Citations

Abstract Background: In an adaptive randomized trial, when new treatment combinations are being tested, it is important to be able to identify patients who are progressing on treatment so that they can be changed to a different therapeutic regimen. We know that even within the molecularly high risk patients in I-SPY 2, there is considerable variation in biology. In this study, we will present results of using MRI-calculated functional tumor volume (FTV) to identify tumor progression for each breast cancer subtype. Methods: Patients (n=990) enrolled in the I-SPY 2 TRIAL who were randomized to the graduated experimental drug arms or controls from 2010 to 2016 were analyzed. Four MRI exams were performed for each patient: pre-NAC (T0), after 3 weeks of NAC (T1), between regimens (T2), and post-NAC (T3). Functional tumor volume (FTV) was calculated at each exam by summing voxels meeting enhancement thresholds. Tumor progression at T1, T2 or T3 was identified by a positive FTV change relative to T0. Visual inspection was used to exclude false progression due to strong background parenchymal enhancement post-contrast, prominent vessels, motion, or insufficient image quality. pCR was defined as no invasive disease in the breast and lymph nodes. Negative predictive value for pCR was defined as:NPV=number of true non-pCRs / number of patients with MRI assessed tumor progressions, where “true non-pCRs” referred to patients who were non-pCRs at surgery and were assessed as progressors by MRI. The analysis was performed in the full cohort and in sub-cohorts defined by HR and HER2 statuses. Results: Out of 990 patients, 878 had pCR outcome data (pCR or non-pCR, pCR rate = 35%). Total and non-pCR numbers for each subtype, number of patients with tumor progression assessed by MRI at T1, T2, and T3, and NPVs, are shown in Table 1. In the full cohort, the NPV increased consistently over treatment, from T1 (NPV=83%) to T2 (93%), and to T3 (100%). The HER2+ cancer subtypes showed fewer MRI-assessed tumor progressions than HER2- subtypes: e.g. 10/209 (5%) vs. 108/669 (16%) at T1. NPV was 100% for HER2+ subtypes at T1 and T2 except for a single misclassification of a HR- tumor at T1. Only 6 tumor progressors, all HER2- were identified at T3, and all were confirmed at surgery as non-pCRs (NPV=100%). For HR+/HER2-, the NPV increased slightly from 89% at T1 to 91% at T2, while triple negative subtype had a more substantial increase, from 78% to 92%. Conclusions: Our study showed strong association between tumor progressors assessed by MRI with true non-pCRs after NAC. For HER2+ tumors, although MRI progressors are rare, they strongly indicate non-pCR at all treatment time points, while HER2- subtypes show more accurate results later in treatment. We are evaluating MRI change at 6 weeks to determine if that time point is sufficient to predict progressors. Table 1 MRI assessed tumor progression at different treatment time pointN/non-pCRs/%non-pCRMRI assessed tumor progressionT1 (after 3 weeks)T2 (inter-regimen)T3 (post-NAC)NNPV (%)NNPV (%)NNPV (%)Full cohort878/572/65%11883.14192.76100%HR+/HER2-344/280/81%4588.91190.93100%HR+/HER2+134/85/63%610021000N/AHR-/HER2+75/23/31%47521000N/Atriple negative325/184/57%6377.82692.33100% Citation Format: Wen Li, Natsuko Onishi, David C Newitt, Jessica Gibbs, Lisa J Wilmes, Ella F Jones, Bonnie N Joe, Laura S Sit, Christina Yau, A. Jo Chien, Elissa Price, Kathy S Albain, Theresa Kuritza, Kevin Morley, Judy C Boughey, Kathy Brandt, Sadia Choudhery, Amy S Clark, Mark Rosen, Elizabeth S McDonald, Anthony D Elias, Dulcy Wolverton, Kelly Fountain, David M Euhus, Heather S Han, Bethany Niell, Jennifer Drukteinis, Julie E Lang, Janice Lu, Jane L Meisel, Zaha Mitri, Rita Nanda, Donald W Northfelt, Tara Sanft, Erica Stringer-Reasor, Rebecca K Viscusi, Anne M Wallace, Douglas Yee, Rachel Yung, Smita M Asare, Michelle E Melisko, Jane Perlmutter, Hope S Rugo, Richard Schwab, W. Fraser Symmans, Laura J van't Veer, Donald A Berry, Angela DeMichele, Hiroyuki Abe, Deepa Sheth, Kirsten K Edmiston, Erin D Ellis, Richard Ha, Ralph Wynn, Erin P Crane, Charlotte Dillis, Michael Nelson, An Church, Claudine Isaacs, Qamar J Khan, Karen Y Oh, Neda Jafarian, Dae Hee Bang, Christiane Mullins, Stefanie Woodard, Kathryn W Zamora, Haydee Ojeda-Fornier, Pulin Sheth, Linda Hovanessian-Larsen, Mohammad Eghtedari, Michael Spektor, Marina Giurescu, Mary S Newell, Michael A Cohen, Elise Berman, Constance Lehman, William Smith, Kim Fitzpatrick, Marisa H Borders, Wei Yang, Basak Dogan, Sally Goudreau, Thelma Brown, Laura J Esserman, Nola M Hylton. Breast cancer subtype specific association of pCR with MRI assessed tumor volume progression during NAC in the I-SPY 2 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 PD9-04.

