Tripathy, Debu

AbstractBackgroundThe management of early breast cancer (BC) has witnessed an uprise in the use of neoadjuvant therapy and a remarkable reshaping of the systemic therapy postneoadjuvant treatment in the last few years, with the evolution of many controversial clinical situations that require consensus.MethodsDuring the 14th Breast‐Gynecological and Immuno‐Oncology International Cancer Conference held in Egypt in 2022, a panel of 44 BC experts from 13 countries voted on statements concerning debatable challenges in the neo/adjuvant treatment setting. The recommendations were subsequently updated based on the most recent data emerging. A modified Delphi approach was used to develop this consensus. A consensus was achieved when ≥75% of voters selected an answer.Results and ConclusionsThe consensus recommendations addressed different escalation and de‐escalation strategies in the setting of neoadjuvant therapy for early BC. The recommendations recapitulate the available clinical evidence and expert opinion to individualize patient management and optimize therapy outcomes. Consensus was reached in 63% of the statements (52/83), and the rationale behind each statement was clarified.

ImportanceThere has been little consideration of genomic risk of recurrence by breast cancer subtype despite evidence of racial disparities in breast cancer outcomes.ObjectiveTo evaluate associations between clinical trial end points, namely pathologic complete response (pCR) and distant recurrence–free survival (DRFS), and race and examine whether gene expression signatures are associated with outcomes by race.Design, Setting, and ParticipantsThis retrospective cohort study used data from the Investigation of Serial Studies to Predict Your Therapeutic Response With Imaging and Molecular Analysis 2 (I-SPY 2) multicenter clinical trial of neoadjuvant chemotherapy with novel agents and combinations for patients with previously untreated stage II/III breast cancer. Analyses were conducted of associations between race and short- and long-term outcomes, overall and by receptor subtypes, and their association with 28 expression biomarkers. The trial enrolled 990 female patients between March 30, 2010, and November 5, 2016, with a primary tumor size of 2.5 cm or greater and clinical or molecular high risk based on MammaPrint or hormone receptor (HR)-negative/ERBB2 (formerly HER2 or HER2/neu)–positive subtyping across 9 arms. This data analysis was performed between June 10, 2021, and October 20, 2022.ExposureRace, tumor receptor subtypes, and genomic biomarker expression of early breast cancer.Main Outcomes and MeasuresThe primary outcomes were pCR and DRFS assessed by race, overall, and by tumor subtype using logistic regression and Cox proportional hazards regression models. The interaction between 28 expression biomarkers and race, considering pCR and DRFS overall and within subtypes, was also evaluated.ResultsThe analytic sample included 974 participants (excluding 16 self-reporting as American Indian or Alaska Native, Native Hawaiian or Other Pacific Islander, or multiple races due to small sample sizes), including 68 Asian (7%), 120 Black (12%), and 786 White (81%) patients. Median (range) age at diagnosis was 47 (25-71) years for Asian, 49 (25-77) for Black, and 49 (23-73) years for White patients. The pCR rates were 32% (n = 22) for Asian, 30% for Black (n = 36), and 32% for White (n = 255) patients (P = .87). Black patients with HR-positive/ERBB2-negative tumors not achieving pCR had significantly worse DRFS than their White counterparts (hazard ratio, 2.28; 95% CI, 1.24-4.21; P = .01), with 5-year DRFS rates of 55% (n = 32) and 77% (n = 247), respectively. Black patients with HR-positive/ERBB2-negative tumors, compared with White patients, had higher expression of an interferon signature (mean [SD], 0.39 [0.87] and −0.10 [0.99]; P = .007) and, compared with Asian patients, had a higher mitotic score (mean [SD], 0.07 [1.08] and −0.69 [1.06]; P = .01) and lower estrogen receptor/progesterone receptor signature (mean [SD], 0.31 [0.90] and 1.08 [0.95]; P = .008). A transforming growth factor β signature had a significant association with race relative to pCR and DRFS, with a higher signature associated with lower pCR and worse DRFS outcomes among Black patients only.Conclusions and RelevanceThe findings show that women with early high-risk breast cancer who achieve pCR have similarly good outcomes regardless of race, but Black women with HR-positive/ERBB2-negative tumors without pCR may have worse DRFS than White women, highlighting the need to develop and test novel biomarker-informed therapies in diverse populations.

