, 95% CI 0.62-1.81), and higher hematologic toxicity and dose reductions in the platinum arm. These data support the continued use of capecitabine in this population, and the high event rate highlights the need for more effective therapies in this setting.

The majority of patients with HR+/HER2- MBC will receive a CDK 4/6 inhibitor at some point during their treatment course. In an updated analysis of the phase 3 MONALEESA-3 trial which included postmenopausal patients with HR+HER2- MBC, with median follow-up of 56.3 months, ribociclib plus fulvestrant continued to show an overall survival (OS) benefit of greater than 1 year compared with fulvestrant alone (median OS 53.7 months vs 41.5 months in the ribociclib vs placebo arm, respectively; HR 0.726, 95% CI 0.59-0.90). Additionally, extended follow-up of the PALOMA-3 trial demonstrated OS benefit with palbociclib plus fulvestrant compared to fulvestrant alone in patients with HR+/HER2- MBC; at median follow-up of 73.3 months, median OS was 34.8 months in the palbociclib arm vs 28.0 months in the placebo arm (HR 0.81, P = .0221). Sequencing of other targeted therapies (such as PI3K inhibitors), predictors of CDK 4/6 inhibitor response in different intrinsic subtypes, and the role of CDK 4/6 inhibitor use beyond progression are areas where further research is warranted.

References:

Robson M, Im SA, Senkus E, et al. Olaparib for Metastatic Breast Cancer in Patients with a Germline BRCA Mutation. N Engl J Med. 2017;377(6):523-533.

Litton JK, Beck JT, Jones JM, et al. Neoadjuvant talazoparib in patients with germline BRCA1/2 (gBRCA1/2) mutation-positive, early HER2-negative breast cancer (BC): Results of a phase 2 study. J Clin Oncol 39, 2021 (suppl 15; abstr 505).

Symmans WF, Wei C, Gould R, et al. Long-Term Prognostic Risk After Neoadjuvant Chemotherapy Associated With Residual Cancer Burden and Breast Cancer Subtype. J Clin Oncol. 2017;35:1049-1060.

Masuda N, Lee SJ, Ohtani S, et al. Adjuvant Capecitabine for Breast Cancer after Preoperative Chemotherapy. N Engl J Med. 2017;376:2147-2159.

Cristofanilli M, Rugo H, Im SA, et al. Overall survival (OS) with palbociclib (PAL) + fulvestrant (FUL) in women with hormone receptor–positive (HR+), human epidermal growth factor receptor 2–negative (HER2–) advanced breast cancer (ABC): Updated analyses from PALOMA-3. J Clin Oncol. 2021; 39:15_suppl, 1000-1000.

Adjuvant endocrine therapy (ET) has been shown to reduce risk of recurrence and improve survival in HR+ early breast cancer (EBC). A retrospective matched cohort analysis of 1,972 patients ≥70 years of age with HR+/HER2-negative, node-negative EBC and multiple medical co-morbidities, demonstrated higher median overall survival (OS) in patients who received ET versus those who did not (79.2 months compared to 67.7 months, p<0.0001). Older women with multiple medical co-morbidities may be at greater risk of toxicities related to ET, which can impact quality of life and adherence. The probability of initiating ET has been shown to be greater among patients who underwent radiation, thus highlighting the need to identify those who will adhere to ET when making decisions regarding radiation therapy to optimize care. ET should be discussed with all women who are candidates for this therapy, with a focus on individualized benefit and risk of these agents.

Studies of immunotherapy in metastatic triple-negative breast cancer have shown promising results, notably in patients with PD-L1 enriched tumors (IMpassion 130 and KEYNOTE-355). KEYNOTE-119 was a phase 3 study including 1,098 patients with metastatic TNBC who had received one or two previous systemic therapies for metastatic disease and progressed on most recent treatment, with randomization to pembrolizumab or physician’s choice chemotherapy . Median OS for pembrolizumab compared to chemotherapy was similar in the overall population (9.9 months versus 10.8 months, HR 0.97) and in patients with PD-L1 CPS score of ≥10 (12.7 months versus 11.6 months, HR 0.78, p=0.057). Although not statistically significant, greater PD-L1 expression was associated with longer median OS with pembrolizumab. Responses to immunotherapy may be durable in select patients, and these agents have an overall favorable toxicity profile. Novel immunotherapy combinations as well as biomarkers to predict response are certainly desired in this space.

Combination endocrine therapy plus a CDK 4/6 inhibitor is standard first-line treatment for metastatic HR+/HER2-negative breast cancer. Neutropenia is a common adverse event (AE) seen with the CDK 4/6 inhibitor palbociclib, and dosing guidelines provide a clear algorithm for drug monitoring and adjustment for cytopenias. Cutaneous toxicities, although not commonly seen, have been reported in the literature. Chawla and colleagues performed a retrospective analysis including 324 patients with advanced HR+/HER2-negative breast cancer who received palbociclib plus endocrine therapy. Cutaneous AEs were seen in 14.2%, with a significant proportion occurring early (41% occurred during or after the first cycle) and 50% resolved within 14 days (average 43 days). Of those who developed cutaneous AEs (n=46), only 15% and 4% required temporary hold and permanent cessation of therapy, respectively. These findings indicate a low overall incidence of cutaneous AEs associated with palbociclib, however highlight the importance of prompt recognition, management, and dermatology referral as appropriate, to help maintain patients on effective cancer-directed therapy.

References:

Yau C, van der Noordaa M, Wei J, et al. Residual cancer burden after neoadjuvant therapy and long-term survival outcomes in breast cancer: a multi-center pooled analysis. Presented at: 2019 San Antonio Breast Cancer Symposium; December 10-14, 2019; San Antonio, TX. Abstract GS5-01.

Wei M, Wang X, Zimmerman DN, Burt LM, Haaland B, Henry NL. Endocrine therapy and radiotherapy use among older women with hormone receptor-positive, clinically node-negative breast cancer. Breast Cancer Res Treat. 2021 Jan 9. doi: 10.1007/s10549-020-06071-w.Epub ahead of print.

Emens LA, Adams S, Barrios CH, et al. IMpassion130: Final OS analysis from the pivotal phase III study of atezolizumab plus nabpaclitaxel versus placebo plus nabpaclitaxel in previously untreated locally advanced or metastatic triple-negative breast cancer. Presented at: ESMO Virtual Congress 2020, Ann Oncol. 2020;31S:ESMO #LBA16.

Khan NAJ, Alsharedi M. Bullous Skin Rash: A Rare Case of Palbociclib-Induced Dermatological Toxicity. Cureus. 2020 Sep 3;12(9):e10229. doi: 10.7759/cureus.10229.

