Jaskowiak, Nora

ImportancePathologic complete response (pCR) after neoadjuvant chemotherapy (NAC) in breast cancer strongly correlates with overall survival and has become the standard end point in neoadjuvant trials. However, there is controversy regarding whether the definition of pCR should exclude or permit the presence of residual ductal carcinoma in situ (DCIS).ObjectiveTo examine the association of residual DCIS in surgical specimens after neoadjuvant chemotherapy for breast cancer with survival end points to inform standards for the assessment of pathologic complete response.Design, Setting, and ParticipantsThe study team analyzed the association of residual DCIS after NAC with 3-year event-free survival (EFS), distant recurrence-free survival (DRFS), and local-regional recurrence (LRR) in the I-SPY2 trial, an adaptive neoadjuvant platform trial for patients with breast cancer at high risk of recurrence. This is a retrospective analysis of clinical specimens and data from the ongoing I-SPY2 adaptive platform trial of novel therapeutics on a background of standard of care for early breast cancer. I-SPY2 participants are adult women diagnosed with stage II/III breast cancer at high risk of recurrence.InterventionsParticipants were randomized to receive taxane and anthracycline-based neoadjuvant therapy with or without 1 of 10 investigational agents, followed by definitive surgery.Main Outcomes and MeasuresThe presence of DCIS and EFS, DRFS, and LRR.ResultsThe study team identified 933 I-SPY2 participants (aged 24 to 77 years) with complete pathology and follow-up data. Median follow-up time was 3.9 years; 337 participants (36%) had no residual invasive disease (residual cancer burden 0, or pCR). Of the 337 participants with pCR, 70 (21%) had residual DCIS, which varied significantly by tumor-receptor subtype; residual DCIS was present in 8.5% of triple negative tumors, 15.6% of hormone-receptor positive tumors, and 36.6% of ERBB2-positive tumors. Among those participants with pCR, there was no significant difference in EFS, DRFS, or LRR based on presence or absence of residual DCIS.Conclusions and RelevanceThe analysis supports the definition of pCR as the absence of invasive disease after NAC regardless of the presence or absence of DCIS.Trial RegistrationClinicalTrials.gov Identifier NCT01042379.

Abstract Background: Patients who achieve a pathological complete response (pCR- defined as no invasive cancer) after neoadjuvant chemotherapy (NAC) for breast cancer (BC) have improved outcomes, but there is still controversy about the significance of residual ductal carcinoma in situ (DCIS) on local recurrence rate (LRR). The I-SPY 2 TRIAL is an adaptive neoadjuvant platform trial evaluating novel experimental regimens in comparison to standard chemotherapy in women with high-risk breast cancer. The purpose of this study is to determine if residual DCIS after NAC in early BC affects LRR in patients with or without residual invasive disease in the I-SPY 2 TRIAL. Methods: 933 I-SPY 2 patients with residual cancer burden (RCB) and follow-up data were included in this analysis. Residual DCIS was defined as any carcinoma in situ > 0% on RCB evaluation. Local recurrence was defined as recurrence in breast, chest wall or locoregional nodes and/or skin and subcutaneous tissue. We stratified our cohort into four groups: those without residual invasive disease (defined as RCB0) ± residual DCIS, and those with residual invasive disease (RCB>0) ± residual DCIS. We estimated LRR within each group using the Kaplan Meier method; and used Cox proportional hazards models to assess LRR differences between groups, with: patients with no residual disease (invasive or in situ) as reference group. Results: Among 933 patients assessed, median follow up time was 3.9 years. RCB 0 status was achieved in 