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Parsing Pathologic Complete Response in Patients Receiving Neoadjuvant Chemotherapy for Breast Cancer

Parsing Pathologic Complete Response in Patients Receiving Neoadjuvant Chemotherapy for Breast... The association between pathologic complete response (pCR) to neoadjuvant chemotherapy for breast cancer and improved relapse-free survival (RFS) and overall survival (OS) outcomes has been documented in multiple clinical trials, single-institution retrospective studies, and a recent pooled analysis of clinical trials.1 This association is strongest when the definition of pCR includes eradication of invasive cancer in both the breast and axilla, and in patients with human epidermal growth factor receptor 2 (HER2)-overexpressing and triple-negative breast cancers.1 In this issue of JAMA Oncology, Mougalian and co-authors2 examine the relative impact of residual disease in the axillary lymph nodes compared to residual disease in the breast on 10-year RFS and OS outcomes in a heterogenous population of 1600 women with operable and locally advanced breast cancer treated with neoadjuvant chemotherapy at a single institution between 1989 and 2007. Pathologic complete response in both the breast and the axilla was seen in only 19% of patients, nearly identical to the 18% reported by Cortazar et al1 in the pooled analysis of clinical trials, in spite of the fact that almost 75% of patients in the study of Mougalian et al2 were treated with an anthracycline and a taxane. Additionally, pCR in the axilla was seen in a minority of women in the overall study population (28%), but a striking 67% of the 153 HER2-positive patients receiving HER2-directed therapy had an axillary pCR. Patients with pCR in both the breast and axilla had 10-year OS of 90% compared with 72% for those with axillary pCR and residual breast disease (P < .001), and 10-year OS for those with residual axillary disease and breast pCR was 66% compared with 56% for those with residual disease in both the breast and axilla (P = .02), indicating that any residual tumor, regardless of location, has a significant negative effect on prognosis. In multivariable models, residual disease in the axilla or the breast was a significant predictor of an increased risk of recurrence and death. The relatively low rates of pCR outside the HER2-overexpressing patients are disappointing, yet the opening sentence of the article states, “For patients with large operable and locally advanced breast cancer, primary systemic chemotherapy is currently the standard of care.”2 Is this really true for those with operable cancers? Neoadjuvant chemotherapy, compared with adjuvant chemotherapy, has not been shown to improve survival for any subgroup of patients.3 Outside the setting of clinical trials, the rationale for neoadjuvant chemotherapy in operable breast cancer is to allow breast-conserving surgery in women who desire the procedure but have unicentric cancers too large—relative to the size of the breast—to allow breast conservation with a good cosmetic outcome and, more recently, to avoid axillary dissection in women with nodal metastases. In the meta-analysis by Mieog et al3 of 5500 patients in 14 randomized trials, the mastectomy rate decreased by only 17% in patients receiving neoadjuvant therapy compared with those undergoing primary surgery; but many of these patients were candidates for breast conservation at study entry, leading to a potential underestimation of the benefit of neoadjuvant therapy in decreasing the mastectomy rate. This issue was addressed in a recent study of 696 patients with triple-negative and HER2-overexpressing breast cancers enrolled in 2 Cancer and Leukemia Group B trials of neoadjuvant therapy. At study entry, 340 patients (49%) were eligible for breast-conserving surgery, but after chemotherapy, only 296 had breast conservation, primarily due to patient preference for mastectomy.4 Thus, whereas neoadjuvant chemotherapy may allow the individual patient to downstage to breast conservation, it is not clear that its use has a major impact on mastectomy rates. Neoadjuvant therapy may also be used to decrease the extent of axillary surgery, and the study of Mougalian et al2 provides information on how likely this is to happen since axillary pCR is needed to avoid axillary dissection. The SENTINA5 and American College of Surgeons Oncology Group (ACOSOG) Z10716 trials suggest that in patients presenting with nodal metastases that resolve clinically after neoadjuvant chemotherapy, sentinel node biopsy accurately stages the axilla only when 3 or more sentinel nodes are identified and found to be free of metastases. Axillary pCR was seen in 28% of patients in this study overall, and in 32% of those receiving an anthracycline and a