Adjuvant endocrine therapy (ET) has been shown to reduce risk of recurrence and improve survival in HR+ early breast cancer (EBC). A retrospective matched cohort analysis of 1,972 patients ≥70 years of age with HR+/HER2-negative, node-negative EBC and multiple medical co-morbidities, demonstrated higher median overall survival (OS) in patients who received ET versus those who did not (79.2 months compared to 67.7 months, p<0.0001). Older women with multiple medical co-morbidities may be at greater risk of toxicities related to ET, which can impact quality of life and adherence. The probability of initiating ET has been shown to be greater among patients who underwent radiation, thus highlighting the need to identify those who will adhere to ET when making decisions regarding radiation therapy to optimize care. ET should be discussed with all women who are candidates for this therapy, with a focus on individualized benefit and risk of these agents.

Studies of immunotherapy in metastatic triple-negative breast cancer have shown promising results, notably in patients with PD-L1 enriched tumors (IMpassion 130 and KEYNOTE-355). KEYNOTE-119 was a phase 3 study including 1,098 patients with metastatic TNBC who had received one or two previous systemic therapies for metastatic disease and progressed on most recent treatment, with randomization to pembrolizumab or physician’s choice chemotherapy . Median OS for pembrolizumab compared to chemotherapy was similar in the overall population (9.9 months versus 10.8 months, HR 0.97) and in patients with PD-L1 CPS score of ≥10 (12.7 months versus 11.6 months, HR 0.78, p=0.057). Although not statistically significant, greater PD-L1 expression was associated with longer median OS with pembrolizumab. Responses to immunotherapy may be durable in select patients, and these agents have an overall favorable toxicity profile. Novel immunotherapy combinations as well as biomarkers to predict response are certainly desired in this space.

Combination endocrine therapy plus a CDK 4/6 inhibitor is standard first-line treatment for metastatic HR+/HER2-negative breast cancer. Neutropenia is a common adverse event (AE) seen with the CDK 4/6 inhibitor palbociclib, and dosing guidelines provide a clear algorithm for drug monitoring and adjustment for cytopenias. Cutaneous toxicities, although not commonly seen, have been reported in the literature. Chawla and colleagues performed a retrospective analysis including 324 patients with advanced HR+/HER2-negative breast cancer who received palbociclib plus endocrine therapy. Cutaneous AEs were seen in 14.2%, with a significant proportion occurring early (41% occurred during or after the first cycle) and 50% resolved within 14 days (average 43 days). Of those who developed cutaneous AEs (n=46), only 15% and 4% required temporary hold and permanent cessation of therapy, respectively. These findings indicate a low overall incidence of cutaneous AEs associated with palbociclib, however highlight the importance of prompt recognition, management, and dermatology referral as appropriate, to help maintain patients on effective cancer-directed therapy.

References:

Yau C, van der Noordaa M, Wei J, et al. Residual cancer burden after neoadjuvant therapy and long-term survival outcomes in breast cancer: a multi-center pooled analysis. Presented at: 2019 San Antonio Breast Cancer Symposium; December 10-14, 2019; San Antonio, TX. Abstract GS5-01.

Wei M, Wang X, Zimmerman DN, Burt LM, Haaland B, Henry NL. Endocrine therapy and radiotherapy use among older women with hormone receptor-positive, clinically node-negative breast cancer. Breast Cancer Res Treat. 2021 Jan 9. doi: 10.1007/s10549-020-06071-w.Epub ahead of print.

Emens LA, Adams S, Barrios CH, et al. IMpassion130: Final OS analysis from the pivotal phase III study of atezolizumab plus nabpaclitaxel versus placebo plus nabpaclitaxel in previously untreated locally advanced or metastatic triple-negative breast cancer. Presented at: ESMO Virtual Congress 2020, Ann Oncol. 2020;31S:ESMO #LBA16.

Khan NAJ, Alsharedi M. Bullous Skin Rash: A Rare Case of Palbociclib-Induced Dermatological Toxicity. Cureus. 2020 Sep 3;12(9):e10229. doi: 10.7759/cureus.10229.

Adjuvant endocrine therapy (ET) has been shown to reduce risk of recurrence and improve survival in HR+ early breast cancer (EBC). A retrospective matched cohort analysis of 1,972 patients ≥70 years of age with HR+/HER2-negative, node-negative EBC and multiple medical co-morbidities, demonstrated higher median overall survival (OS) in patients who received ET versus those who did not (79.2 months compared to 67.7 months, p<0.0001). Older women with multiple medical co-morbidities may be at greater risk of toxicities related to ET, which can impact quality of life and adherence. The probability of initiating ET has been shown to be greater among patients who underwent radiation, thus highlighting the need to identify those who will adhere to ET when making decisions regarding radiation therapy to optimize care. ET should be discussed with all women who are candidates for this therapy, with a focus on individualized benefit and risk of these agents.

Studies of immunotherapy in metastatic triple-negative breast cancer have shown promising results, notably in patients with PD-L1 enriched tumors (IMpassion 130 and KEYNOTE-355). KEYNOTE-119 was a phase 3 study including 1,098 patients with metastatic TNBC who had received one or two previous systemic therapies for metastatic disease and progressed on most recent treatment, with randomization to pembrolizumab or physician’s choice chemotherapy . Median OS for pembrolizumab compared to chemotherapy was similar in the overall population (9.9 months versus 10.8 months, HR 0.97) and in patients with PD-L1 CPS score of ≥10 (12.7 months versus 11.6 months, HR 0.78, p=0.057). Although not statistically significant, greater PD-L1 expression was associated with longer median OS with pembrolizumab. Responses to immunotherapy may be durable in select patients, and these agents have an overall favorable toxicity profile. Novel immunotherapy combinations as well as biomarkers to predict response are certainly desired in this space.

Combination endocrine therapy plus a CDK 4/6 inhibitor is standard first-line treatment for metastatic HR+/HER2-negative breast cancer. Neutropenia is a common adverse event (AE) seen with the CDK 4/6 inhibitor palbociclib, and dosing guidelines provide a clear algorithm for drug monitoring and adjustment for cytopenias. Cutaneous toxicities, although not commonly seen, have been reported in the literature. Chawla and colleagues performed a retrospective analysis including 324 patients with advanced HR+/HER2-negative breast cancer who received palbociclib plus endocrine therapy. Cutaneous AEs were seen in 14.2%, with a significant proportion occurring early (41% occurred during or after the first cycle) and 50% resolved within 14 days (average 43 days). Of those who developed cutaneous AEs (n=46), only 15% and 4% required temporary hold and permanent cessation of therapy, respectively. These findings indicate a low overall incidence of cutaneous AEs associated with palbociclib, however highlight the importance of prompt recognition, management, and dermatology referral as appropriate, to help maintain patients on effective cancer-directed therapy.

References:

Yau C, van der Noordaa M, Wei J, et al. Residual cancer burden after neoadjuvant therapy and long-term survival outcomes in breast cancer: a multi-center pooled analysis. Presented at: 2019 San Antonio Breast Cancer Symposium; December 10-14, 2019; San Antonio, TX. Abstract GS5-01.

Wei M, Wang X, Zimmerman DN, Burt LM, Haaland B, Henry NL. Endocrine therapy and radiotherapy use among older women with hormone receptor-positive, clinically node-negative breast cancer. Breast Cancer Res Treat. 2021 Jan 9. doi: 10.1007/s10549-020-06071-w.Epub ahead of print.