Abstract Introduction: Although HER2+ breast cancer (BC) is considered a moderately immunogenic tumor, several studies have shown a role of pre-existing immunity associated with favorable long-term prognosis and better response to treatment. In this study, we performed exploratory analyses to assess whether the efficacy of HER2 targeted treatment in the MARIANNE trial correlated with immune gene expression. Methods: MARIANNE (NCT01120184) is a phase 3 study in patients (pts) with centrally confirmed HER2+ local advanced/metastatic BC naïve to prior treatments in the advanced disease. Pts were randomized (1:1:1) to trastuzumab+taxane (HT), T-DM1, or T-DM1+Petuzumab (P) and the trial showed noninferior PFS of T-DM1 and T-DM1+P vs HT. Gene expression (RNA) analysis was performed on tumor samples by a custom 800-gene codeset on the nCounter platform. PD-L1, CD8 expressions and immune gene signatures (sign) analyses were assessed by multivariate Cox regression models using median (cut-off) as categorical variable and adjusted by prior HT, presence of visceral disease, world region, baseline ECOG, measureable disease at baseline, therapy setting, HER2 mRNA expression, PIK3CA mutation status. Results: MARIANNE randomized 1095 pts (HT, n=365; T-DM1, n=367; T-DM1+P, n=363). Gene expression results were available for 671 pts (61.3% of the intent-to-treat [ITT] population) which was representative of ITT. In ITT, HR below 1 was observed when comparing pts with high (>median) vs low (≤median) immune gene expression by clinical outcome suggesting a potential association of high immune marker expression with improved PFS (Table 1) and to some extent with OS (data not shown). This association was primarily observed in the T-DM1 arm where the HR suggested a risk reduction of disease progression(PD)/death especially in the high Teff, high PD-L1 and high CD8 subgroups, and to some extent in the HT arm (Table 1). When assessing the predictive impact on PFS by comparing T-DM1 vs HT, HR below 1 was observed especially in pts with high Teff signature, high PD-L1 and high CD8 expressions (HR 0.67 (95% CI (0.47-0.95)), HR 0.68 (95% CI (0.48-0.97), and HR 0.64 (95%CI 0.44-0.93), respectively). When comparing T-DM1+P vs. HT, HR below 1 was observed especially in pts with low Teff signature and low PD-L1 expression (HR 0.70 (95% CI (0.50-0.99), and HR 0.68 (95% CI (0.48-0.96) respectively). No clear differences between immune gene expression subgroups was observed when comparing treatment arms in regards to OS (data not shown). Conclusions: In the exploratory analysis from the MARIANNE study, high immune gene expression, especially in the high PD-L1, CD8 and Teff subgroups, showed an association with improved clinical benefit with HRs reflecting for a risk reduction of PD/death for PFS and partially for OS. This association was less obvious in the T-DM1+P arm. When comparing the treatments effect, the data showed a potential impact of high Teff signature, and high CD8 and PD-L1 expressions on T-DM1 and less on HT. The potential opposite association of low Teff signature and low PD-L1 expression with improved benefit in the T-DM1+P arm was unexpected and needs further investigation. Table 1: Prognostic biomarker effect on PFSBiomarker by categories (>Median vs ≤Median)HR (95% CI) ITT n=671HR (95% CI) HT n=220HR (95% CI) T-DM1 n=227HR (95% CI) T-DM1+P n=224Teff sign0.89 (0.73-1.09)0.97 (0.68-1.38)0.64 (0.45-0.91)1.09 (0.75-1.58)Th1 cytokine sign0.91 (0.74-1.11)0.92 (0.64-1.31)0.78 (0.55-1.11)0.96 (0.67-1.36)Checkpoint inhibitor sign0.95 (0.78-1.15)0.91 (0.64-1.29)0.90 (0.64-1.26)1.02 (0.71-1.47)PD-L10.80 (0.66-0.98)0.79 (0.55-1.13)0.62 (0.44-0.87)1.07 (0.74-1.55)CD80.91 (0.75-1.11)1.10 (0.77-1.57)0.66 (0.46-0.93)0.98 (0.68-1.41) Citation Format: Edith A Perez, Sanne Lysbet de Haas, Carlos H Barrios, Wolfgang Eiermann, Masakazu Toi, Young-Hyuck Im, Pier Franco Conte, Miguel Martin, Tadeusz Pienkowski, Xavier B Pivot, Howard A Burris III, Chiara Lambertini, Silke Hoersch, Monika Patre, Paul Anthony Ellis. Association of immune gene expression with outcome in the MARIANNE phase 3 clinical trial in HER2-positive metastatic breast cancer (MBC) [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 PD5-11.

