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Tumor Biology and Response to Chemotherapy Impact Breast Cancer-specific Survival in Node-positive Breast Cancer Patients Treated With Neoadjuvant Chemotherapy: Long-term Follow-up From ACOSOG Z1071 (Alliance).

ABSTRACT: BACKGROUND:Women with node-positive breast cancer are at high risk for recurrence. We evaluate the impact of approximated tumor subtype and response to chemotherapy on long-term outcomes in a node-positive cohort receiving neoadjuvant chemotherapy. METHODS:ACOSOG Z1071 enrolled cT0-4N1-2 breast cancer patients treated with neoadjuvant chemotherapy from 2009 to 2011. Factors impacting breast cancer-specific survival (BCSS) and overall survival (OS) were analyzed. RESULTS:Median follow-up of 701 eligible patients was 4.1 years (0.4-6.5). Ninety patients (12.8%) died from breast cancer. Approximated subtype and chemotherapy response were significantly associated with BCSS and OS (P < 0.0001). BCSS and OS were highest in patients who achieved pathologic complete response (pCR) (P < 0.0001 and P < 0.0001, respectively).Five-year BCSS was highest in human epidermal growth factor receptor 2 (HER2)-positive disease [95.8%; 95% confidence interval (CI): 87.7-98.6], followed by hormone receptor-positive/HER2-negative (80.4%; 95% CI: 73.2-85.9) and lowest in triple-negative (TNBC) (74.8%; 95% CI: 66.6-81.2; P < 0.0001). Similar patterns were seen in OS.In TNBC (n = 174), 5-year BCSS was higher in patients with pCR versus residual disease (89.8%; 95% CI: 78.8-95.3 vs 65.8%; 95% CI: 54.5-74.9; P = 0.0013). In hormone receptor-positive/HER2-negative (n = 318) disease, BCSS was 100% in patients with pCR and 78.3% (95% CI: 70.4-84.3) in those with residual disease (P = 0.018). In HER2-positive disease (n = 204) there was no difference between pCR and residual disease (96.0%; 95% CI: 83.6-99.1 vs 95.8%; 95% CI: 81.4-99.1; P = 0.77). CONCLUSIONS:In node-positive breast cancer patients treated with neoadjuvant chemotherapy, BCSS and OS were associated with approximated subtype and chemotherapy response and were lowest in TNBC patients with residual disease. Five-year BCSS was > 95% in HER2-positive disease independent of chemotherapy response.

SUBMITTER: Boughey JC

PROVIDER: S-EPMC5755619 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Tumor Biology and Response to Chemotherapy Impact Breast Cancer-specific Survival in Node-positive Breast Cancer Patients Treated With Neoadjuvant Chemotherapy: Long-term Follow-up From ACOSOG Z1071 (Alliance).

Boughey Judy C JC Ballman Karla V KV McCall Linda M LM Mittendorf Elizabeth A EA Symmans William Fraser WF Julian Thomas B TB Byrd David D Hunt Kelly K KK

Annals of surgery 20171001 4

<h4>Background</h4>Women with node-positive breast cancer are at high risk for recurrence. We evaluate the impact of approximated tumor subtype and response to chemotherapy on long-term outcomes in a node-positive cohort receiving neoadjuvant chemotherapy.<h4>Methods</h4>ACOSOG Z1071 enrolled cT0-4N1-2 breast cancer patients treated with neoadjuvant chemotherapy from 2009 to 2011. Factors impacting breast cancer-specific survival (BCSS) and overall survival (OS) were analyzed.<h4>Results</h4>Med ...[more]

PMID: 28657941

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Project description:Sentinel lymph node (SLN) surgery provides reliable nodal staging information with less morbidity than axillary lymph node dissection (ALND) for patients with clinically node-negative (cN0) breast cancer. The application of SLN surgery for staging the axilla following chemotherapy for women who initially had node-positive cN1 breast cancer is unclear because of high false-negative results reported in previous studies.To determine the false-negative rate (FNR) for SLN surgery following chemotherapy in women initially presenting with biopsy-proven cN1 breast cancer.The American College of Surgeons Oncology Group (ACOSOG) Z1071 trial enrolled women from 136 institutions from July 2009 to June 2011 who had clinical T0 through T4, N1 through N2, M0 breast cancer and received neoadjuvant chemotherapy. Following chemotherapy, patients underwent both SLN surgery and ALND. Sentinel lymph node surgery using both blue dye (isosulfan blue or methylene blue) and a radiolabeled colloid mapping agent was encouraged.The primary end point was the FNR of SLN surgery after chemotherapy in women who presented with cN1 disease. We evaluated the likelihood that the FNR in patients with 2 or more SLNs examined was greater than 10%, the rate expected for women undergoing SLN surgery who present with cN0 disease.Seven hundred fifty-six women were enrolled in the study. Of 663 evaluable patients with cN1 disease, 649 underwent chemotherapy followed by both SLN surgery and ALND. An SLN could not be identified in 46 patients (7.1%). Only 1 SLN was excised in 78 patients (12.0%). Of the remaining 525 patients with 2 or more SLNs removed, no cancer was identified in the axillary lymph nodes of 215 patients, yielding a pathological complete nodal response of 41.0% (95% CI, 36.7%-45.3%). In 39 patients, cancer was not identified in the SLNs but was found in lymph nodes obtained with ALND, resulting in an FNR of 12.6% (90% Bayesian credible interval, 9.85%-16.05%).Among women with cN1 breast cancer receiving neoadjuvant chemotherapy who had 2 or more SLNs examined, the FNR was not found to be 10% or less. Given this FNR threshold, changes in approach and patient selection that result in greater sensitivity would be necessary to support the use of SLN surgery as an alternative to ALND.clinicaltrials.gov Identifier: NCT00881361.