Emens LA, Adams S, Barrios CH, et al. IMpassion130: Final OS analysis from the pivotal phase III study of atezolizumab plus nabpaclitaxel versus placebo plus nabpaclitaxel in previously untreated locally advanced or metastatic triple-negative breast cancer. Presented at: ESMO Virtual Congress 2020, Ann Oncol. 2020;31S:ESMO #LBA16.

Khan NAJ, Alsharedi M. Bullous Skin Rash: A Rare Case of Palbociclib-Induced Dermatological Toxicity. Cureus. 2020 Sep 3;12(9):e10229. doi: 10.7759/cureus.10229.

Peripheral neuropathy is a well-recognized complication of taxane therapy that can impact functioning and quality of life. Dose-reductions are applied in an effort to continue treatment and minimize risk of worsening neuropathy. In a prospective analysis of breast cancer patients receiving weekly paclitaxel, Timmins et al showed neuropathy symptoms affected 85% with severe symptoms in 38%, and about half of the cohort had persistent symptoms up to 12 months post-chemotherapy. Patients who received dose reductions reported worse neuropathy and symptom burden compared to those who received full dose paclitaxel chemotherapy. It is challenging to predict with certainty which patients may experience significant neuropathy, and important to acknowledge individual patients factors such as age and other medical co-morbidities. Additional research is warranted to refine individual risk assessment as well as prevention and management strategies.

The treatment landscape for metastatic HER2-positive breast cancer is evolving at a rapid pace. Margetuximab is a chimeric antibody with similar epitope specificity to trastuzumab, but with an engineered Fc region that enhances immune activation. The phase 3 SOPHIA trial included 536 patients with pretreated HER2-positive advanced breast cancer and demonstrated modest improvement in progression free-survival with margetuximab plus chemotherapy compared to trastuzumab plus chemotherapy (median PFS 5.8 versus 4.9 months; HR 0.76, p=0.03). The introduction of other therapies in this space (tucatinib, trastuzumab deruxtecan, neratinib) provides patients with many options, but simultaneously creates a complex treatment algorithm when it comes to therapy selection. Toxicity profiles and sites of metastases should be taken into consideration when deciding on best therapy for an individual patient.

Given the impressive outcomes seen with endocrine therapy plus CDK 4/6 inhibitors in the advanced HR+/HER2- population, these combinations are being studied in the curative setting. The phase 3 PALLAS study randomized 5,760 patients with stage I-III HR+/HER2- breast cancer to ongoing endocrine therapy with or without palbociclib for 2 years. Data from the second interim analysis of this trial showed similar invasive disease-free survival rates for the two arms (3 years iDFS 88.2% for palbociclib plus endocrine therapy versus 88.5% for endocrine therapy alone; HR 0.93, p=0.51). In contrast, the phase 3 monarchE trial showed improvement in iDFS with abemaciclib for 2 years with ongoing endocrine therapy compared to endocrine therapy alone (2 year iDFS rate of 92.3% versus 89.3%; HR 0.713, p=0.0009). Differences in study populations, mechanism of action of various CDK 4/6 inhibitors, dosing and drug exposure, may possibly impact results. Long-term follow-up and biomarker studies are desired to further delineate the role of CDK 4/6 inhibitors in this setting.

References:

Runowicz CD, Leach CR, Henry NL, Henry KS, Mackey HT, Cowens-Alvarado RL, Cannady RS, Pratt-Chapman ML, Edge SB, Jacobs LA, Hurria A, Marks LB, LaMonte SJ, Warner E, Lyman GH, Ganz PA. American Cancer Society/American Society of Clinical Oncology Breast Cancer Survivorship Care Guideline. J Clin Oncol. 2016;34:611-35.

Ghoreishi Z, Keshavarz S, Asghari Jafarabadi M, Fathifar Z, Goodman KA, Esfahani A. Risk factors for paclitaxel-induced peripheral neuropathy in patients with breast cancer. BMC Cancer. 2018;18:958.

O'Shaughnessy JA, Johnston S, Harbeck N, Toi M, Im Y-H, Reinisch M, Shao Z, Kellokumpu Lehtinen PL, Huang C-S, Tryakin A, Goetz M, Rugo HS, Senkus E, Testa L, Andersson M, Tamura K, Steger GG, Del Mastro L, Cox J, Forrester T, Sherwood S, Li X, Wei R, Martin M, Rastogi P. Primary outcome analysis of invasive disease-free survival for monarchE: abemaciclib combined with adjuvant endocrine therapy for high risk early breast cancer. Presented at: 2020 Virtual San Antonio Breast Cancer Symposium; December 8-11, 2020. Abstract GS1-01.

Peripheral neuropathy is a well-recognized complication of taxane therapy that can impact functioning and quality of life. Dose-reductions are applied in an effort to continue treatment and minimize risk of worsening neuropathy. In a prospective analysis of breast cancer patients receiving weekly paclitaxel, Timmins et al showed neuropathy symptoms affected 85% with severe symptoms in 38%, and about half of the cohort had persistent symptoms up to 12 months post-chemotherapy. Patients who received dose reductions reported worse neuropathy and symptom burden compared to those who received full dose paclitaxel chemotherapy. It is challenging to predict with certainty which patients may experience significant neuropathy, and important to acknowledge individual patients factors such as age and other medical co-morbidities. Additional research is warranted to refine individual risk assessment as well as prevention and management strategies.

The treatment landscape for metastatic HER2-positive breast cancer is evolving at a rapid pace. Margetuximab is a chimeric antibody with similar epitope specificity to trastuzumab, but with an engineered Fc region that enhances immune activation. The phase 3 SOPHIA trial included 536 patients with pretreated HER2-positive advanced breast cancer and demonstrated modest improvement in progression free-survival with margetuximab plus chemotherapy compared to trastuzumab plus chemotherapy (median PFS 5.8 versus 4.9 months; HR 0.76, p=0.03). The introduction of other therapies in this space (tucatinib, trastuzumab deruxtecan, neratinib) provides patients with many options, but simultaneously creates a complex treatment algorithm when it comes to therapy selection. Toxicity profiles and sites of metastases should be taken into consideration when deciding on best therapy for an individual patient.

Given the impressive outcomes seen with endocrine therapy plus CDK 4/6 inhibitors in the advanced HR+/HER2- population, these combinations are being studied in the curative setting. The phase 3 PALLAS study randomized 5,760 patients with stage I-III HR+/HER2- breast cancer to ongoing endocrine therapy with or without palbociclib for 2 years. Data from the second interim analysis of this trial showed similar invasive disease-free survival rates for the two arms (3 years iDFS 88.2% for palbociclib plus endocrine therapy versus 88.5% for endocrine therapy alone; HR 0.93, p=0.51). In contrast, the phase 3 monarchE trial showed improvement in iDFS with abemaciclib for 2 years with ongoing endocrine therapy compared to endocrine therapy alone (2 year iDFS rate of 92.3% versus 89.3%; HR 0.713, p=0.0009). Differences in study populations, mechanism of action of various CDK 4/6 inhibitors, dosing and drug exposure, may possibly impact results. Long-term follow-up and biomarker studies are desired to further delineate the role of CDK 4/6 inhibitors in this setting.