Abstract Background: Strong background parenchymal enhancement (BPE) may cause overestimation in tumor volume measured from dynamic contrast-enhanced (DCE) MRI, which may adversely affect the ability of MR tumor volume to predict treatment outcome for patients undergoing neoadjuvant chemotherapy (NAC). Specifically, an overestimation of tumor volume can result in misclassification of patients with complete pathologic response (pCR) as non-responders, leading to less confidence in MRI prediction. As well, overestimation of extent of disease might lead to more aggressive surgical therapy than necessary. This study investigated whether high BPE in the contralateral breast influences the predictive performance of MRI-measured functional tumor volume (FTV) for patients with locally advanced breast cancer undergoing NAC. Methods: patients (n=990) enrolled in the I-SPY 2 TRIAL who were randomized to the graduated experimental drug arms or controls from 2010 to 2016 were analyzed. Each patient had 4 MRI exams: pre-NAC (T0), after 3 weeks of NAC (T1), between NAC regimens (T2), and post-NAC (T3). FTV was calculated at each MRI exam by summing voxels meeting enhancement thresholds. Background parenchymal enhancement (BPE) in the contralateral breast was calculated automatically as mean percentage enhancement on the early (nominal 150sec post-contrast) image in the fibroglandular tissue segmented from 5 continuous axial slices centered in the inferior-to-superior stack. For each treatment time point, patients having both FTV and BPE measurements were included in the analysis. The area under the ROC curve (AUC) was estimated as the association between FTV and pCR at T1, T2, and T3. The analysis was conducted in the full patient cohort and in sub-cohorts defined by hormone receptor (HR) and HER2 status. In each patient cohort, a cut-off BPE value was selected to classify patients with high vs. low BPE by testing AUCs estimated with low-BPE patients reached maximum when the cut-off value varied from median to maximum in steps of 10%. Results: Out of 990 patients, 878 had pCR outcome data (pCR or non-pCR, pCR rate = 35%). Table 1 shows the number of patients, pCR rate, and AUC of FTV for predicting pCR using all patients available vs. a subset patients with low BPE (< BPE cut-off). In the full cohort, AUC increased slightly across all time points after patients with high BPE were removed. In the HR+/HER2- subtype, AUC increased at T1 after removal of cases with high BPE (0.65 vs. 0.71). For HR-/HER2+, AUC increased substantially after removal of high BPE cases (0.65 to 0.86 at T1, 0.71 to 0.87 at T2, and 0.71 to 0.89 at T3), with greater improvement at the early time point (T1) compared to later time points (T2 and T3). Only a slight improvement in the AUC was observed in the HR+/HER2+ and HR-/HER2- subtypes across all time points. Conclusions: High background parenchymal enhancement adversely affected the predictive performance of functional tumor volume measured by DCE-MRI, at early treatment time point for HR+/HER2- and across all time points for HR-/HER2+ cancer subtype. The adverse effect might be offset using subtype-optimized enhancement threshold in calculating functional tumor volume. Table 1 Effect of BPE on the prediction of pCR using FTV at various treatment time pointsT1T2T3npCR rateAUCBPE cut-offnpCR rateAUCBPE cut-offnpCR rateAUCBPE cut-offFullAll64734%0.662762334%0.701761134%0.6925Subset45334%0.6831133%0.7230534%0.72HR+/HER2-All26218%0.651924918%0.718225518%0.7519Subset13118%0.7124818%0.7120419%0.76HR+/HER2+All10636%0.642110538%0.62269634%0.7120Subset5332%0.668438%0.665740%0.73HR-/HER2+All5175%0.65204774%0.71204973%0.7116Subset3073%0.862871%0.872475%0.89HR-/HER2-All22842%0.682822243%0.751821143%0.6916Subset15940%0.7111137%0.7810540%0.75 Citation Format: Wen Li, Natsuko Onishi, David C Newitt, Roy Harnish, Ella F Jones, Lisa J Wilmes, Jessica Gibbs, Elissa Price, Bonnie N Joe, A. Jo Chien, Donald A Berry, Judy C Boughey, Kathy S