Project description:PURPOSE:Use of adjuvant radiation therapy (RT) after neoadjuvant chemotherapy (NAC) in node-positive breast cancer (BC) is highly variable. In ACOSOG Z1071, RT after NAC was used at the discretion of treating physicians. Herein, we report the impact of RT and pathologic response on locoregional recurrence (LRR) after NAC. METHODS AND MATERIALS:ACOSOG Z1071 enrolled women with cT0-4N1-2 BC treated with NAC from 2009 to 2011. Patients underwent sentinel node surgery and completion axillary lymph node dissection. The RT was at the discretion of the treating physicians. Patient outcomes were analyzed as a function of clinical-pathologic factors and use of RT. RESULTS:Of 701 eligible patients, mastectomy was performed in 423 (59.6%) and breast-conserving surgery in 277 (40.4%). After NAC, residual disease was observed in 506 (72.2%), and 195 (27.8%) had a pathologic complete response. Of the patients, 591 (85.3%) received adjuvant RT and 102 (14.7%) did not. Median follow-up was 5.9 years. Forty-three patients (6.1%) experienced LRR, 145 (20.7%) experienced distant metastasis, and 142 (20.4%) died. Patients with pathologic complete response had the best LRR-relapse-free survival (hazard ratio [HR], 0.32; 95% confidence interval, 0.12-0.81; P = .016), distant metastasis-free survival (HR, 0.31; 95% CI, 0.19-0.52; P < .0001), BC-specific survival (HR, 0.34; 95% CI, 0.19-0.59; P = .0001) and overall survival (HR, 0.39; 95% CI, 0.240-0.63; P = .001) compared to patients with residual disease after NAC. Patients with triple-negative BC had a higher LRR rate compared to those with hormone receptor-positive BC (HR, 5.91; 95% CI, 2.80-12.49). There was a trend toward lower LRR with the use of postmastectomy and regional nodal RT, but there was no impact on overall, disease-free, or BC-specific survival. CONCLUSION:In the ACOSOG Z1071 trial, in which the use of RT after NAC was at the discretion of the treating physicians, RT was associated with a trend toward decreased LRR. There was no association of RT with overall survival, BC-specific survival, or Disease Specific Survival. Triple-negative BC was associated with higher locoregional relapse rates.

Project description:Background:HER2 (ERBB2) gene amplification and its corresponding overexpression are present in 15-30% of invasive breast cancers. While HER2-targeted agents are effective treatments, resistance remains a major cause of death. The American College of Surgeons Oncology Group Z1041 trial (NCT00513292) was designed to compare the pathologic complete response (pCR) rate of distinct regimens of neoadjuvant chemotherapy and trastuzumab, but ultimately identified no difference. Patients and methods:In supplement to tissues from 37 Z1041 cases, 11 similarly treated cases were obtained from a single institution study (NCT00353483). We have extracted genomic DNA from both pre-treatment tumor biopsies and blood of these 48 cases, and performed whole genome (WGS) and exome sequencing. Coincident with these efforts, we have generated RNA-seq profiles from 42 of the tumor biopsies. Among patients in this cohort, 24 (50%) achieved a pCR. Results:We have characterized the genomic landscape of HER2-positive breast cancer and investigated associations between genomic features and pCR. Cases assigned to the HER2-enriched subtype by RNA-seq analysis were more likely to achieve a pCR compared to the luminal, basal-like, or normal-like subtypes (19/27 versus 3/15; P?=?0.0032). Mutational events led to the generation of putatively active neoantigens, but were overall not associated with pCR. ERBB2 and GRB7 were the genes most commonly observed in fusion events, and genomic copy number analysis of the ERBB2 locus indicated that cases with either no observable or low-level ERBB2 amplification were less likely to achieve a pCR (7/8 versus 17/40; P?=?0.048). Moreover, among cases that achieved a pCR, tumors consistently expressed immune signatures that may contribute to therapeutic response. Conclusion:The identification of these features suggests that it may be possible to predict, at the time of diagnosis, those HER2-positive breast cancer patients who will not respond to treatment with chemotherapy and trastuzumab. ClinicalTrials.gov identifiers:NCT00513292, NCT00353483.