References:

Runowicz CD, Leach CR, Henry NL, Henry KS, Mackey HT, Cowens-Alvarado RL, Cannady RS, Pratt-Chapman ML, Edge SB, Jacobs LA, Hurria A, Marks LB, LaMonte SJ, Warner E, Lyman GH, Ganz PA. American Cancer Society/American Society of Clinical Oncology Breast Cancer Survivorship Care Guideline. J Clin Oncol. 2016;34:611-35.

Ghoreishi Z, Keshavarz S, Asghari Jafarabadi M, Fathifar Z, Goodman KA, Esfahani A. Risk factors for paclitaxel-induced peripheral neuropathy in patients with breast cancer. BMC Cancer. 2018;18:958.

O'Shaughnessy JA, Johnston S, Harbeck N, Toi M, Im Y-H, Reinisch M, Shao Z, Kellokumpu Lehtinen PL, Huang C-S, Tryakin A, Goetz M, Rugo HS, Senkus E, Testa L, Andersson M, Tamura K, Steger GG, Del Mastro L, Cox J, Forrester T, Sherwood S, Li X, Wei R, Martin M, Rastogi P. Primary outcome analysis of invasive disease-free survival for monarchE: abemaciclib combined with adjuvant endocrine therapy for high risk early breast cancer. Presented at: 2020 Virtual San Antonio Breast Cancer Symposium; December 8-11, 2020. Abstract GS1-01.

Peripheral neuropathy is a well-recognized complication of taxane therapy that can impact functioning and quality of life. Dose-reductions are applied in an effort to continue treatment and minimize risk of worsening neuropathy. In a prospective analysis of breast cancer patients receiving weekly paclitaxel, Timmins et al showed neuropathy symptoms affected 85% with severe symptoms in 38%, and about half of the cohort had persistent symptoms up to 12 months post-chemotherapy. Patients who received dose reductions reported worse neuropathy and symptom burden compared to those who received full dose paclitaxel chemotherapy. It is challenging to predict with certainty which patients may experience significant neuropathy, and important to acknowledge individual patients factors such as age and other medical co-morbidities. Additional research is warranted to refine individual risk assessment as well as prevention and management strategies.

The treatment landscape for metastatic HER2-positive breast cancer is evolving at a rapid pace. Margetuximab is a chimeric antibody with similar epitope specificity to trastuzumab, but with an engineered Fc region that enhances immune activation. The phase 3 SOPHIA trial included 536 patients with pretreated HER2-positive advanced breast cancer and demonstrated modest improvement in progression free-survival with margetuximab plus chemotherapy compared to trastuzumab plus chemotherapy (median PFS 5.8 versus 4.9 months; HR 0.76, p=0.03). The introduction of other therapies in this space (tucatinib, trastuzumab deruxtecan, neratinib) provides patients with many options, but simultaneously creates a complex treatment algorithm when it comes to therapy selection. Toxicity profiles and sites of metastases should be taken into consideration when deciding on best therapy for an individual patient.

Given the impressive outcomes seen with endocrine therapy plus CDK 4/6 inhibitors in the advanced HR+/HER2- population, these combinations are being studied in the curative setting. The phase 3 PALLAS study randomized 5,760 patients with stage I-III HR+/HER2- breast cancer to ongoing endocrine therapy with or without palbociclib for 2 years. Data from the second interim analysis of this trial showed similar invasive disease-free survival rates for the two arms (3 years iDFS 88.2% for palbociclib plus endocrine therapy versus 88.5% for endocrine therapy alone; HR 0.93, p=0.51). In contrast, the phase 3 monarchE trial showed improvement in iDFS with abemaciclib for 2 years with ongoing endocrine therapy compared to endocrine therapy alone (2 year iDFS rate of 92.3% versus 89.3%; HR 0.713, p=0.0009). Differences in study populations, mechanism of action of various CDK 4/6 inhibitors, dosing and drug exposure, may possibly impact results. Long-term follow-up and biomarker studies are desired to further delineate the role of CDK 4/6 inhibitors in this setting.

References:

Runowicz CD, Leach CR, Henry NL, Henry KS, Mackey HT, Cowens-Alvarado RL, Cannady RS, Pratt-Chapman ML, Edge SB, Jacobs LA, Hurria A, Marks LB, LaMonte SJ, Warner E, Lyman GH, Ganz PA. American Cancer Society/American Society of Clinical Oncology Breast Cancer Survivorship Care Guideline. J Clin Oncol. 2016;34:611-35.

Ghoreishi Z, Keshavarz S, Asghari Jafarabadi M, Fathifar Z, Goodman KA, Esfahani A. Risk factors for paclitaxel-induced peripheral neuropathy in patients with breast cancer. BMC Cancer. 2018;18:958.

O'Shaughnessy JA, Johnston S, Harbeck N, Toi M, Im Y-H, Reinisch M, Shao Z, Kellokumpu Lehtinen PL, Huang C-S, Tryakin A, Goetz M, Rugo HS, Senkus E, Testa L, Andersson M, Tamura K, Steger GG, Del Mastro L, Cox J, Forrester T, Sherwood S, Li X, Wei R, Martin M, Rastogi P. Primary outcome analysis of invasive disease-free survival for monarchE: abemaciclib combined with adjuvant endocrine therapy for high risk early breast cancer. Presented at: 2020 Virtual San Antonio Breast Cancer Symposium; December 8-11, 2020. Abstract GS1-01.

Systemic therapy advances for metastatic breast cancer (MBC) have led to improved overall survival; however, the CNS sanctuary site can be challenging to treat and cause significant neurologic symptoms. Kuksis and colleagues reported that HER2-positive and triple-negative breast MBC subtypes have high incidence of brain metastases, with pooled cumulative incidences of 31% and 32%, respectively. The incidence per patient-year was 13% for both subtypes. The treatment landscape for HER2-positive MBC is rapidly evolving. The combination of tucatinib/capecitabine/trastuzumab demonstrated reduced risk of intracranial progression or death (HR 0.32), improvement in intracranial objective response rate (47.3% versus 20.0%) and reduced risk of death (0.58) in the HER2CLIMB study. An MRI screening program may enhance early detection and study prevention of brain metastases.

Trastuzumab and pertuzumab have significantly improved outcomes in early-stage and advanced HER2-positive breast cancer. These monoclonal antibodies are given with chemotherapy initially, followed by dual antibody therapy to complete one year for curative treatment and until disease progression in the metastatic setting. The FeDeriCa randomized phase 3 study demonstrated that fixed-dose subcutaneous combination of pertuzumab and trastuzumab was non-inferior to intravenous formulations with a geometric mean ratio of cycle 7 pertuzumab serum trough concentration of 1.22 (90% CI 1.14-1.31). Furthermore, efficacy appeared similar with pathologic complete response rates of 60% for both groups. Trastuzumab and pertuzumab administration in an infusion center requires hospital resources, cost, and patient’s time. The MetasphHER study showed that patients preferred subcutaneous trastuzumab compared to IV, and further investigation into long-term outcomes and impact on quality of life and resource allocation is desired.