Albain, Amy S Clark, Kirsten K Edmiston, Anthony D Elias, Erin D Ellis, David M Euhus, Heather S Han, Claudine Isaacs, Qamar J Khan, Julie E Lang, Janice Lu, Jane L Meisel, Zaha Mitri, Rita Nanda, Donald W Northfelt, Tara Sanft, Erica Stringer-Reasor, Rebecca K Viscusi, Anne M Wallace, Douglas Yee, Rachel Yung, Michelle E Melisko, Jane Perlmutter, Hope S Rugo, Richard Schwab, W. Fraser Symmans, Laura J van't Veer, Christina Yau, Smita M Asare, Angela DeMichele, Sally Goudreau, Hiroyuki Abe, Deepa Sheth, Dulcy Wolverton, Kelly Fountain, Richard Ha, Ralph Wynn, Erin P Crane, Charlotte Dillis, Theresa Kuritza, Kevin Morley, Michael Nelson, An Church, Bethany Niell, Jennifer Drukteinis, Karen Y Oh, Neda Jafarian, Kathy Brandt, Sadia Choudhery, Dae Hee Bang, Christiane Mullins, Stefanie Woodard, Kathryn W Zamora, Haydee Ojeda-Fornier, Mohammad Eghedari, Pulin Sheth, Linda Hovanessian-Larsen, Mark Rosen, Elizabeth S McDonald, Michael Spektor, Marina Giurescu, Mary S Newell, Michael A Cohen, Elise Berman, Constance Lehman, William Smith, Kim Fitzpatrick, Marisa H Borders, Wei Yang, Basak Dogan, Laura J Esserman, Nola M Hylton. The effect of background parenchymal enhancement on the predictive performance of functional tumor volume measured in MRI [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 P6-02-01.

Abstract Background: I-SPY2 is a multicenter, phase 2 trial using response-adaptive randomization within biomarker subtypes to evaluate novel agents as neoadjuvant therapy for high-risk breast cancer. The primary endpoint is pathologic complete response (pCR) at surgery. The goal is to identify (graduate) regimens with ≥ 85% Bayesian predictive probability of success (i.e., demonstrating superiority to control) in a future 300-patient phase 3 1:1 randomized neoadjuvant trial with pCR endpoint within signatures defined by hormone-receptor (HR), HER2, and MammaPrint (MP) status. Regimens may leave the trial for futility (< 10% probability of success), maximum sample size accrual (with probability of success ≥ 10% and < 85%), or safety concerns as recommended by the independent DSMB. For HER2+ patients, the I-SPY2 control arm was 12 weekly cycles of paclitaxel+trastuzumab (TH, control) followed by doxorubicin/cyclophosphamide (AC) q2-3 weeks x4 and surgery. Patritumab is a fully human monoclonal antibody that inhibits HER3. In this experimental arm for HER2+ patients, patritumab was given q3w x 4 cycles (18mg/kg loading dose followed by 9mg/kg/dose) concurrent with paclitaxel and trastuzumab q1w x 12 weeks (PTH, treatment), followed by AC q2-3w. Methods: Women with tumors ≥ 2.5cm were eligible for screening. MP low/HR+ tumors were ineligible. MRI scans (baseline, 3 weeks after start of therapy, prior to AC, and prior to surgery) were used in a longitudinal statistical model to predict pCR for individual patients. Analysis was intention to treat. Patients who switched to non-protocol therapy count as non-pCR. Patients on treatment arm therapy at the time of arm closure are non-evaluable. Graduation potential was in 3 of 10 pre-defined signatures: all HER2+, HR-/HER2+, and HR+/HER2+. Results: The PTH regimen was stopped at the recommendation of the Safety Working Group and DSMB based on a safety event (bilateral sensorineural hearing loss, Gr 3) observed in one patient. At the time of arm closure, N=31 patients had received PTH treatment; 4 patients receiving PTH were changed to non-protocol therapy and removed from the analysis. The final estimated pCR report will consider 27 PTH and 31 TH as evaluable patients. Accrual was insufficient to assess graduation, however, there appears to be good signal in the HER2+HR- but not HER2+HR+ signatures. I-SPY 2 TRIAL Est. pCR at time of arm closureSignaturesPTH (Treatment)N= 31TH (Control)N = 31All (HER2+)0.40 (0.22 - 0.59), n=310.23 (0.09 - 0.37), n=31HR-/HER2+0.64 (0.36 - 0.91), n=110.30 (0.12 - 0.47), n=12HR+/HER2+0.28 (0.08 - 0.48), n=200.20 (0.06 - 0.34), n=19 HR+/HER2+0.28 (0.08 - 0.48), n=200.20 (0.06 - 0.34), n=19The patient who developed Gr3 sensorineural hearing loss 6 days after the 2nd patritumab (and 4th paclitaxel/trastuzumab) treatment, did not recover her hearing after patritumab was stopped, and also reported Gr3 vulvovaginal pain, vulvitis, and vaginal inflammation. Other gynecological symptoms in the PTH arm include: 1 pt with Gr1 vaginal hemorrhage, and 1 pt with Gr2 dyspareunia. There was a higher frequency of Gr3 hypokalaemia (12.5% vs. 3.2%). One pt in the PTH arm reported Gr3 small intestinal obstruction which resolved with conservative management. Conclusion: The I-SPY 2 study aims to assess the probability that investigational regimens will be successful in a phase 3 neoadjuvant trial; PTH was stopped due to safety concerns, although there was activity in the HER2+ HR- signature. This is the first report of Gr3 hearing loss associated with patritumab/paclitaxel/trastuzumab, and thus attribution is uncertain. Citation Format: Teresa L Helsten, Shelly S Lo, Christina Yau, Kevin Kalinsky, Anthony D Elias, Anne M Wallace, A. Jo Chien, Janice Lu, Julie E Lang, Kathy S Albain, Erica Stringer-Reasor, Amy S Clark, Judy C Boughey, Erin D Ellis, Douglas Yee, Angela DeMichele, Claudine Isaacs, Jane Perlmutter, Hope S Rugo, Richard Schwab, Nola M. Hylton, W. Fraser Symmans, Michelle E Melisko, Laura J van't Veer, Amy Wilson, Ruby Singhrao, Smita M Asare, Ashish Sanil, Donald A Berry, Laura J Esserman. Evaluation of patritumab/paclitaxel/trastuzumab over standard paclitaxel/trastuzumab in early stage, high-risk HER2 positive breast cancer: Results from the neoadjuvant I-SPY 2 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 P3-11-02.

Abstract Background: Achieving a pathologic complete response (pCR) has been shown on the patient level to predict excellent long-term event-free survival outcomes. Residual cancer burden (RCB) quantifies the extent of residual disease for patients who did not achieve pCR. A high proportion of metastatic events to the central nervous system (CNS), a known chemotherapy sanctuary site, was previously observed among the small number of relapses in patients achieving a pCR (Symmans et al 2017), raising the possibility that these CNS events may be independent of response in the breast. I-SPY2 is an adaptively randomized, phase II, platform trial that evaluates new drugs and combinations in the neoadjuvant setting for women with high-risk primary breast cancer. In this study, we evaluated the type and sites of recurrences by RCB classes in the I-SPY 2 TRIAL. Methods: I-SPY 2 patients enrolled prior to 11/2016 across 9 experimental and control arms, with available RCB and event-free survival (EFS) data were included in this analysis. The median follow-up is 3.8 years. We summarized the EFS event type, further sub-dividing the distant recurrence events by their site of relapse (CNS-only, CNS and other sites, Non-CNS). We estimated the overall and site-specific distant recurrence incidence in each RCB class at 3 years using a competing risk (Fine-Gray) model. In addition, we assessed the association between RCB and distant recurrence free survival including all distant recurrences (DRFS), as well as excluding the CNS-only recurrences (non-CNS DRFS) using a Cox model. Our statistics do not adjust for multiplicities beyond variables evaluated in this study. Results: Among 938 subjects, there were 180 EFS events, including 28 (16%) local recurrences (without distant recurrence and/or death) and 152 DRFS events. Among the DRFS events, 25 patients died without a distant recurrence. 