Abstract Purpose: The neutralizing peptibody trebananib prevents angiopoietin-1 and angiopoietin-2 from binding with Tie2 receptors, inhibiting angiogenesis and proliferation. Trebananib was combined with paclitaxel±trastuzumab in the I-SPY2 breast cancer trial. Patients and Methods: I-SPY2, a phase II neoadjuvant trial, adaptively randomizes patients with high-risk, early-stage breast cancer to one of several experimental therapies or control based on receptor subtypes as defined by hormone receptor (HR) and HER2 status and MammaPrint risk (MP1, MP2). The primary endpoint is pathologic complete response (pCR). A therapy “graduates” if/when it achieves 85% Bayesian probability of success in a phase III trial within a given subtype. Patients received weekly paclitaxel (plus trastuzumab if HER2-positive) without (control) or with weekly intravenous trebananib, followed by doxorubicin/cyclophosphamide and surgery. Pathway-specific biomarkers were assessed for response prediction. Results: There were 134 participants randomized to trebananib and 133 to control. Although trebananib did not graduate in any signature [phase III probabilities: Hazard ratio (HR)-negative (78%), HR-negative/HER2-positive (74%), HR-negative/HER2-negative (77%), and MP2 (79%)], it demonstrated high probability of superior pCR rates over control (92%–99%) among these subtypes. Trebananib improved 3-year event-free survival (HR 0.67), with no significant increase in adverse events. Activation levels of the Tie2 receptor and downstream signaling partners predicted trebananib response in HER2-positive disease; high expression of a CD8 T-cell gene signature predicted response in HR-negative/HER2-negative disease. Conclusions: The angiopoietin (Ang)/Tie2 axis inhibitor trebananib combined with standard neoadjuvant therapy increased estimated pCR rates across HR-negative and MP2 subtypes, with probabilities of superiority >90%. Further study of Ang/Tie2 receptor axis inhibitors in validated, biomarker-predicted sensitive subtypes is warranted.

Abstract Introduction: Use of long-term endocrine therapy (ET) for ER+ breast cancer often leads to acquired ESR1 mutations (mutESR1), causing endocrine resistance, tumor progression, and poor prognosis. An unmet clinical need exists for treating ER+ mBC patients with mutESR1, particularly after progression on CDK4/6 inhibitors (CDK4/6i). ELAINE 2 is an open-label, phase 2, multicenter trial evaluating safety and efficacy of lasofoxifene (LAS [selective estrogen receptor modulator]) plus abemaciclib (Abema [CDK4/6i], provided by Eli Lilly) in patients with ER+/HER2- and mutESR1 mBC who progressed after prior ET. Preliminary data with LAS plus Abema showed median progression-free survival of 55.7 wks, objective response rate of 50%, and 24-wk clinical benefit (CB) rate of 69%, with an acceptable safety and tolerability profile. Here, we report ESR1 ctDNA mutant allele frequency (MAF) and correlations of ESR1 MAF changes with CB. Methods: ELAINE 2 patients with detectable ctDNA mutESR1 at baseline (BL) were analyzed. Oral LAS 5 mg/day and Abema 150 mg BID were taken until disease progression, death, unacceptable toxicity, or withdrawal from the study. ctDNA was assessed by the Sysmex-Inostics SafeSeq assay—which detects mutESR1 at low allele fractions—at BL, every 4 wks, and end of treatment. MAF changes from BL to wk 4 were characterized as decreased (decrease in ESR1 MAF or none detected [ND]), increased (increase in MAF), or equivocal (in polyclonal patients [>1 mutESR1] with some MAF increasing and decreasing trends). Correlations of MAF change at 4 wks with CB at 24 wks were explored. Results: 29 patients (median of 2 prior metastatic therapies: 97% CDK4/6i, 79% fulvestrant, 48% chemotherapy) had BL mutESR1 of Y537S (66%), D538G (45%), Y537N (28%), and other less frequently detected mutations; 14 (48.3%) patients were polyclonal. 