Alvarado, Michael

Neoadjuvant chemotherapy (NAC) increases rates of successful breast-conserving surgery (BCS) in patients with breast cancer. However, some studies suggest that BCS after NAC may confer an increased risk of locoregional recurrence (LRR). We assessed LRR rates and locoregional recurrence-free survival (LRFS) in patients enrolled on I-SPY2 (NCT01042379), a prospective NAC trial for patients with clinical stage II to III, molecularly high-risk breast cancer. Cox proportional hazards models were used to evaluate associations between surgical procedure (BCS vs mastectomy) and LRFS adjusted for age, tumor receptor subtype, clinical T category, clinical nodal status, and residual cancer burden (RCB). In 1462 patients, surgical procedure was not associated with LRR or LRFS on either univariate or multivariate analysis. The unadjusted incidence of LRR was 5.4% after BCS and 7.0% after mastectomy, at a median follow-up time of 3.5 years. The strongest predictor of LRR was RCB class, with each increasing RCB class having a significantly higher hazard ratio for LRR compared with RCB 0 on multivariate analysis. Triple-negative receptor subtype was also associated with an increased risk of LRR (hazard ratio: 2.91, 95% CI: 1.8–4.6, P < 0.0001), regardless of the type of operation. In this large multi-institutional prospective trial of patients completing NAC, we found no increased risk of LRR or differences in LRFS after BCS compared with mastectomy. Tumor receptor subtype and extent of residual disease after NAC were significantly associated with recurrence. These data demonstrate that BCS can be an excellent surgical option after NAC for appropriately selected patients.

Abstract Background: Treatment of estrogen receptor (ER)-positive breast cancer with selective estrogen receptor degraders (SERDs) frequently results in the loss or reduction of ER expression. Whether these changes are due to on-target effects of SERDs degrading ER or arise as a mechanism of tumor resistance with associated changes in cellular phenotypes remains unknown. It is critical to distinguish between these possibilities to accurately assess treatment response and determine the most appropriate subsequent therapy. To this end, we created and conducted molecular analyses on patient-derived organoid cultures from post-treatment tissue in patients receiving neoadjuvant SERD therapy for early-stage ER+ breast cancer in the I-SPY2 Endocrine Optimization Protocol (EOP). Methods: The I-SPY2 EOP study is a prospective, randomized substudy within the I-SPY TRIAL testing the oral SERD amcenestrant alone or in combination with letrozole or abemaciclib in stage 2/3 ER+ Her2-negative breast cancer. Enrollment is ongoing, with patients receiving amcenestrant neoadjuvantly for 6 months until the day before surgery. Tumor tissue is collected at baseline, 3 weeks, and at surgery. Organoids were generated from post-treatment surgical samples. Organoid cultures were optimized based on established methods (Dekkers et al., Nature Protocols, 2021) to assess ER levels and activity. Pre- and post-treatment tissue samples were also assessed for ER, PR, Ki67, and GATA3, a luminal marker and transcription factor that is functionally linked with ER, via immunohistochemistry. Results: In 7 patients with both pre- and post-treatment tissue samples including fresh surgical samples for organoid generation, the ER in baseline tumor tissue was &gt;=90% in all patients, PR ranged from 40-90%, and Ki67 ranged from 5-30%. In post-treatment surgical tissue from these cases, ER ranged from 0-30%, PR from 0-50%, Ki67 from &lt; 1%-10%, and GATA3 was positive in 5 of 5 cases tested to-date. The creation of organoids from residual disease at surgery was attempted for these 7 patients, with organoids successfully propagated in 5 cases thus far. 3 of 5 organoid cultures were ready for analysis and in all cases strong ER and PR expression in organoids was observed after culture for &gt; 1 month in the absence of amcenestrant. Detailed gene expression profiling (including Mammaprint/Blueprint) and gene set enrichment analyses (GSEA) to assess for intrinsic breast cancer subtype and ER activity in each sample and corresponding organoid culture are in progress and will be reported with the full dataset. Conclusion: Patient-derived organoid culturing of residual disease after neoadjuvant endocrine therapy is feasible. Neoadjuvant treatment with a SERD can render ER and PR low or absent at the time of surgical resection, which does not necessarily imply the presence of endocrine therapy resistant disease. The use of organoids and additional IHC markers (GATA3) demonstrate that receptor negativity may be an indicator of the drug hitting its target, suggesting ER signaling is still intact. In general, patient-derived tumor organoid cultures modeling residual disease states can be a useful adjunct to existing methods used to monitor the effects of neoadjuvant endocrine therapy and is being explored in the I-SPY EOP trial. Citation Format: Jennifer Rosenbluth, Christopher J. Schwartz, Tam Binh Bui, Shruti Warhadpande, Pravin Phadatare, Sigal Eini, Michael Bruck, Julissa Molina-Vega, Kami Pullakhandam, Nicole Schindler, Lamorna A. Brown Swigart, Christina Yau, Gillian Hirst, Rita Mukhtar, Karthik V. Giridhar, Olufunmilayo I. Olopade, Kevin Kalinsky, Cheryl A. Ewing, Jasmine M. Wong, Michael D. Alvarado, Laura Van’t Veer, Laura J. Esserman, Jo Chien. Characterization of residual disease after neoadjuvant selective estrogen receptor degrader (SERD) therapy using tumor organoids in the I-SPY Endocrine Optimization Protocol (EOP) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-09-01.