127 experienced distant recurrences, including 22 (17.3%) with CNS-only, 16 (12.6%) with CNS and other sites, 87 (68.5%) with non-CNS distant recurrence; 2 (1.6%) patients had missing recurrence site information. Incidence of CNS-only recurrences are low and are similar across RCB classes (pCR/RCB-0 (n=338): 1%, RCB-I (n=129): 3%, RCB-II (n=328): 2%, RCB-III (n=143): 2% at 3 years). In contrast, the incidence of non-CNS recurrences increase with increasing RCB (RCB-0: 2%, RCB-I: 4%, RCB-II: 11%, RCB-III: 19% at 3 years). DRFS of RCB-I patients do not significantly differ from those achieving a pCR/RCB-0 (DRFS at 3 years: 92% vs. 95%, hazard ratio: 1.77 (0.87-3.63)); the small numerical difference is further reduced when the CNS-only recurrences are excluded (non-CNS DRFS at 3 years: 95% vs. 96%, hazard ratio: 1.48 (0.61-3.58)). CNS recurrences among DRFS events are proportionally higher within the pCR (5/16 (31%)) and RCB-I (5/12 (42%)) than in the RCB-II (8/57 (14%)) and RCB-III (4/42 (9%)) groups largely because of the relative low frequency of non-CNS recurrence events. Conclusions: In our high-risk I-SPY 2 cohort, CNS-only recurrences are uncommon but appear similar across RCB groups, independent of response, suggesting that the CNS is a treatment sanctuary site. In contrast, non-CNS recurrence rates increase as RCB increases. These findings, if confirmed, support the use of RCB to identify patients with excellent outcomes beyond those achieving a pCR; and suggest that inclusion of CNS only recurrences as an outcome event may impact the association between neoadjuvant therapy response and long-term outcome. Citation Format: Christina Yau, Angela DeMichele, W. Fraser Symmans, Lajos Pusztai, Douglas Yee, Amy S. Clark, Christos Hatzis, Jeffrey B. Matthews, Jodi Carter, Yunn-Yi Chen, Kimberly Cole, Laila Khazai, Molly Klein, Dina Kokh, Gregor Krings, Sunati Sahoo, Kathy S. Albain, A. Jo Chien, Kirsten K. Edmiston, Anthony D. Elias, Erin D. Ellis, David M. Euhus, Heather S. Han, Claudine Isaacs, Qamar J. Khan, Julie E. Lang, Janice Lu, Jane L. Meisel, Zaha Mitri, Rita Nanda, Donald W. Northfelt, Tara Sanft, Erica Stringer-Reasor, Rebecca K. Viscusi, Anne M. Wallace, Rachel Yung, Nola M. Hylton, Judy C. Boughey, Michelle E. Melisko, Jane Perlmutter, Hope S. Rugo, Richard Schwab, Laura J. van' t Veer, Donald A. Berry, Laura J. Esserman. Site of recurrence after neoadjuvant therapy: Clues to biology and impact on endpoints [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 P2-20-02.

534 Background: mTOR plays a critical role in promoting tumor cell growth. In preclinical studies, the anti-tumor activity of mTOR inhibitors is attenuated by feedback up-regulation of AKT mediated by IGF-1R. We designed a phase I trial to determine the maximum-tolerated dose (MTD), dose-limiting toxicities (DLT) and pharmacodynamic effects of the IGF-1R antibody IMC-A12 in combination with temsirolimus (tem) in patients (pts) with metastatic breast cancer (MBC) where mTOR is frequently activated. Methods: A 3+3 phase I design was chosen. Tem and IMC-A12 were administered IV days (d) 1, 8, 15, and 22 of a 4-week cycle in pts with MBC refractory to standard therapies. Tumor response was evaluated by RECIST. Adverse events (AE) were reported using CTC v3.0. Serum IGF 1 and C-peptide levels on d2 (24h post infusion) and d8 prior to drug infusion were compared to baseline (BL) using paired t-test. Results: Of 26 pts enrolled, 4 did not complete cycle 1 due to progression (3) or co-morbid condition (1). MTD was determined from remaining 22 pts aged 34-72 (median 48) years with ECOG PS 0 (55%) or 1 (45%). 86% had ER+ cancer. Median number of regimens for MBC was 4. Two DLTs at the starting DL (DL 1) necessitated dose de-escalation of tem to 20mg (DL-1), then to 15 mg (DL-2) which was tolerable (Table). Subsequent dose escalation of IMC-A12 led to DLTs in 0 of 6 in DL-2A and 2 of 3 pts in DL-2B. The MTD was defined as DL-2A. Other AEs included gr 1/2 fatigue, neutropenia, anemia, and hyperglycemia. No CR or PR, but 4 SD lasting ≥ 4 months were observed. At DL-2, -2A and -2B, serum IGF 1 levels were significantly elevated on d2 (p <0.002) and d8 compared to BL (p <0.001), but C-peptide levels were not found to differ from BL. Conclusions: The MTD for the combination of IMC-A12 and tem in pts with MBC is lower than that observed for single agents alone. A phase II study is ongoing in MBC. The study is supported in part by ASCO CDA, Komen Craft to CXM, N01-CM62205 and N01-CM-2011-00071. [Table: see text]