26 of 29 patients had evaluable BL and wk-4 ctDNA results: 21 patients had decreased MAF (81% [54% with ND]), 3 (12%) had increased, and 2 (8%) had equivocal ESR1 MAF changes (Table). CB at 24 wks was seen in 17 patients with a decrease, 2 with an increase, and 1 with equivocal MAF change. A sensitivity of 89.5% and specificity of 20% were calculated for predicting CB based on direction of ESR1 MAF change. The positive predictive value (PPV) for CB with decreased MAF was 81% and the negative predictive value (NPV) for an increased MAF was 33%. Of the 14 (54%) patients with ND ESR1 MAF, 13 had CB resulting in 87% sensitivity, 50% specificity, 93% PPV, and 33% NPV. Conclusion: In ELAINE 2, 81% of patients had decrease/cleared (ND) mutESR1 after 4 wks of LAS plus Abema, which correlated with clinical benefit. All mutESR1 detected appear targeted with this therapy. High sensitivity and favorable PPV were observed in patients with decreased MAF, and even more so in those with ND MAF; however, increased MAF was less specific and not as predictive of treatment failure. Our results indicate that ESR1 liquid biopsy evaluation may be an adequate non-invasive surrogate marker for monitoring patients on treatment. Further study in a larger population of women with endocrine-resistant mBC and acquired mutESR1 is warranted to explore this potential for monitoring treatment response or resistance to this novel LAS-Abema combination. Table. Change from baseline to week 4 in ESR1 MAF and clinical benefit at 24 weeks. CI, confidence interval; MAF, mutant allele fraction; ND, none detected; NPV, negative predictive value; PPV, positive predictive value. *Sensitivity and specificity analyses do not include equivocal results. Citation Format: Senthil Damodaran, Halle Moore, Ciara C. O’Sullivan, Paul V. Plourde, Gary Riordan, Hillary S. Sloane, Debu Tripathy, Dominic Carroll, David J Portman. Estrogen receptor 1 (ESR1) mutations in circulating tumor DNA (ctDNA) from patients with ER+/HER2- metastatic breast cancer (mBC) treated with lasofoxifene plus abemaciclib in the ELAINE 2 study [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 P5-05-02.

Abstract Background: We compared the predictive and prognostic value of ctDNA dynamics in high-risk hormone receptor-positive/HER2-negative (HR+/HER2-) and triple negative breast cancer (TNBC) receiving neoadjuvant chemotherapy (NAC) enrolled in the I-SPY 2 trial (NCT01042379). To our knowledge, this is the largest ctDNA study in breast cancer in the neoadjuvant setting. Methods: Blood samples were collected at pre-treatment (T0), during treatment (T1 at 3 weeks, and T2 at 12 weeks) and after NAC (T3 at 24 weeks) from 106 HR+/HER2- and 97 TNBC patients. Plasma samples (n=734) were analyzed using a personalized and tumor-informed mPCR NGS-based ctDNA test (SignateraTM). Patients, all high risk for recurrence by MammaPrint, received paclitaxel-based treatment +/- experimental therapy followed by anthracycline. The median follow-up was 3.0 years (0.5 to 6.5). The predictive and prognostic value of ctDNA dynamics and status at different timepoints were examined. Our analysis is exploratory and does not adjust for other biomarkers. Results: Pretreatment ctDNA positivity (Fisher p<0.0001) and levels (mean tumor molecules/mL, MTM/mL, t test p=0.0062) were significantly higher in TNBC (90.7%, 14.7 MTM/mL) than in high risk HR+/HER2- (66.0%, 5.5 MTM/mL). Early and late ctDNA clearance during treatment (3 and 12 weeks of NAC) was predictive of pathologic complete response (pCR) and residual cancer burden (RCB), class 0-III, in TNBC but not HR+/HER2- (Table). In both subtypes: (1) ctDNA was a significant negative prognostic factor for distant recurrence-free survival (DRFS) at all timepoints (p<0.05) except at pretreatment; (2) all patients who achieved pCR were ctDNA-negative after NAC; (3) among non-responding patients, ctDNA-negativity after NAC was associated with improved DRFS (Table). Conclusions: The predictive value of ctDNA for prediction of pCR and RCB differed between subtypes (HR+/HER2- vs. TNBC), while similar prognostic value was observed. In TNBC, early clearance of ctDNA at 3 weeks was a significant predictor of favorable response to NAC. Compared to patients who were ctDNA-positive after NAC, ctDNA-negative status in both subtypes was associated with improved DRFS even in patients with residual cancer (no pCR or RCB-II/III). These findings could inform on the design of future studies that seek to demonstrate the utility of ctDNA in the curative setting. Predictive and prognostic significance of ctDNA in early breast cancer in the neoadjuvant setting HR+HER2- (n=106) TNBC (n=97) Predictive value for prediction of pCR and RCB Fisher p-value Fisher p-value Early ctDNA clearance (between T0 and T1) and pCR 0.4521 <0.0001 Late ctDNA clearance (between T0 and T2) and pCR 0.8071 0.0004 Early ctDNA clearance (between T0 and T1) and RCB (0-III) 0.1360 <0.0001 Late ctDNA clearance (between T0 and T2) and RCB (0-III) 0.4869 0.0004 Early ctDNA clearance at T1 and pCR rates pCR rate pCR rate ctDNA clearance (ctDNA+ at T0/ctDNA- at T1) 21% 67% Late ctDNA clearance (betweeNo early clearance (ctDNA+ at T0/ctDNA+ at T1) 13% 14% Prognostic value for prediction of DRFS Log rank p-value Log rank p-value ctDNA at T3 and pCR vs no PCR 0.0002 <0.0001 ctDNA at T3 and RCB (0-I vs II-III) 0.0110 <0.0001 Timepoints: T0 - pretreatment; T1 - three weeks after treatment initiation; T2 - at 12 weeks, between paclitaxel-based and anthracycline regimens; T3- after neoadjuvant chemotherapy prior to surgery Citation Format: Mark Jesus Mendoza Magbanua, Lamorna Brown Swigart, Derrick Renner, Svetlana Shchegrova, Gillian L. Hirst, Christina Yau, Denise M. Wolf, Hsin-Ta Wu, Ekaterina Kalashnikova, Amy L. Delson, A. Jo Chien, Debu Tripathy, Smita Asare, Raheleh Salari, Angel Rodriguez, Bernhard Zimmermann, Himanshu Sethi, Alexey Aleshin, Paul Billings, Rita Nanda, Hope S. Rugo, Laura J. Esserman, Minetta C. Liu, Angela DeMichele, Laura van 't Veer. Comparison of the predictive and prognostic significance of circulating tumor DNA in patients with high risk HER2-negative breast cancer receiving neoadjuvant chemotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB111.

Abstract Background Transcriptomic immune-related gene signatures have been associated with achievement of pathologic complete response (pCR) and prognosis in the neoadjuvant setting. I-SPY 2 is a multicenter, phase 2 platform trial using response-adaptive randomization within subtypes defined by receptor status (HR/HER2) and MammaPrint (MP) risk to evaluate novel agents as neoadjuvant therapy for women with high-risk breast cancer. Given racial disparities in mortality from breast cancer and the paucity of racial demographic data from clinical trials, we aimed to evaluate the association between racial groups and baseline characteristics, including expression-based subtypes and immune signatures, treatment response, and prognosis of patients enrolled in the I-SPY 2 TRIAL. Methods Our study population included 990 I-SPY 2 patients. 