507 Background: The 21-gene Recurrence Score (OncotypeDX Breast Cancer Assay) predicts outcome and benefit from chemotherapy (CT) in early stage ER+ BC treated with adjuvant endocrine therapy. We evaluated the association between Recurrence Score (RS), time to progression (TTP), and overall survival (OS) in patients with stage IV BC enrolled in TBCRC 013. Methods: TBCRC 013 is a registry study evaluating surgery of the primary tumor in pts presenting with Stage IV BC. From 7/09 - 4/12, 128 evaluable pts were enrolled in two cohorts (A: metastases (mets) with intact primary tumor (n=112); B: mets within 3 months of primary surgery (n=16)). This study includes 110 pts with pre-treatment primary tumor samples available for analysis. Clinical variables, TTP and OS were correlated with RS using long-rank, Kaplan-Meier and Cox regression. Results: Median pt age was 52yrs (21-79) and median tumor size 3.1cm (0.7-15). 82 (80%) were ER+, 83 (81%) Her2(-) and 51 (46%) had bone-only mets. Cohorts A and B did not differ. At a median follow-up of 26 mos (1-47), median TTP is 19 mos (95%CI16-25) and surgery is not associated with OS. 102 samples qualified for RS. 23 (23%) had low RS<18, 29 (28%) intermediate RS, 18-30; and 50 (49%) high RS≥31. Age, tumor size or site of 1stmets was not associated with RS. Risk groups were prognostic for TTP in ER+ pts and for 2 yr OS in ER+Her2- pts (Table). In Cox models continuous RS was also prognostic for TTP in ER+ pts (HR 3.5; for 50 point difference (PD) 95%CI 1.5-8.1, p=0.003) and for OS in ER+Her2- pts (HR 21.4, for 50 PD 95%CI 2.2-204.4, p=0.008). In MVA, adjusting for clinical variables, RS remained prognostic for TTP in ER+ pts (p=0.01). Further analysis of surgery in this trial is ongoing. Conclusions: The 21-gene RS is independently prognostic for TTP in ER+ Stage IV BC. RS is also prognostic for OS in ER+Her2- BC, suggesting that a high RS may be a surrogate for endocrine resistance and could be used to select pts with ER+ Stage IV BC for CT. A randomized trial to address this hypothesis is warranted. Clinical trial information: NCT00941759. [Table: see text]

Abstract Background:Neoadjuvant chemotherapy (NCT) is used frequently to downstage locally advanced tumors and facilitate breast conservation. However, we have previously reported that achievement of radiographic complete response (rCR) or pathologic complete response (pCR) does not impact choice of surgery for many patients. This secondary analysis reports treatment outcomes across 9 NCI comprehensive cancer centers in women receiving both NCT and breast MR imaging to assess whether treatment outcomes among women receiving NCT differs according to choice of locoregional treatment. Methods:1077 women from 9 institutions were retrospectively identified as having undergone NCT with MR imaging obtained both before and after systemic treatment. Systemic treatment regimen was not prespecified, but receipt of at least 80% of all planned cycles was required prior to final MR imaging. We performed a univariate analysis as well as a multivariable Cox proportional hazard regression to identify covariates associated with overall survival (OS), disease-free survival (DFS) and time to recurrence (TTR). rCR was defined as no residual enhancement on post-treatment breast MRI. Results:1077 patients diagnosed and treated with NCT for stage I-III invasive breast cancer from January 1, 2002 to June 16, 2014 were analyzed for all endpoints. Median follow-up was 4.2 years, (range 0.1 to 13 years). Median age of the cohort was 50 years, (range 19-87 years). 473 (43.9%) had ER(+) and/or PR(+)/HER2(-) disease, 348 (32.3%) had HER2(+) disease, and 256 (23.8%) had ER(-)/PR(-)/HER2(-) (triple negative) disease. Mastectomy or breast conserving therapy (BCT) was recorded as the definitive surgery in 675 (62.7%) and 402 (37.3%) of patients, respectively. Radiation receipt was confirmed in 84.1% of BCT and 68.3% of mastectomy patients. Overall there were 134 recurrences, 168 disease events and 89 deaths. Among patients with pCR, there were 7/161 (7.2%) recurrences in those undergoing mastectomy and 6/143 (5.1%) in those undergoing lumpectomy (p=0.81). Among patients who achieved an rCR, there were recurrences in 5% of those undergoing mastectomy and 2.9% in those undergoing lumpectomy (p=0.53). In multivariable analysis of the entire cohort, only clinical stage, ER status and pCR remained independently associated with DFS. Notably, subset analysis showed that lumpectomy was independently associated with improved TTR (HR 0.40; 95% CI 0.17-0.97) in the triple negative group only, but this did not translate into improved DFS with lumpectomy in this group. Radiographic CR as determined by breast MRI accurately predicted presence or absence of pCR in 74% of cases, but was not independently associated with DFS, OS or TTP. Conclusions:Among a contemporary cohort of women receiving neoadjuvant systemic therapy and breast MR imaging at 9 NCI designated cancer centers, type of surgery did not impact DFS, OS or TTP. The only exception was found in the triple negative group in which the lumpectomy group had a more favorable TTP compared to the mastectomy group. These findings provide additional evidence that in women who are appropriate candidates for lumpectomy after NCT, BCT does not compromise long-term cancer outcomes. Citation Format: De Los Santos J, Hyslop T, Alvarado M, Forero A, Golshan M, Hieken T, Horton J, Hudis C, McGuire K, Meric-Bernstam F, Nanda R, Zagar T, Hwang S. Treatment outcomes in patients with invasive breast cancer treated with neoadjuvant systemic therapy and breast MR imaging: Results of a secondary analysis of TBCRC 017. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr S3-06.