337 patients (36%). Of these, 267 (29%) had no residual DCIS, which represents our reference group, and 70 (7%) had residual DCIS. Among 596 (64%) patients who had RCB>0, 296 (32%) had residual DCIS. For patients with RCB0 without DCIS and RCB0 with DCIS, the LRR at 3 years were similar: 2% vs 3% respectively (Hazard ratio: 1.29 [0.26-6.39]). Results were also similar in the RCB>0 group, with a LRR of 10% at 3 years in those without residual DCIS, and 11% in those with residual DCIS. Both RCB>0 groups had significantly higher LRR when compared to the patients with RCB0 without DCIS (Hazard ratio: 5.25 [2.20-12.5]) and HR 5.85 [2.47-13.9] respectively). Conclusion: There was no association between residual DCIS and LRR after neoadjuvant chemotherapy, regardless of resolution of invasive disease. Further work is needed to determine whether residual DCIS should drive locoregional therapy decisions after neoadjuvant chemotherapy for invasive breast cancer. Citation Format: Marie Osdoit, Christina Yau, W. Fraser Symmans, Judy C. Boughey, Smita M. Asare, Ron Balassanian, Jodi M. Carter, Yunn-Yi Chen, Kimberly Cole, Laila Khazai, Molly Klein, Dina Kokh, Gregor Krings, Sunati Sahoo, Gretchen Ahrendt, Akiko Chiba, Cheryl Ewing, Constantine Godellas, Nora Jaskowiak, Brigid Killelea, Helen Krontiras, Rachael Lancaster, Julie Lang, M. Catherine Lee, Arpana Naik, Roshni Rao, Julia Tchou, Shannon Tierney, Eleni Tousimis, Tod Tuttle, Anne Wallace, I-SPY 2 TRIAL Consortium, Bev Parker, Laura J. Esserman, Rita A. Mukhtar. The impact of residual ductal carcinoma in situ on breast cancer recurrence in the neoadjuvant I-SPY2 TRIAL [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-08-16.

PURPOSEThe phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin is a key pathway of survival and therapeutic resistance in breast cancer. We evaluated the pan-Akt inhibitor MK-2206 in combination with standard therapy in patients with high-risk early-stage breast cancer.PATIENTS AND METHODSI-SPY 2 is a multicenter, phase II, open-label, adaptively randomized neoadjuvant platform trial that screens experimental therapies and efficiently identifies potential predictive biomarker signatures. Patients are categorized by human epidermal growth factor receptor 2 (HER2), hormone receptor (HR), and MammaPrint statuses in a 2 × 2 × 2 layout. Patients within each of these 8 biomarker subtypes are adaptively randomly assigned to one of several experimental therapies, including MK-2206, or control. Therapies are evaluated for 10 biomarker signatures, each of which is a combination of these subtypes. The primary end point is pathologic complete response (pCR). A therapy graduates with one or more of these signatures if and when it has an 85% Bayesian predictive probability of success in a hypothetical phase III trial, adjusting for biomarker covariates. Patients in the current report received standard taxane- and anthracycline-based neoadjuvant therapy without (control) or with oral MK-2206 135 mg/week.RESULTSMK-2206 graduated with 94 patients and 57 concurrently randomly assigned controls in 3 graduation signatures: HR-negative/HER2-positive, HR-negative, and HER2-positive. Respective Bayesian mean covariate-adjusted pCR rates and percentage probability that MK-2206 is superior to control were 0.48:0.29 (97%), 0.62:0.36 (99%), and 0.46:0.26 (94%). In exploratory analyses, MK-2206 evinced a numerical improvement in event-free survival in its graduating signatures. The most significant grade 3-4 toxicity was rash (14% maculopapular, 8.6% acneiform).CONCLUSIONThe Akt inhibitor MK-2206 combined with standard neoadjuvant therapy resulted in higher estimated pCR rates in HR-negative and HER2-positive breast cancer. Although MK-2206 is not being further developed at this time, this class of agents remains of clinical interest.

