Abstract LB111: Comparison of the predictive and prognostic significance of circulating tumor DNA in patients with high risk HER2-negative breast cancer receiving neoadjuvant chemotherapy

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.

LowIGFBP7expression identifies a subset of breast cancers with favorable prognosis and sensitivity to IGF-1 receptor targeting with ganitumab: Data from I-SPY2 and SCAN-B

“…Had IGFBP7 been included in the initial assessment of predictive biomarkers in I-SPY2, it would have identified the distinct subgroup where ganitumab showed benefit. Our findings add to the list of important studies 8,[10][11][12][13] where the I-SPY2 trial detected activity of novel agents 7,8,12,13 , even if the benefit is shown to be confined to a biomarker-defined subset of patients.…”

“…Further, eleven putative IGF-1R signaling axis biomarkers were tested, but none were predictive of ganitumab benefit 5 . I-SPY2 has been able to identify treatment predictive biomarkers for emerging treatments due to its unique design [6][7][8][9] , and to evaluate efficacy of new treatments [10][11][12][13] . To further this goal, the I-SPY2-990 Data Resource has been made publicly available 10 .…”

Postneoadjuvant treatment for triple-negative breast cancer

“…A follow-up study with longitudinal ctDNA monitoring, confirmed the strong prognostic significance of ctDNA persistence in patients with TNBC (hazard ratio: 27.6, 5.9-128.8) [65]. Consistently, the investigators of the I-SPY 2 adaptive, multiarm clinical trial reported retrospective data on MRD in patients treated with neoadjuvant therapy, and not experiencing pCR [63,66]. In a multivariate model, they showed that pCR has no independent prognostic significance, when ctDNA is included as a variable: the only independent factor associated with disease recurrence was the persistence of ctDNA postsurgically (hazard ratio: 14.9, 2.66-83.11) [63].…”

“…The proportion of patients with residual disease and detectable ctDNA was 14% in this study, suggesting that not all patients with residual disease are at highest risk of recurrence but perhaps a smaller subset. Of note, ctDNA was not detectable in all patients with pCR [63,66]. The risk of distant relapse was similar for patients achieving pCR and patients with residual disease but negative postsurgical ctDNA (hazard ratio: 1.4, 0.15-13.5).…”

Virtual patient analysis identifies strategies to improve the performance of predictive biomarkers for PD-1 blockade

“…It should also be noted that the blood-based biomarkers tested only included T cell counts and ratios of cell counts. Liquid biopsy-based biomarkers such as circulating tumor cells and circulating tumor DNA have potential for predicting outcomes and recurrence risk in early-stage breast cancer 58, 59 . These biomarkers could also predict immunotherapy efficacy in metastatic cancer 17 , though this requires further investigation.…”