The phase 3 CLEOPATRA study demonstrated improvement in overall survival with the addition of pertuzumab to docetaxel and trastuzumab in patients with HER2-positive MBC. Rash and diarrhea are well-recognized potential side effects related to pertuzumab. Ferreira et al demonstrated that rash was prognostic for PFS and OS both during and after docetaxel discontinuation, while diarrhea was only prognostic after docetaxel. Neither rash nor diarrhea were predictive of pertuzumab benefit. Studies have shown that patients who developed immune-related adverse events during anti-PD-1 treatment had PFS and OS benefit compared to those who did not. These results may help inform and encourage patients and providers regarding benefit of various treatments in the setting of toxicities. Future research exploring biomarker prognostic and predictive capability is certainly warranted. 

Endocrine therapy plus a CDK 4/6 inhibitor is standard first-line treatment for hormone receptor-positive MBC. Progression that occurs rapidly or through multiple lines of endocrine therapy combinations, may indicate endocrine resistance. The phase 3 PEARL trial did not demonstrate superior PFS among patients with wild type ESR1 AI-resistant MBC with palbociclib/endocrine therapy compared to capecitabine (mPFS 8.0 vs 10.6 months, adjusted HR 1.11; p=0.404); similar PFS and aHR were seen in palbociclib/fulvestrant versus capecitabine cohort. Therapy sequencing in HR+/HER2-negative MBC is indeed relevant, and a previous meta-analysis demonstrated chemotherapy was not better than endocrine therapy plus CDK 4/6 inhibitor in first- or second-line setting. Importantly, palbociclib plus endocrine therapy was associated with better tolerability and quality of life, which should be considered when selecting treatment with similar PFS outcomes.

References:

Lin NU, Borges V, Anders C, Murthy RK, Paplomata E, Hamilton E, Hurvitz S, Loi S, Okines A, Abramson V, Bedard PL, Oliveira M, Mueller V, Zelnak A, DiGiovanna MP, Bachelot T, Chien AJ, O'Regan R, Wardley A, Conlin A, Cameron D, Carey L, Curigliano G, Gelmon K, Loibl S, Mayor J, McGoldrick S, An X, Winer EP. Intracranial efficacy and survival with tucatinib plus trastuzumab and capecitabine for previously treated HER2-positive breast cancer with brain metastases in the HER2CLIMB trial. J Clin Oncol. 2020;38:2610-2619.

Pivot X, Spano JP, Espie M, Cottu P, Jouannaud C, Pottier V, Moreau L, Extra JM, Lortholary A, Rivera P, Spaeth D, Attar-Rabia H, Benkanoun C, Dima-Martinez L, Esposito N, Gligorov J. Patients' preference of trastuzumab administration (subcutaneous versus intravenous) in HER2-positive metastatic breast cancer: Results of the randomised MetaspHer study. Eur J Cancer. 2017;82:230-236.

Das S, Ciombor KK, Haraldsdottir S, Pumpalova Y, Sahin IH, Pineda G, Shyr Y, Lin EP, Hsu CY, Chu SK, Goff LW, Cardin DB, Bilen MA, Fisher GA, Wu C, Berlin J. Immune-related adverse events and immune checkpoint inhibitor efficacy in patients with gastrointestinal cancer with Food and Drug Administration-approved indications for immunotherapy. Oncologist. 2020;25:669-679.

Giuliano M, Schettini F, Rognoni C, Milani M, Jerusalem G, Bachelot T, De Laurentiis M, Thomas G, De Placido P, Arpino G, De Placido S, Cristofanilli M, Giordano A, Puglisi F, Pistilli B, Prat A, Del Mastro L, Venturini S, Generali D. Endocrine treatment versus chemotherapy in postmenopausal women with hormone receptor-positive, HER2-negative, metastatic breast cancer: a systematic review and network meta-analysis. Lancet Oncol. 2019;20:1360-1369.

Systemic therapy advances for metastatic breast cancer (MBC) have led to improved overall survival; however, the CNS sanctuary site can be challenging to treat and cause significant neurologic symptoms. Kuksis and colleagues reported that HER2-positive and triple-negative breast MBC subtypes have high incidence of brain metastases, with pooled cumulative incidences of 31% and 32%, respectively. The incidence per patient-year was 13% for both subtypes. The treatment landscape for HER2-positive MBC is rapidly evolving. The combination of tucatinib/capecitabine/trastuzumab demonstrated reduced risk of intracranial progression or death (HR 0.32), improvement in intracranial objective response rate (47.3% versus 20.0%) and reduced risk of death (0.58) in the HER2CLIMB study. An MRI screening program may enhance early detection and study prevention of brain metastases.

Trastuzumab and pertuzumab have significantly improved outcomes in early-stage and advanced HER2-positive breast cancer. These monoclonal antibodies are given with chemotherapy initially, followed by dual antibody therapy to complete one year for curative treatment and until disease progression in the metastatic setting. The FeDeriCa randomized phase 3 study demonstrated that fixed-dose subcutaneous combination of pertuzumab and trastuzumab was non-inferior to intravenous formulations with a geometric mean ratio of cycle 7 pertuzumab serum trough concentration of 1.22 (90% CI 1.14-1.31). Furthermore, efficacy appeared similar with pathologic complete response rates of 60% for both groups. Trastuzumab and pertuzumab administration in an infusion center requires hospital resources, cost, and patient’s time. The MetasphHER study showed that patients preferred subcutaneous trastuzumab compared to IV, and further investigation into long-term outcomes and impact on quality of life and resource allocation is desired.

The phase 3 CLEOPATRA study demonstrated improvement in overall survival with the addition of pertuzumab to docetaxel and trastuzumab in patients with HER2-positive MBC. Rash and diarrhea are well-recognized potential side effects related to pertuzumab. Ferreira et al demonstrated that rash was prognostic for PFS and OS both during and after docetaxel discontinuation, while diarrhea was only prognostic after docetaxel. Neither rash nor diarrhea were predictive of pertuzumab benefit. Studies have shown that patients who developed immune-related adverse events during anti-PD-1 treatment had PFS and OS benefit compared to those who did not. These results may help inform and encourage patients and providers regarding benefit of various treatments in the setting of toxicities. Future research exploring biomarker prognostic and predictive capability is certainly warranted. 

Endocrine therapy plus a CDK 4/6 inhibitor is standard first-line treatment for hormone receptor-positive MBC. Progression that occurs rapidly or through multiple lines of endocrine therapy combinations, may indicate endocrine resistance. The phase 3 PEARL trial did not demonstrate superior PFS among patients with wild type ESR1 AI-resistant MBC with palbociclib/endocrine therapy compared to capecitabine (mPFS 8.0 vs 10.6 months, adjusted HR 1.11; p=0.404); similar PFS and aHR were seen in palbociclib/fulvestrant versus capecitabine cohort. Therapy sequencing in HR+/HER2-negative MBC is indeed relevant, and a previous meta-analysis demonstrated chemotherapy was not better than endocrine therapy plus CDK 4/6 inhibitor in first- or second-line setting. Importantly, palbociclib plus endocrine therapy was associated with better tolerability and quality of life, which should be considered when selecting treatment with similar PFS outcomes.