taxane, and not all patients have 3 identifiable sentinel nodes, indicating that axillary dissection will be avoided in a minority with the neoadjuvant approach. The exception is women with HER2-overexpressing cancers receiving HER2-directed therapy, in whom axillary pCR rates approached 70% and for whom the benefit of the neoadjuvant approach is clear. In patients with tumors small enough to undergo primary breast conservation who are clinically node negative, the low nodal pCR rate after neoadjuvant therapy results in an interesting clinical dilemma. Many advocate screening the clinically negative axilla with ultrasound, and biopsying any abnormal nodes. The presence of nodal metastases is then used as a rationale for neoadjuvant chemotherapy. The alternative is initial breast-conserving surgery without axillary imaging studies. Axillary dissection is performed only when 3 or more nodes contain metastases, an approach—demonstrated to be safe in the ACOSOG Z0011 trial—which has been shown to avoid axillary dissection in 85% of women.7 These findings suggest that neoadjuvant therapy does not always lead to a less morbid surgical approach than primary surgery in patients with operable cancer. The study by Mougalian et al2 provides further information that helps to tailor our approach to neoadjuvant therapy in operable breast cancer outside clinical trials. Patients with clinically node-positive (palpable) disease at presentation, those with larger tumors desiring breast conservation, and those with HER2-overexpressing tumors have a clear rationale for neoadjuvant therapy. For the remainder, it is an option, but it cannot be considered the standard of care. The as-yet unrealized role of neoadjuvant therapy may be to allow tailoring of the extent of both systemic and locoregional treatment based on the presence of pCR after neoadjuvant chemotherapy. Recognition of the poorer survival outcomes of those who do not achieve pCR with neoadjuvant therapy, particularly in the setting of triple-negative breast cancer, has led to a new generation of clinical trials examining the use of additional chemotherapy, immunotherapy, and anti-HER2 therapy in this setting. Conversely, the high rates of RFS in patients having pCR reported in the study of Mougalian et al2 support the premise being tested in the ongoing NRG 9353 trial that patients presenting with nodal metastases who have a nodal pCR after neoadjuvant therapy may not require nodal field irradiation or postmastectomy chest wall irradiation. Positive results in any of these studies would provide compelling evidence that neoadjuvant therapy allows more precise tailoring of treatment and should be the standard of care for operable breast cancer. Back to top Article Information Published Online: December 30, 2015. doi:10.1001/jamaoncol.2015.4919. Conflict of Interest Disclosures: None reported. Corresponding Author: Monica Morrow, MD, Breast Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, 300 E 66th St, New York, NY 10065 (morrowm@mskcc.org). References 1. Cortazar P, Zhang L, Untch M, et al. Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet. 2014;384(9938):164-172.PubMedGoogle ScholarCrossref 2. Mougalian SS, Hernandez M, Lei X, et al. Ten-year outcomes of patients with breast cancer with cytologically confirmed axillary lymph node metastases and pathologic complete response after primary systemic chemotherapy [published online December 30, 2015]. JAMA Oncol. doi:10.1001/jamaoncol.2015.4935.Google Scholar 3. Mieog JS, van der Hage JA, van de Velde CJ. Neoadjuvant chemotherapy for operable breast cancer. Br J Surg. 2007;94(10):1189-1200.PubMedGoogle ScholarCrossref 4. Golshan M, Cirrincione CT, Carey LA, et al. Impact of neoadjuvant therapy on breast conservation rates in triple-negative and HER2-positive breast cancer: combined results of CALGB 40603 and 40601 (Alliance). J Clin Oncol.2015;33(suppl):abstr 1007.Google Scholar 5. Kuehn T, Bauerfeind I, Fehm T, et al. Sentinel-lymph-node biopsy in patients with breast cancer before and after neoadjuvant chemotherapy (SENTINA): a prospective, multicentre cohort study. Lancet Oncol. 2013;14(7):609-618.PubMedGoogle ScholarCrossref 6. Boughey JC, Suman VJ, Mittendorf EA, et al; Alliance for Clinical Trials in Oncology. Sentinel lymph node surgery after neoadjuvant chemotherapy in patients with node-positive breast cancer: the ACOSOG Z1071 (Alliance) clinical trial. JAMA. 2013;310(14):1455-1461.PubMedGoogle ScholarCrossref 7. Dengel LT, Van Zee KJ, King TA, et al. Axillary dissection can be avoided in the majority of clinically node-negative patients undergoing breast-conserving therapy. Ann Surg Oncol. 2014;21(1):22-27.PubMedGoogle ScholarCrossref http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png JAMA Oncology American Medical Association