15 patients identified as part of a racial group with <10 patients enrolled in the trial and were excluded from analysis. Pre-treatment expression data was available for 971 patients. Follow-up data was available for 907 patients; median follow-up time of 4.4 yrs. Chi-square test was used to assess associations between racial groups and pre-treatment SBR grade, HR/HER2 defined subtypes, intrinsic subtype (defined by BluePrint 80-gene molecular subtyping) and residual cancer burden (RCB) class. Logistic regression was used to evaluate race association with pCR. Cox proportional hazard modeling was used to assess the association between racial groups and event free survival (EFS) in a univariate setting, adjusting for pCR status. Association between racial groups and 28 expression signatures related to immune, proliferation, ER and HER2 pathway was analyzed using ANOVA with post-hoc Tukey test in the overall population and in each receptor subtype. Results Of 975 patients included in our analysis, 787 (81%) were White, 68 (7%) were Asian, and 120 (12%) were Black or African American. No significant associations between race and pre-treatment SBR grade (p=0.49), HR/HER2 defined subtypes (p=0.09), or expression-based subtypes (p=0.25) were observed. pCR rates do not significantly differ by racial groups (Odds ratio of pCR relative to White: 1.00 for Asian and 0.89 for Black or African American); and no significant differences in RCB class distribution by race was observed (p=0.88). Event free survival was not associated with patient racial group in a univariate Cox model (Hazard ratio relative to White: 1.10, p=0.73 for Asian and 1.37, p=0.13 for Black or African American). Among the 28 expression signatures evaluated, four were differentially expressed among racial groups within the overall population (F-test p<0.05): IFN module, B cell signature, Dendritic cell signature, and Mitotic score. Pairwise comparisons between racial groups with post-hoc Tukey test identified significant differences in IFN module expression between Black or African American vs. White (p=0.019) and Dendritic cell signature expression between Asian vs White (p=0.047). Among patients in the TNBC subtype, three signatures (dendritic cell signature, macrophage signature and ERBB2 module) were differentially expressed between Black or African American and White patients (p=0.002, 0.016 and 0.007). Conclusion Our analysis demonstrates that among women with high risk breast cancer, race does not affect subtype specific response rates nor event free survival. Distribution of subtypes previously shown to be associated with pCR in the I-SPY2 trial did not significantly differ among racial groups indicating race is less likely than tumor biology to predict response. The decreased expression of immune signatures observed in Black or African American women with TNBC suggests possible differential sensitivity to immunotherapy plus combination chemotherapy. Tumor immune multiplex studies are underway to further investigate. Citation Format: Beverly Kyalwazi, Christina Yau, Olufunmilayo Olopade, A. Jo Chien, Anne Wallace, Andres Forero-Torres, Lajos Pusztai, Erin Ellis, Kathy Albain, Anne Blaes, Barbara Haley, Judy Boughey, Anthony Elias, Amy Clark, Claudine Isaacs, Rita Nanda, Hyo Han, Rachel Yung, Debu Tripathy, Kristen Edmiston, Rebecca Viscusi, Donald Northfelt, Qamar Khan, Ashish Sanil, Scott Berry, Smita Asare, Amy Wilson, Gillian Hirst, Nola Hylton, Michelle Melisko, Jane Perlmutter, Hope Rugo, Fraser Symmans, Laura van ‘t Veer, Donald Berry, Laura Esserman. Analysis of clinical outcomes and expression-based immune signatures by race in the I-SPY 2 trial [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr GS4-02.