Project description:PurposeNeoadjuvant chemotherapy (NAC) is less effective for luminal breast cancer because luminal breast cancer has a lower rate of pathological complete response (pCR) after NAC than human epidermal growth factor receptor 2 (HER2)-type and triple-negative breast cancer (TNBC). We investigated the efficacy of NAC and the predictive factors of a better response in luminal breast cancer.MethodsBetween 2010 and 2016, we retrieved data of 244 patients with clinically node-positive breast cancer who were treated with NAC followed by surgery from a prospectively collected database. We classified breast cancer into luminal HER2- and non-luminal HER2- breast cancer (luminal HER2+, HER2+, and TNBC types). We analyzed each subtype with respect to surgical outcomes, response to NAC, and determined variables associated with surgical outcomes and response in patients with luminal HER2- breast cancer.ResultsThe total, breast, and axillary pCR rates were significantly lower in 114 patients with luminal HER2- breast cancer than in those with other subtypes (7.9%, 12.3%, and 22.8%, respectively). However, breast-conserving surgery (BCS) conversion and tumor response rates did not significantly differ between patients with luminal HER2- and those with non-luminal HER2- breast cancer (p = 0.836 and p = 0.180, respectively). In the multivariate analysis, high tumor response rate (? 46.4%) was significantly associated with an increased BCS conversion rate. In the subgroup analysis of luminal HER2- breast cancer, the multivariate analysis showed that higher Ki67 expression and axilla pCR and BCS conversion rates were significantly associated with tumor response to NAC.ConclusionDespite the low pCR rate, the tumor response and BCS conversion rates after NAC of luminal HER2- breast cancer were similar to those of other subtypes. NAC has the potential benefit of reducing the size of breast cancer, thereby increasing the BCS conversion rate in luminal HER2- breast cancer.

Project description:The purpose of this study was to evaluate breast MRI radiomics in predicting, prior to any treatment, the response to neoadjuvant chemotherapy (NAC) in patients with invasive lymph node (LN)-positive breast cancer for two tasks: (1) prediction of pathologic complete response and (2) prediction of post-NAC LN status. Our study included 158 patients, with 19 showing post-NAC complete pathologic response (pathologic TNM stage T0,N0,MX) and 139 showing incomplete response. Forty-two patients were post-NAC LN-negative, and 116 were post-NAC LN-positive. We further analyzed prediction of response by hormone receptor subtype of the primary cancer (77 hormone receptor-positive, 39 HER2-enriched, 38 triple negative, and 4 cancers with unknown receptor status). Only pre-NAC MRIs underwent computer analysis, initialized by an expert breast radiologist indicating index cancers and metastatic axillary sentinel LNs on DCE-MRI images. Forty-nine computer-extracted radiomics features were obtained, both for the primary cancers and for the metastatic sentinel LNs. Since the dataset contained MRIs acquired at 1.5 T and at 3.0 T, we eliminated features affected by magnet strength using the Mann-Whitney U-test with the null-hypothesis that 1.5 T and 3.0 T samples were selected from populations having the same distribution. Bootstrapping and ROC analysis were used to assess performance of individual features in the two classification tasks. Eighteen features appeared unaffected by magnet strength. Pre-NAC tumor features generally appeared uninformative in predicting response to therapy. In contrast, some pre-NAC LN features were able to predict response: two pre-NAC LN features were able to predict pathologic complete response (area under the ROC curve (AUC) up to 0.82 [0.70; 0.88]), and another two were able to predict post-NAC LN-status (AUC up to 0.72 [0.62; 0.77]), respectively. In the analysis by a hormone receptor subtype, several potentially useful features were identified for predicting response to therapy in the hormone receptor-positive and HER2-enriched cancers.

Dataset Information

Tumor Biology and Response to Chemotherapy Impact Breast Cancer-specific Survival in Node-positive Breast Cancer Patients Treated With Neoadjuvant Chemotherapy: Long-term Follow-up From ACOSOG Z1071 (Alliance).

Publications

Tumor Biology and Response to Chemotherapy Impact Breast Cancer-specific Survival in Node-positive Breast Cancer Patients Treated With Neoadjuvant Chemotherapy: Long-term Follow-up From ACOSOG Z1071 (Alliance).

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