Abstract Background: Retrospective studies suggest that primary breast surgery is associated with improved overall survival (OS) in Stage IV breast cancer. TBCRC 013 is a multi-center prospective registry study evaluating the role of surgery for the primary tumor in Stage IV disease. Methods: From 7/09 - 4/12, 128 eligible pts from 14 sites were enrolled in two cohorts (A: Stage IV with intact primary tumor (n = 112); B: metastases (mets) within 3 months of primary surgery (n = 16)). Baseline patient and tumor characteristics, and surgery of the primary were correlated with 2yr overall survival (OS) using log rank, Kaplan Meier and Cox regression for all patients. Comparisons were also made between cohorts A and B and within cohort A stratified by response to systemic therapy. Responders included those with any response (partial,complete) or stable disease at distant sites. Results: Median pt age was 52yrs(21-79) and median primary tumor size 3.2cm(0.7-15). Phenotypes were ER+ 106 (83%), HER2neg 91(71%), and triple neg 10(8%). 60(47%) had bone-only mets. The only significant baseline difference between cohorts A and B was the presence of palpable nodes (A:62% vs B:0%, p&lt;0.001). There were no differences in age, tumor size, ECOG scores, ER or HER2 status, number or sites of mets between cohorts A and B. At a median follow-up of 25 mo (95%CI, 23-31), 2yr OS for all pts is 86% (80-92) and is superior in cohort B as compared to A, (100% vs 84%, p = 0.03). On multivariate analysis (MVA) including all pts, only surgery, ER and HER2 positivity were associated with improved OS (table). Among 112 pts with an intact primary (Arm A), 17(15%) were non-responsive (NR) to systemic therapy, 3(18%) of whom required palliative surgery at a median time of 10.4mos. 2yr OS among NR was 33% (15-69) as compared to 94% (88-99) in Arm A responders (R) (p&lt;0.001). ER positivity was the only baseline difference between NR (65%) and R (88%) within Arm A (p = 0.02). Among 94(85%) Arm A responders, 39(41%) had elective surgery (median 8.4 mos, 95%CI:6.9-10.3) and only 1 of the remaining 47(2%) required palliation. When limited to Arm A responders, elective surgery was not associated with improved 2yr OS (surgery vs not: 94% vs 92%, p = 0.5). Median time to progression following elective surgery was 12 mos (95%CI,8-19mos). When cohort B (n = 16) and cohort A surgery groups (n = 39) are combined, surgery of the primary tumor is associated with improved 2yr OS (96% vs 74%, p = 0.002). Conclusions: In this prospective registry study, patients diagnosed with mets within 3 months of primary breast surgery have an improved 2yr OS. When all pts having surgery (A + B) are examined, surgery is associated with improved OS on MVA, but when limited to Arm A responders, elective surgery does not improve OS. Given that the number of Arm A responders is small, results from the prospective randomized trial will be needed to address this question. These data also demonstrate that the need for surgical palliation of the primary tumor is uncommon in the modern era. Multivariate Analysis for OSN = 128HR Death (95%CI)pvalueSurgery0.28 (0.10-0.74)0.01ER positivity0.28 (0.10-0.72)0.01HER2 positivity0.21 (0.06-0.74)0.01MVA included: age, tumor size, ECOG, ER, PR, HER2, met sites, and surgery Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-18-09.