Parsing Pathologic Complete Response in Patients Receiving Neoadjuvant Chemotherapy for Breast Cancer

JAMA Oncology , Volume 2 (4) – Apr 1, 2016

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References (7)

Publisher
American Medical Association
Copyright
Copyright © 2016 American Medical Association. All Rights Reserved.
ISSN
2374-2437
eISSN
2374-2445
DOI
10.1001/jamaoncol.2015.4919
Publisher site
See Article on Publisher Site

Abstract

The association between pathologic complete response (pCR) to neoadjuvant chemotherapy for breast cancer and improved relapse-free survival (RFS) and overall survival (OS) outcomes has been documented in multiple clinical trials, single-institution retrospective studies, and a recent pooled analysis of clinical trials.1 This association is strongest when the definition of pCR includes eradication of invasive cancer in both the breast and axilla, and in patients with human epidermal growth factor receptor 2 (HER2)-overexpressing and triple-negative breast cancers.1 In this issue of JAMA Oncology, Mougalian and co-authors2 examine the relative impact of residual disease in the axillary lymph nodes compared to residual disease in the breast on 10-year RFS and OS outcomes in a heterogenous population of 1600 women with operable and locally advanced breast cancer treated with neoadjuvant chemotherapy at a single institution between 1989 and 2007. Pathologic complete response in both the breast and the axilla was seen in only 19% of patients, nearly identical to the 18% reported by Cortazar et al1 in the pooled analysis of clinical trials, in spite of the fact that almost 75% of patients in the study of Mougalian et al2 were treated with an anthracycline and a taxane. Additionally, pCR in the axilla was seen in a minority of women in the overall study population (28%), but a striking 67% of the 153 HER2-positive patients receiving HER2-directed therapy had an axillary pCR. Patients with pCR in both the breast and axilla had 10-year OS of 90% compared with 72% for those with axillary pCR and residual breast disease (P < .001), and 10-year OS for those with residual axillary disease and breast pCR was 66% compared with 56% for those with residual disease in both the breast and axilla (P = .02), indicating that any residual tumor, regardless of location, has a significant negative effect on prognosis. In multivariable models, residual disease in the axilla or the breast was a significant predictor of an increased risk of recurrence and death. The relatively low rates of pCR outside the HER2-overexpressing patients are disappointing, yet the opening sentence of the article states, “For patients with large operable and locally advanced breast cancer, primary systemic chemotherapy is currently the standard of care.”2 Is this really true for those with operable cancers? Neoadjuvant chemotherapy, compared with adjuvant chemotherapy, has not been shown to improve survival for any subgroup of patients.3 Outside the setting of clinical trials, the rationale for neoadjuvant chemotherapy in operable breast cancer is to allow breast-conserving surgery in women who desire the procedure but have unicentric cancers too large—relative to the size of the breast—to allow breast conservation with a good cosmetic outcome and, more recently, to avoid axillary dissection in women with nodal metastases. In the meta-analysis by Mieog et al3 of 5500 patients in 14 randomized trials, the mastectomy rate decreased by only 17% in patients receiving neoadjuvant therapy compared with those undergoing primary surgery; but many of these patients were candidates for breast conservation at study entry, leading to a potential underestimation of the benefit of neoadjuvant therapy in decreasing the mastectomy rate. This issue was addressed in a recent study of 696 patients with triple-negative and HER2-overexpressing breast cancers enrolled in 2 Cancer and Leukemia Group B trials of neoadjuvant therapy. At study entry, 340 patients (49%) were eligible for breast-conserving surgery, but after chemotherapy, only 296 had breast conservation, primarily due to patient preference for mastectomy.4 Thus, whereas neoadjuvant chemotherapy may allow the individual patient to downstage to breast conservation, it is not clear that its use has a major impact on mastectomy rates. Neoadjuvant therapy may also be used to decrease the extent of axillary surgery, and the study of Mougalian et al2 provides information on how likely this is to happen since axillary pCR is needed to avoid axillary dissection. The SENTINA5 and American College of Surgeons Oncology Group (ACOSOG) Z10716 trials suggest that in patients presenting with nodal metastases that resolve clinically after neoadjuvant chemotherapy, sentinel node biopsy accurately stages the axilla only when 3 or more sentinel nodes are identified and found to be free of metastases. Axillary pCR was seen in 28% of patients in this study overall, and in 32% of those receiving an anthracycline and a taxane, and not all patients have 3 identifiable sentinel nodes, indicating that axillary dissection will be avoided in a minority with