Abstract Funding: Supported by National Cancer Institute grants U10CA180888, U10CA180819, U10CA180820, U10CA180821, U10CA180868, U10CA180863; and in part by Susan G. Komen for the Cure® Research Program, The Hope Foundation for Cancer Research, Breast Cancer Research Foundation, and Genomic Health, Inc. Acknowledgement: The authors wish to thank Dr. Ana M. Gonzalez-Angulo, MD, for her invaluable contributions to the design and implementation of this study. Background: The clinical utility of the RS to determine CT benefit is well established in pts with HR+, HER2-, axillary lymph node (LN)-negative BC. Retrospective analyses from SWOG S8814 support the potential prognostic and predictive role of RS for CT benefit in postmenopausal pts with LN+ BC. SWOG S1007 is a prospective, randomized trial of endocrine therapy (ET) vs. chemoendocrine therapy (CET) in women with 1-3 +LN and a RS < 25 (NCT01272037). Methods: Eligibility criteria included women > 18 years of age with HR+, HER2- BC and 1-3 +LN and no contraindications to taxane and/or anthracycline based CT. Women with a RS < 25 were randomized to receive ET or CET in 1:1 randomization using 3 stratification factors: (1) RS (0-13 vs.14-25); (2) menopausal status; and (3) axillary nodal dissection vs. sentinel node biopsy. The primary objective was to determine the effect of CT on invasive disease-free survival (IDFS) and whether the effect depended on the RS. The primary analysis was to test for a significant interaction of the treatment arm and continuous RS using a Cox regression model for IDFS, adjusting for treatment, RS, and menopausal status. A total of 832 IDFS events were expected for the final analysis. Secondary objectives included overall survival (OS). The protocol specified that interaction between treatment and the stratification variables was to be tested and, if significant, separate analyses performed by stratum. Annual interim analyses were planned starting at 24% of events. At the third interim analysis with 410 IDFS events, the Data and Safety Monitoring Committee recommended reporting results, with a decision by the NCI’s Cancer Therapy Evaluation Program, the study sponsor. Results: Of the 9,383 women screened from 2/28/11-9/29/17, 5,083 pts (54.2%) were randomized. With a median follow-up of 5.1 years, 447 IDFS events have been observed. For the primary analysis, the interaction test for CT benefit and continuous RS was not statistically significant, p=0.30. In a model with CT, RS, and menopausal status (no interaction term), higher continuous RS was associated with worse IDFS [HR 1.06, 2-sided p<0.001, 95% Confidence Interval (CI) 1.04-1.07], and CT was associated with an improvement in IDFS (HR 0.81, p=0.026, 95% CI 0.67-0.98). In a pre-specified analysis, a significant interaction was identified between CT and menopausal status (p=0.004), necessitating separate analyses by menopausal status. In postmenopausal pts (N=3350, 67%), adjusting for continuous RS, the HR for CET vs. ET was not significant (HR=0.97, p=0.82, 95% CI 0.78-1.22; 5-year IDFS 91.6% vs. 91.9%) indicating no benefit from CT. In premenopausal pts (N=1665, 33%), the HR (0.54) was statistically significant (p=0.0004, 95% CI 0.38-0.76; 5-year IDFS 94.2% vs. 89.0%), indicating CT benefit. In premenopausal pts, ovarian suppression was performed in 15.9% vs. 3.7% (ET vs. CET), and 47.9% vs. 26.4% reported menstruation after 6 months of treatment. Although the number of events is limited, the HR for treatment adjusted by RS for OS in premenopausal pts was 0.47 (p=0.032, 95% CI 0.24-0.94). At this time, there is no differential effect with CT in regard to other stratification factors. Conclusions: There is a significant differential treatment effect of CT benefit based on RS for premenopausal vs. postmenopausal women requiring separate analyses. While only 54% of the protocol specified events are recorded and pts will be followed for 15 years, the current data show that adjuvant therapy can be de-escalated to ET alone in postmenopausal pts with a RS < 25 and 1-3 +LN. However, there is a strong IDFS benefit for CET in premenopausal pts, with an early indication of an OS improvement. Citation Format: Kevin Kalinsky, William E Barlow, Funda Meric-Bernstam, Julie R Gralow, Kathy S Albain, Daniel Hayes, Nancy Lin, Edith A Perez, Lori J Goldstein, Stephen Chia, Subkhbinder Dhesy-Thind, Priya Rastogi, Emilio Alba, Suzette Delaloge, Miguel Martín, Miguel Gil Gil, Claudia Arce-Salinas, Etienne Brain, In Hae Park, Jean-Yves Pierga, Ana Hernandez Lluch, Manuel Ramos Vasquez, Manuel Ruiz Borrego, Kyung Hae Jung, Jean-Marc Ferrero, Anne Schott, Steve Shak, Priyanka Sharma, Danika L Lew, Jieling Miao, Debu Tripathy, Gabriel Hortobagyi, Lajos Pusztai. First results from a phase III randomized clinical trial of standard adjuvant endocrine therapy (ET) +/- chemotherapy (CT) in patients (pts) with 1-3 positive nodes, hormone receptor-positive (HR+) and HER2-negative (HER2-) breast cancer (BC) with recurrence score (RS) < 25: SWOG S1007 (RxPonder) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr GS3-00.