References:

Lin NU, Borges V, Anders C, Murthy RK, Paplomata E, Hamilton E, Hurvitz S, Loi S, Okines A, Abramson V, Bedard PL, Oliveira M, Mueller V, Zelnak A, DiGiovanna MP, Bachelot T, Chien AJ, O'Regan R, Wardley A, Conlin A, Cameron D, Carey L, Curigliano G, Gelmon K, Loibl S, Mayor J, McGoldrick S, An X, Winer EP. Intracranial efficacy and survival with tucatinib plus trastuzumab and capecitabine for previously treated HER2-positive breast cancer with brain metastases in the HER2CLIMB trial. J Clin Oncol. 2020;38:2610-2619.

Pivot X, Spano JP, Espie M, Cottu P, Jouannaud C, Pottier V, Moreau L, Extra JM, Lortholary A, Rivera P, Spaeth D, Attar-Rabia H, Benkanoun C, Dima-Martinez L, Esposito N, Gligorov J. Patients' preference of trastuzumab administration (subcutaneous versus intravenous) in HER2-positive metastatic breast cancer: Results of the randomised MetaspHer study. Eur J Cancer. 2017;82:230-236.

Das S, Ciombor KK, Haraldsdottir S, Pumpalova Y, Sahin IH, Pineda G, Shyr Y, Lin EP, Hsu CY, Chu SK, Goff LW, Cardin DB, Bilen MA, Fisher GA, Wu C, Berlin J. Immune-related adverse events and immune checkpoint inhibitor efficacy in patients with gastrointestinal cancer with Food and Drug Administration-approved indications for immunotherapy. Oncologist. 2020;25:669-679.

Giuliano M, Schettini F, Rognoni C, Milani M, Jerusalem G, Bachelot T, De Laurentiis M, Thomas G, De Placido P, Arpino G, De Placido S, Cristofanilli M, Giordano A, Puglisi F, Pistilli B, Prat A, Del Mastro L, Venturini S, Generali D. Endocrine treatment versus chemotherapy in postmenopausal women with hormone receptor-positive, HER2-negative, metastatic breast cancer: a systematic review and network meta-analysis. Lancet Oncol. 2019;20:1360-1369.

Systemic therapy advances for metastatic breast cancer (MBC) have led to improved overall survival; however, the CNS sanctuary site can be challenging to treat and cause significant neurologic symptoms. Kuksis and colleagues reported that HER2-positive and triple-negative breast MBC subtypes have high incidence of brain metastases, with pooled cumulative incidences of 31% and 32%, respectively. The incidence per patient-year was 13% for both subtypes. The treatment landscape for HER2-positive MBC is rapidly evolving. The combination of tucatinib/capecitabine/trastuzumab demonstrated reduced risk of intracranial progression or death (HR 0.32), improvement in intracranial objective response rate (47.3% versus 20.0%) and reduced risk of death (0.58) in the HER2CLIMB study. An MRI screening program may enhance early detection and study prevention of brain metastases.

Trastuzumab and pertuzumab have significantly improved outcomes in early-stage and advanced HER2-positive breast cancer. These monoclonal antibodies are given with chemotherapy initially, followed by dual antibody therapy to complete one year for curative treatment and until disease progression in the metastatic setting. The FeDeriCa randomized phase 3 study demonstrated that fixed-dose subcutaneous combination of pertuzumab and trastuzumab was non-inferior to intravenous formulations with a geometric mean ratio of cycle 7 pertuzumab serum trough concentration of 1.22 (90% CI 1.14-1.31). Furthermore, efficacy appeared similar with pathologic complete response rates of 60% for both groups. Trastuzumab and pertuzumab administration in an infusion center requires hospital resources, cost, and patient’s time. The MetasphHER study showed that patients preferred subcutaneous trastuzumab compared to IV, and further investigation into long-term outcomes and impact on quality of life and resource allocation is desired.

The phase 3 CLEOPATRA study demonstrated improvement in overall survival with the addition of pertuzumab to docetaxel and trastuzumab in patients with HER2-positive MBC. Rash and diarrhea are well-recognized potential side effects related to pertuzumab. Ferreira et al demonstrated that rash was prognostic for PFS and OS both during and after docetaxel discontinuation, while diarrhea was only prognostic after docetaxel. Neither rash nor diarrhea were predictive of pertuzumab benefit. Studies have shown that patients who developed immune-related adverse events during anti-PD-1 treatment had PFS and OS benefit compared to those who did not. These results may help inform and encourage patients and providers regarding benefit of various treatments in the setting of toxicities. Future research exploring biomarker prognostic and predictive capability is certainly warranted. 

Endocrine therapy plus a CDK 4/6 inhibitor is standard first-line treatment for hormone receptor-positive MBC. Progression that occurs rapidly or through multiple lines of endocrine therapy combinations, may indicate endocrine resistance. The phase 3 PEARL trial did not demonstrate superior PFS among patients with wild type ESR1 AI-resistant MBC with palbociclib/endocrine therapy compared to capecitabine (mPFS 8.0 vs 10.6 months, adjusted HR 1.11; p=0.404); similar PFS and aHR were seen in palbociclib/fulvestrant versus capecitabine cohort. Therapy sequencing in HR+/HER2-negative MBC is indeed relevant, and a previous meta-analysis demonstrated chemotherapy was not better than endocrine therapy plus CDK 4/6 inhibitor in first- or second-line setting. Importantly, palbociclib plus endocrine therapy was associated with better tolerability and quality of life, which should be considered when selecting treatment with similar PFS outcomes.

References:

Lin NU, Borges V, Anders C, Murthy RK, Paplomata E, Hamilton E, Hurvitz S, Loi S, Okines A, Abramson V, Bedard PL, Oliveira M, Mueller V, Zelnak A, DiGiovanna MP, Bachelot T, Chien AJ, O'Regan R, Wardley A, Conlin A, Cameron D, Carey L, Curigliano G, Gelmon K, Loibl S, Mayor J, McGoldrick S, An X, Winer EP. Intracranial efficacy and survival with tucatinib plus trastuzumab and capecitabine for previously treated HER2-positive breast cancer with brain metastases in the HER2CLIMB trial. J Clin Oncol. 2020;38:2610-2619.

Pivot X, Spano JP, Espie M, Cottu P, Jouannaud C, Pottier V, Moreau L, Extra JM, Lortholary A, Rivera P, Spaeth D, Attar-Rabia H, Benkanoun C, Dima-Martinez L, Esposito N, Gligorov J. Patients' preference of trastuzumab administration (subcutaneous versus intravenous) in HER2-positive metastatic breast cancer: Results of the randomised MetaspHer study. Eur J Cancer. 2017;82:230-236.