Abstract Background: I-SPY2 is a multicenter, Phase II trial using response-adaptive randomization within biomarker subtypes to evaluate novel agents as neoadjuvant therapy for high-risk at least T2N0 breast cancer. The primary endpoint is pathologic complete response (pCR) at surgery. The goal is to identify regimens that have ≥ 85% Bayesian predictive probability of success in a 300-patient phase 3 neoadjuvant trial defined by hormone-receptor (HR) and HER2 status, and MammaPrint (MP). Regimens may leave the trial for futility (< 10% probability of success), maximum sample size accrual (with probability of success ≥ 10% and < 85%), or as recommended by the independent DSMB. For HER2- subjects the control arm is weekly paclitaxel x12 then doxorubicin & cyclophosphamide (AC) q2-3 weeks x4. For this arm, paclitaxel was omitted and replaced with maximum tolerated dose PARPi talazoparib with synergy dosed irinotecan (25mg/m2). Paclitaxel could be given adjuvantly for these subjects and non-responding subjects could be taken off of experimental therapy. Methods: Women with tumors ≥ 2.5cm were eligible for screening. MP low/HR+ tumors were ineligible. MRI scans (baseline, 3 cycles after start of therapy, prior to AC, and prior to surgery) were used in a longitudinal statistical model to predict pCR for individual patients. Talazoparib was given at 1mg daily with 25mg/m2 irinotecan q2wks. Analysis was intention to treat. Subjects who switched to non-protocol therapy count as non-pCR. Subjects on experimental therapy at time of arm closure are non-evaluable. Talazoparib/irinotecan (TI) was open only to HER2- tumors and eligible for graduation in 3 of 10 pre-defined signatures: HER2-, HR+HER2- and HR-/HER2-. Results: TI did not meet criteria for graduation and was stopped at the recommendation of the DSMB based on expectations of limited activity beyond that seen with standard treatment. Maximum sample size had been reached at the time of this recommendation and subjects currently receiving TI were allowed to continue or change to standard therapy. Exploratory “as treated” analysis for response in gBRCA mutation carriers showed 6/10 gBRCA carriers attained a pCR in the TI arm. Except for 1 patient these gBRCA pCR subjects had >90% tumor reduction by MRI after TI and prior to AC (range: 68-96%). In the TI arm pCR rates were also higher in subjects with a PARPi7-High/MP2 gene expression signature (0.344 vs 0.146). Expected differences in toxicity were seen between arms including g3/4 peripheral neuropathy on control therapy which included paclitaxel (2.6% vs none) and g3/4 neutropenia with TI (30.2% vs 8.2%). Notably gBRCA mutation carriers receiving TI had higher rates of g3/4 neutropenia (60% vs 25.9%). Conclusion: The I-SPY2 study finds the probability that investigational regimens will be successful in a Phase III neoadjuvant trial; TI did not reach the efficacy threshold of 85% probability of success in Phase III in any of the 3 signatures. However by adding talazoparib with synergy dosed irinotecan we were able to omit paclitaxel and observe similar estimated pCR rates. This informs current work to evolve the I-SPY2 trial design to reduce toxicity without compromising outcomes and develop successful combinations targeted to biology, including DNA repair deficiency. Citation Format: Richard Schwab, Amy S. Clark, Christina Yau, Nola Hylton, Wen Li, Denise Wolfe, A Jo Chien, Anne M. Wallace, Andres Forero-Torres, Erica Stringer-Reasor, Rita Nanda, Nora Jaskowiak, Judy Boughey, Tufia Haddad, Heather S. Han, Catherine Lee, Kathy Albain, Claudine Isaacs, Anthony D. Elias, Erin D. Ellis, Payal Shah, Julie E. Lang, Janice Lu, Debasish Tripathy, Kathleen Kemmer, Douglas Yee, Barbara Haley, Melanie Majure, Erin Roesch, Christos Vaklavas, Cheryl Ewing, Teresa Helsten, W Fraser Symmans, Jane Perlmutter, Hope S. Rugo, Michelle Melisko, Amy Wilson, Ruby Singhrao, Laura van 't Veer, Angela DeMichele, Smita Asare, Don Berry, Laura J. Esserman. Evaluation of talazoparib in combination with irinotecan in early stage, high-risk HER2 negative breast cancer: Results from the I-SPY 2 TRIAL [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT136.