the neoadjuvant approach. The exception is women with HER2-overexpressing cancers receiving HER2-directed therapy, in whom axillary pCR rates approached 70% and for whom the benefit of the neoadjuvant approach is clear. In patients with tumors small enough to undergo primary breast conservation who are clinically node negative, the low nodal pCR rate after neoadjuvant therapy results in an interesting clinical dilemma. Many advocate screening the clinically negative axilla with ultrasound, and biopsying any abnormal nodes. The presence of nodal metastases is then used as a rationale for neoadjuvant chemotherapy. The alternative is initial breast-conserving surgery without axillary imaging studies. Axillary dissection is performed only when 3 or more nodes contain metastases, an approach—demonstrated to be safe in the ACOSOG Z0011 trial—which has been shown to avoid axillary dissection in 85% of women.7 These findings suggest that neoadjuvant therapy does not always lead to a less morbid surgical approach than primary surgery in patients with operable cancer. The study by Mougalian et al2 provides further information that helps to tailor our approach to neoadjuvant therapy in operable breast cancer outside clinical trials. Patients with clinically node-positive (palpable) disease at presentation, those with larger tumors desiring breast conservation, and those with HER2-overexpressing tumors have a clear rationale for neoadjuvant therapy. For the remainder, it is an option, but it cannot be considered the standard of care. The as-yet unrealized role of neoadjuvant therapy may be to allow tailoring of the extent of both systemic and locoregional treatment based on the presence of pCR after neoadjuvant chemotherapy. Recognition of the poorer survival outcomes of those who do not achieve pCR with neoadjuvant therapy, particularly in the setting of triple-negative breast cancer, has led to a new generation of clinical trials examining the use of additional chemotherapy, immunotherapy, and anti-HER2 therapy in this setting. Conversely, the high rates of RFS in patients having pCR reported in the study of Mougalian et al2 support the premise being tested in the ongoing NRG 9353 trial that patients presenting with nodal metastases who have a nodal pCR after neoadjuvant therapy may not require nodal field irradiation or postmastectomy chest wall irradiation. Positive results in any of these studies would provide compelling evidence that neoadjuvant therapy allows more precise tailoring of treatment and should be the standard of care for operable breast cancer. Back to top Article Information Published Online: December 30, 2015. doi:10.1001/jamaoncol.2015.4919. Conflict of Interest Disclosures: None reported. Corresponding Author: Monica Morrow, MD, Breast Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, 300 E 66th St, New York, NY 10065 (morrowm@mskcc.org). References 1. Cortazar P, Zhang L, Untch M, et al. Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet. 2014;384(9938):164-172.PubMedGoogle ScholarCrossref 2. Mougalian SS, Hernandez M, Lei X, et al. Ten-year outcomes of patients with breast cancer with cytologically confirmed axillary lymph node metastases and pathologic complete response after primary systemic chemotherapy [published online December 30, 2015]. JAMA Oncol. doi:10.1001/jamaoncol.2015.4935.Google Scholar 3. Mieog JS, van der Hage JA, van de Velde CJ. Neoadjuvant chemotherapy for operable breast cancer. Br J Surg. 2007;94(10):1189-1200.PubMedGoogle ScholarCrossref 4. Golshan M, Cirrincione CT, Carey LA, et al. Impact of neoadjuvant therapy on breast conservation rates in triple-negative and HER2-positive breast cancer: combined results of CALGB 40603 and 40601 (Alliance). J Clin Oncol.2015;33(suppl):abstr 1007.Google Scholar 5. Kuehn T, Bauerfeind I, Fehm T, et al. Sentinel-lymph-node biopsy in patients with breast cancer before and after neoadjuvant chemotherapy (SENTINA): a prospective, multicentre cohort study. Lancet Oncol. 2013;14(7):609-618.PubMedGoogle ScholarCrossref 6. Boughey JC, Suman VJ, Mittendorf EA, et al; Alliance for Clinical Trials in Oncology. Sentinel lymph node surgery after neoadjuvant chemotherapy in patients with node-positive breast cancer: the ACOSOG Z1071 (Alliance) clinical trial. JAMA. 2013;310(14):1455-1461.PubMedGoogle ScholarCrossref 7. Dengel LT, Van Zee KJ, King TA, et al. Axillary dissection can be avoided in the majority of clinically node-negative patients undergoing breast-conserving therapy. Ann Surg Oncol. 2014;21(1):22-27.PubMedGoogle ScholarCrossref

Journal

JAMA OncologyAmerican Medical Association

Published: Apr 1, 2016

Keywords: survival analysis,breast neoplasms,disease-free survival,neoplasm recurrence, local,sentinel lymph node biopsy,mastectomy,breast cancer,metastasis, axillary,lymph node metastasis,breast conserving surgery,cancer research,invasive breast cancer,axillary lymph node dissection,complete remission,triple-negative breast cancer,breast cancer prognostic factor,chemotherapy, neoadjuvant,her-2 positive breast cancer,relapse stage

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