Das S, Ciombor KK, Haraldsdottir S, Pumpalova Y, Sahin IH, Pineda G, Shyr Y, Lin EP, Hsu CY, Chu SK, Goff LW, Cardin DB, Bilen MA, Fisher GA, Wu C, Berlin J. Immune-related adverse events and immune checkpoint inhibitor efficacy in patients with gastrointestinal cancer with Food and Drug Administration-approved indications for immunotherapy. Oncologist. 2020;25:669-679.

Giuliano M, Schettini F, Rognoni C, Milani M, Jerusalem G, Bachelot T, De Laurentiis M, Thomas G, De Placido P, Arpino G, De Placido S, Cristofanilli M, Giordano A, Puglisi F, Pistilli B, Prat A, Del Mastro L, Venturini S, Generali D. Endocrine treatment versus chemotherapy in postmenopausal women with hormone receptor-positive, HER2-negative, metastatic breast cancer: a systematic review and network meta-analysis. Lancet Oncol. 2019;20:1360-1369.

Breast cancer patients treated with curative intent do not often experience symptoms related to the cancer itself, and treatment toxicities may impact adherence and subsequently prognosis. Mittendorf et al reported on patient reported outcomes (PROs) from the phase 3 IMpassion031 trial which showed pCR improvement with atezolizumab/chemotherapy compared to placebo/chemotherapy for neoadjuvant early-stage TNBC. Health-related quality of life items and treatment-related symptoms worsened similarly in both arms during neoadjuvant therapy, and recovered/stabilized in the adjuvant setting. Further exploration of immunotherapy PROs is warranted, as clinical benefit is seen with these agents and they do not appear to negatively impact functioning and patient experience with treatment long-term. Side effect profiles of immunotherapy and standard chemotherapy are different, and design of immunotherapy-specific PROs are desired.

The PRIME 2 10 year results evaluating the role of whole breast irradiation in women ≥65 years with early-stage HR-positive breast cancer receiving hormonal therapy showed RT reduced risk of local recurrence from 9.8% to 0.9% at 10 years (p=0.0008). Patients with low ER tumors had higher 10 year local recurrence rate compared to high ER tumors (18.8% versus 9.2% (p0.007)). Rates of overall survival (80.4% in no RT group vs 81.0% in RT group) and metastasis free survival were similar. A shared decision making approach is key, carefully weighing benefits and risks, considering pathologic features, patient preferences and co-morbidities that may influence endocrine therapy adherence. The impact of molecular subtypes and genomic assays is also being explored to help assess radiation benefit and guide treatment recommendations.

Breast cancer in young women presents unique challenges considering the lifetime period during which diagnosis occurs. Previous studies have supported the safety of pregnancy after breast cancer and guidelines recommend oncofertility counseling in young patients. Blondeaux et al found that breast cancer patients had a 60% lower chance of pregnancy after treatment and were more likely to have complications including low birth weight, small for gestational age, preterm delivery and cesarean section. Although increased risk of congenital abnormalities did not appear to be statistically significant, the HR was 1.63. Importantly, pregnancy after breast cancer did not negatively impact maternal outcomes. This study further supports the safety of pregnancy after breast cancer, highlights the need for close monitoring of pregnancies in these women, and emphasizes the importance of fertility and family planning discussion, which is most optimally provided in a multidisciplinary fashion.

References:

Dent R, Oliveira AM, Isakoff SJ, Im SA, Espié M, Blau S, Saura C, Wongchenko MJ, Xu N, Bradley D, Reilly SJ, Mani A, Kim SB. Final results of the double-blind placebo (PBO)-controlled randomised phase II LOTUS trial of first-line ipatasertib (IPAT) + paclitaxel (PAC) for inoperable locally advanced/metastatic triple-negative breast cancer (mTNBC). Presented during 2020 ESMO breast cancer virtual meeting; May 23-24, 2020. Abstract 139O.

Schmid P, Abraham J, Chan S, Wheatley D, Brunt AM, Nemsadze G, Baird RD, Park YH, Hall PS, Perren T, Stein RC, Mangel L, Ferrero JM, Phillips M, Conibear J, Cortes J, Foxley A, de Bruin EC, McEwen R, Stetson D, Dougherty B, Sarker SJ, Prendergast A, McLaughlin-Callan M, Burgess M, Lawrence C, Cartwright H, Mousa K, Turner NC. Capivasertib plus paclitaxel versus placebo plus paclitaxel as first-line therapy for metastatic triple-negative breast cancer: the PAKT trial. J Clin Oncol. 2020;38:423-433.

Mittendorf EA, Zhang H, Barrios CH, Saji S, Jung KH, Hegg R, Koehler A, Sohn J, Iwata H, Telli ML, Ferrario C, Punie K, Penault-Llorca F, Patel S, Duc AN, Liste-Hermoso M, Maiya V, Molinero L, Chui SY, Harbeck N. Neoadjuvant atezolizumab in combination with sequential nab-paclitaxel and anthracycline-based chemotherapy versus placebo and chemotherapy in patients with early-stage triple-negative breast cancer (IMpassion031): a randomised, double-blind, phase 3 trial. Lancet. 2020;396:1090-1100.

King-Kallimanis BL, Howie LJ, Roydhouse JK, Singh H, Theoret MR, Blumenthal GM, Kluetz PG. Patient reported outcomes in anti-PD-1/PD-L1 inhibitor immunotherapy registration trials: FDA analysis of data submitted and future directions. Clin Trials. 2019;16:322-326.

Fodor A, Brombin C, Mangili P, Borroni F, Pasetti M, Tummineri R, Zerbetto F, Longobardi B, Perna L, Dell'Oca I, Deantoni CL, Deli AM, Chiara A, Broggi S, Castriconi R, Esposito PG, Slim N, Passoni P, Baroni S, Villa SL, Rancoita PMV, Fiorino C, Del Vecchio A, Bianchini G, Gentilini OD, Di Serio MS, Di Muzio NG. Impact of molecular subtype on 1325 early-stage breast cancer patients homogeneously treated with hypofractionated radiotherapy without boost: Should the indications for radiotherapy be more personalized? Breast. 2020;55:45-54.

Azim HA Jr, Santoro L, Pavlidis N, Gelber S, Kroman N, Azim H, Peccatori FA. Safety of pregnancy following breast cancer diagnosis: a meta-analysis of 14 studies. Eur J Cancer. 2011;47:74-83.

Breast cancer patients treated with curative intent do not often experience symptoms related to the cancer itself, and treatment toxicities may impact adherence and subsequently prognosis. Mittendorf et al reported on patient reported outcomes (PROs) from the phase 3 IMpassion031 trial which showed pCR improvement with atezolizumab/chemotherapy compared to placebo/chemotherapy for neoadjuvant early-stage TNBC. Health-related quality of life items and treatment-related symptoms worsened similarly in both arms during neoadjuvant therapy, and recovered/stabilized in the adjuvant setting. Further exploration of immunotherapy PROs is warranted, as clinical benefit is seen with these agents and they do not appear to negatively impact functioning and patient experience with treatment long-term. Side effect profiles of immunotherapy and standard chemotherapy are different, and design of immunotherapy-specific PROs are desired.