526 Background: Z1041 randomized women with HER2+ operable breast cancer to: FEC → P+T (Arm 1) or P+T → FEC+T (Arm 2). Treatment administered as 5-FU 500 mg/m2, epirubicin 75 mg/m2 and cyclophosphamide 500 mg/m2 day 1 of a 21-day cycle x 4; paclitaxel 80 mg/m2weekly x 12 and T 4 mg/kg once then 2 mg/kg weekly x 11. T was to continue q3 weeks post-op for 40 weeks. A secondary aim was to examine the cardiotoxicity (CE). Methods: Ejection fraction (EF) was measured at baseline (BL), between regimens (wk 12), prior to surgery (wk 24) and PRN. Eligibility: BL EF ≥ 55%. CEs included decline in EF of > 15%, or >10% points to a value < LLN. Reversibility was adjudicated by blinded investigators as reversible (R: recovery of EF to ≤ 5% below BL), partially reversible (PR: recovery of > 10% points from nadir, but ≤ 5% points below BL), indeterminate (IN: no additional EF data), or irreversible (IRR:follow-up EF studies showed no improvement). Results: Of the 280 patients (Arm 1: 138) who began treatment, 15 pts (Arm 1: 10; Arm 2: 5) did not receive T. The number of weeks of T was 13 (range: 1-18) in Arm 1 and 24 (range: 1-31) in Arm 2. Changes in EF and severe treatment related cardiac toxicities prior to surgery (sx) are tabled below. There were 271 pts (Arm 1: 131) who had post-BL EFs. Prior to sx, there were 11 CE (8.3%) in Arm 1 and 13 CE (9.2%) in Arm 2. CEs were R in 12 pts (Arm 1: 5; Arm 2: 7); PR in 6 pts (Arm 1: 4; Arm 2: 2); IN in 4 pts (Arm 1: 2; Arm 2: 3) and IRR in 1 Arm 2 pt. Conclusions: The number of CE events in arms 1 and 2 showed no significant difference; greater scatter was observed in arm 2 patients. While concern for late cardiac events makes ongoing cardiac surveillance prudent due to A, concomitant use of A and T appear to not be associated with increased cardiac risk. Clinical trial information: NCT00513292. [Table: see text]

502 Background: Neoadjuvant chemotherapy (NAC) and concomitant trastuzumab (T) have produced high pathologic complete response (pCR) rates in HER2+ breast cancers. Z1041 addresses the timing of initiation of T with NAC. Methods: Women with operable HER2+ invasive breast cancer were randomized 1:1 to: FEC → P+T (Arm 1) or P+T → FEC+T (Arm 2) where treatment was administered as 5-FU 500 mg/m2, epirubicin 75 mg/m2 and cyclophosphamide 500 mg/m2 day 1 of a 21-day cycle x 4 (FEC); paclitaxel 80 mg/m2 weekly x 12 and trastuzumab 4 mg/kg once then 2 mg/kg weekly x 11. Eligibility also included: tumor > 2 cm or a positive lymph node and left ventricular ejection fraction > 55%. The primary aim was to compare the pCR rates in the breast (pBCR) between the regimens. Secondary endpoints were pCR rate in the breast and lymph nodes (pBNCR) and safety profile. All pts who began study treatment were included in the analyses. With 128 pts per regimen, a two-sided alpha=0.05 test of proportions would have a 90% chance of detecting a difference of 20% or more in the pBCR rates, when the pBCR rate with the poorer regimen is ≤ 25%. Results: From September 15, 2007 to December 15, 2011, 282 women (Arm 1: 140 pts) were enrolled. Two pts (Arm 1) withdrew without receiving treatment. The two arms were similar in age, stage, and hormone receptor (HR) status (HR neg: 40%). The severe (grade 3+) treatment-related toxicities included: neutropenia (Arm 1: 24.6%; Arm 2: 32.4%), fatigue (Arm 1: 4.3%; Arm 2: 8.5%), and neurosensory problems (Arm 1: 3.6%; Arm 2: 4.9%). The pBCR rate and pBNCR rates (Table) were not found to differ between the two regimens (Fisher’s exact p values: 0.905 and 0.811, respectively). Conclusions: High pCR rates can be achieved with trastuzumab in combination with anthracyclines and taxanes. The pBCR or pBNCR was not different between regimens based on the timing of initiation of trastuzumab. Clinical trial information: NCT00513292. [Table: see text]