The PRIME 2 10 year results evaluating the role of whole breast irradiation in women ≥65 years with early-stage HR-positive breast cancer receiving hormonal therapy showed RT reduced risk of local recurrence from 9.8% to 0.9% at 10 years (p=0.0008). Patients with low ER tumors had higher 10 year local recurrence rate compared to high ER tumors (18.8% versus 9.2% (p0.007)). Rates of overall survival (80.4% in no RT group vs 81.0% in RT group) and metastasis free survival were similar. A shared decision making approach is key, carefully weighing benefits and risks, considering pathologic features, patient preferences and co-morbidities that may influence endocrine therapy adherence. The impact of molecular subtypes and genomic assays is also being explored to help assess radiation benefit and guide treatment recommendations.

Breast cancer in young women presents unique challenges considering the lifetime period during which diagnosis occurs. Previous studies have supported the safety of pregnancy after breast cancer and guidelines recommend oncofertility counseling in young patients. Blondeaux et al found that breast cancer patients had a 60% lower chance of pregnancy after treatment and were more likely to have complications including low birth weight, small for gestational age, preterm delivery and cesarean section. Although increased risk of congenital abnormalities did not appear to be statistically significant, the HR was 1.63. Importantly, pregnancy after breast cancer did not negatively impact maternal outcomes. This study further supports the safety of pregnancy after breast cancer, highlights the need for close monitoring of pregnancies in these women, and emphasizes the importance of fertility and family planning discussion, which is most optimally provided in a multidisciplinary fashion.

References:

Dent R, Oliveira AM, Isakoff SJ, Im SA, Espié M, Blau S, Saura C, Wongchenko MJ, Xu N, Bradley D, Reilly SJ, Mani A, Kim SB. Final results of the double-blind placebo (PBO)-controlled randomised phase II LOTUS trial of first-line ipatasertib (IPAT) + paclitaxel (PAC) for inoperable locally advanced/metastatic triple-negative breast cancer (mTNBC). Presented during 2020 ESMO breast cancer virtual meeting; May 23-24, 2020. Abstract 139O.

Schmid P, Abraham J, Chan S, Wheatley D, Brunt AM, Nemsadze G, Baird RD, Park YH, Hall PS, Perren T, Stein RC, Mangel L, Ferrero JM, Phillips M, Conibear J, Cortes J, Foxley A, de Bruin EC, McEwen R, Stetson D, Dougherty B, Sarker SJ, Prendergast A, McLaughlin-Callan M, Burgess M, Lawrence C, Cartwright H, Mousa K, Turner NC. Capivasertib plus paclitaxel versus placebo plus paclitaxel as first-line therapy for metastatic triple-negative breast cancer: the PAKT trial. J Clin Oncol. 2020;38:423-433.

Mittendorf EA, Zhang H, Barrios CH, Saji S, Jung KH, Hegg R, Koehler A, Sohn J, Iwata H, Telli ML, Ferrario C, Punie K, Penault-Llorca F, Patel S, Duc AN, Liste-Hermoso M, Maiya V, Molinero L, Chui SY, Harbeck N. Neoadjuvant atezolizumab in combination with sequential nab-paclitaxel and anthracycline-based chemotherapy versus placebo and chemotherapy in patients with early-stage triple-negative breast cancer (IMpassion031): a randomised, double-blind, phase 3 trial. Lancet. 2020;396:1090-1100.

King-Kallimanis BL, Howie LJ, Roydhouse JK, Singh H, Theoret MR, Blumenthal GM, Kluetz PG. Patient reported outcomes in anti-PD-1/PD-L1 inhibitor immunotherapy registration trials: FDA analysis of data submitted and future directions. Clin Trials. 2019;16:322-326.

Fodor A, Brombin C, Mangili P, Borroni F, Pasetti M, Tummineri R, Zerbetto F, Longobardi B, Perna L, Dell'Oca I, Deantoni CL, Deli AM, Chiara A, Broggi S, Castriconi R, Esposito PG, Slim N, Passoni P, Baroni S, Villa SL, Rancoita PMV, Fiorino C, Del Vecchio A, Bianchini G, Gentilini OD, Di Serio MS, Di Muzio NG. Impact of molecular subtype on 1325 early-stage breast cancer patients homogeneously treated with hypofractionated radiotherapy without boost: Should the indications for radiotherapy be more personalized? Breast. 2020;55:45-54.

Azim HA Jr, Santoro L, Pavlidis N, Gelber S, Kroman N, Azim H, Peccatori FA. Safety of pregnancy following breast cancer diagnosis: a meta-analysis of 14 studies. Eur J Cancer. 2011;47:74-83.

Breast cancer patients treated with curative intent do not often experience symptoms related to the cancer itself, and treatment toxicities may impact adherence and subsequently prognosis. Mittendorf et al reported on patient reported outcomes (PROs) from the phase 3 IMpassion031 trial which showed pCR improvement with atezolizumab/chemotherapy compared to placebo/chemotherapy for neoadjuvant early-stage TNBC. Health-related quality of life items and treatment-related symptoms worsened similarly in both arms during neoadjuvant therapy, and recovered/stabilized in the adjuvant setting. Further exploration of immunotherapy PROs is warranted, as clinical benefit is seen with these agents and they do not appear to negatively impact functioning and patient experience with treatment long-term. Side effect profiles of immunotherapy and standard chemotherapy are different, and design of immunotherapy-specific PROs are desired.

The PRIME 2 10 year results evaluating the role of whole breast irradiation in women ≥65 years with early-stage HR-positive breast cancer receiving hormonal therapy showed RT reduced risk of local recurrence from 9.8% to 0.9% at 10 years (p=0.0008). Patients with low ER tumors had higher 10 year local recurrence rate compared to high ER tumors (18.8% versus 9.2% (p0.007)). Rates of overall survival (80.4% in no RT group vs 81.0% in RT group) and metastasis free survival were similar. A shared decision making approach is key, carefully weighing benefits and risks, considering pathologic features, patient preferences and co-morbidities that may influence endocrine therapy adherence. The impact of molecular subtypes and genomic assays is also being explored to help assess radiation benefit and guide treatment recommendations.

Breast cancer in young women presents unique challenges considering the lifetime period during which diagnosis occurs. Previous studies have supported the safety of pregnancy after breast cancer and guidelines recommend oncofertility counseling in young patients. Blondeaux et al found that breast cancer patients had a 60% lower chance of pregnancy after treatment and were more likely to have complications including low birth weight, small for gestational age, preterm delivery and cesarean section. Although increased risk of congenital abnormalities did not appear to be statistically significant, the HR was 1.63. Importantly, pregnancy after breast cancer did not negatively impact maternal outcomes. This study further supports the safety of pregnancy after breast cancer, highlights the need for close monitoring of pregnancies in these women, and emphasizes the importance of fertility and family planning discussion, which is most optimally provided in a multidisciplinary fashion.

References:

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