503 Background: To correlate clinical features of estrogen receptor positive breast cancer with somatic mutations, massively parallel sequencing (MPS) was applied to tumor and normal DNAs accrued from patients treated with neoadjuvant aromatase inhibitors (AI). Methods: MPS was applied to 77 baseline tumor biopsy samples from the preoperative letrozole trial (JACS 2009: 208, 906) and the Z1031 trial (JCO 2011: 29, 2342) followed by targeted sequencing in another 240 trial samples. Standard statistical approaches were used to compare mutation status and clinical parameters and pathway-based correlation was used to assess interactions between signaling perturbations induced by gene mutations and response to neoadjuvant AI. Results: Eighteen genes were significantly mutated above background. Aside from PIK3CA mutations, the list is dominated by loss-of-function mutations in tumor suppressor genes. Five (RUNX1, CBFP, MYH9, MLL3 and SF3B1) have been previously linked to benign and malignant hematopoietic disorders. Clinical correlation revealed that TP53 mutation was associated with PAM50 LumB status, high-grade histology and high proliferation rates whereas loss-of-function mutations in MAP3K1 associate with PAM50 lumA status, low proliferation rates, and low grade histology. Mutations in GATA3 were associated with greater suppression of proliferation upon AI treatment suggesting mutGATA3 may predict endocrine response. Notably, mutations in MAP3K1 were more common in PIK3CA mutant cases, suggesting cooperation. Pathway analysis demonstrated that rare MAP2K4 mutations produce similar pathway perturbations as MAP3K1 mutation, a logical finding since MAP2K4 is a substrate for MAP3K1. Signaling network patterns driven by lncRNA MALAT1 mutations were associated with multiple poor clinical outcome features. Rare mutations in druggable kinases included two in the kinase domain of HER2. Conclusions: Tumor heterogeneity in luminal-type breast cancer is driven by specific patterns of somatic mutations, however most druggable or potentially prognostic mutations are infrequent. Prospective clinical trials based on these findings will require comprehensive genome sequencing approaches and large scale investigations.

LBA537 Background: Between 10-1-02 and 12-01-05, SWOG 0012 accrued patients to a two-arm randomized trial, with formal participation from NCCTG and CTSU participation by other cooperative groups. Arm 1 gave A at 60 mg/m2 and C at 600 mg/m2 q 3 wk IV for 5 cycles, arm 2 A at 24 mg/m2/wk × 15 IV and C at 60 mg/m2/day PO for 15 wk with G at 5 mcg/kg/day × 6/7 weekly. Both groups then received T at 80 mg/m2/wk × 12, and proceeded to surgery with pCR by NSABP criteria at the primary site as the endpoint. A total of 372 were randomized, and we report here on 265 patients (pts) evaluable for outcome, including those who did not proceed to surgery. In arm 1, pCR was seen in 17% vs 27% in arm 2 (p = .06); when adjusted for hormone receptor status (ER-PR- in 49% on arm 1, 41% on arm 2) and disease type (locally advanced vs inflammatory), the odds ratio in favor of arm 2 is 1.98 (95% CI 1.05–3.74, p = .034). For ER- PR- pts, pCR rates for Arm 1 vs 2 were 26 vs 43%, while for those with ER or PR+, pCR rates were 9 vs 14%. Inflammatory pts showed a striking difference in pCR rates for arm 1 vs arm 2 (12 vs 33%, p = .033). HER 2 status (+ in 29%) did not predict response or interact with treatment. Grade 3/4 toxicities (arm 1 vs 2, %) were as follows: hand-foot syndrome (0 vs 13), neutropenia (47 vs 16), neutropenic infection (1.8 vs 0.6), stomatitis (2 vs 11), and nausea/vomiting (11 vs 5). Toxicity from T was grade 3 neuropathy in 10%, with grade 3 or 4 neutropenia in 12%. There were no treatment-related deaths. Continuous or “metronomic” chemotherapy with AC is superior to standard intermittent AC, and the pCR rate reported for the continuous arm is the highest reported in a cooperative group experience for this patient population. [Table: see text]