Wei, Jane

Abstract Background: The I-SPY 2 TRIAL enrolls women with locally advanced, molecular high-risk breast cancer. An integrated Residual Cancer Burden (iRCB), based on MRI volume change through treatment, is used to predict pathologic complete response (pCR) in the randomization/evaluation Bayesian engine. With the goal of effective de-escalation of treatment for patients exhibiting an early response, biomarkers are being assessed for their ability to predict pCR, alone or with MR data, during treatment. Here, we present the results of a pilot study to examine if invasive tumor cellularity in mid-treatment tissue core biopsies predicts pCR in a 40-patient cohort of I-SPY 2 patients. Other pathologic variables evaluated include Ki67, tumoral histologic features, and stromal tumor-infiltrating lymphocytes (sTILs). Methods: I-SPY 2 TRIAL pathologists (N=4) were provided images of H&E-stained and Ki67 IHC- labelled (DAKO/Agilent, clone MIB-1) core biopsy sections from 40 patients at the inter-regimen time point, ~12-weeks into treatment. Of the 40 patients, 35 had 4 cores, 3 had 3 cores, and 2 had 2 cores assessed. In total, images from 153 cores were evaluated. For each core, pathologists were asked to score the % area occupied by tumor bed (treatment changes and/or residual cancer), % of viable invasive tumor (0-100%) within tumor bed (with Nottingham grading, % Ki67 labelled, and % sTILs, using standardized guidelines). As decided by the pathologist group, only cores with identified tumor bed were included in the initial analysis. Concordance between pathologists was assessed for all scored criteria, using % agreement for dichotomous variables, and Pearson correlation (r)/standard deviation (sd) for continuous variables. The maximum and average cellularity recorded over all cores/patient, averaged over all pathologists, were analyzed for association with pCR using t- tests (significance threshold: p<0.05). Fisher’s Exact test was used for dichotomous variables, and Pearson’s correlation for association of continuous variables with the residual cancer burden (RCB) index. Results: Pathologist were in general agreement about the presence or absence of tumor bed, with greater than 82% agreement between any two (83-96%), and an overall agreement of 77%. For scoring the % of the tumor bed involved by invasive cancer, correlations between pairs of pathologists ranged from 0.79-0.95 (mean(r)=0.87, sd=5%), and agreement on a binary presence/absence of invasive cancer was 78%. Both the mean (t-test: p=7.59E-05) and maximum (t-test: p=0.0012) %invasive tumor at 12 weeks, scored as an average over all pathologists, were significantly higher in patients who did not achieve pCR than in responders. We also treated %invasive cellularity as a dichotomous variable (present/absent). 90% (9/10) of patients scored by all pathologists as 0% invasive tumor cells (absent) achieved a pCR, vs only 20% (6/30) of patients scored as >0% invasive cellularity by one or more pathologists (present) (OR=32, Fisher p=0.0005); yielding a positive predictive value for pCR of 0.9. Ki67 and sTILS at 12 weeks were fairly concordant across pathologists ((r,sd)=(0.92, 8.45%) and (0.82,5.5%), respectively), but did not associate with response (p>0.05 for pCR, RCB01, or RCB index). Tumor histologic grade at 12 weeks, assessed in 29/30 patients with non-zero cellularity, trended toward association (Fisher p=0.078): 44% (4/9) with Grade 3 went on to have a pCR, vs. 15% (2/13) with Grade 2 and 0 with Grade 1. These data demonstrate the utility of invasive tumor cellularity as a predictor of pCR in a clinical setting. Conclusion: In this pilot study we demonstrate that the absence of invasive cancer cells within identified tumor bed in mid-treatment core biopsy samples is highly predictive of pCR. Citation Format: Sara J Venters, Denise M Wolf, Lamorna Brown-Swigart, Christina Yau, Amy L Delson, Bev Parker, Ron Balassanian, Jodi Carter, Yunn-Yi Chen, Kimberly Cole, Laila Khazai, Molly Klein, Dina Kokh, Gregor Krings, Sunati Sahoo, Jane Wei, I-SPY 2 TRIAL Consortium, Laura J Esserman, Laura J van't Veer, W Fraser Symmans. Assessing biomarkers to inform treatment de-escalation: Mid-treatment biopsy cellularity predicts pCR 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 P6-10-02.

Abstract Background: Recent studies have demonstrated independent validation of the prognostic relevance of residual cancer burden (RCB) after neoadjuvant chemotherapy. However, a pooled subject-level analysis of multiple cohorts is needed to determine estimates of long-term prognosis for each class of RCB in each phenotypic subtype of breast cancer (BC) to better inform on patient outcomes. Also, a pooled subject-level analysis allows more detailed analyses of generalizability of the prognostic meaning of RCB assessments in a broader experience of practice settings. Method: Subject-level RCB results, with relevant clinical and pathologic stage, tumor subtype and grade, demographic, treatment and follow-up data from 11 institutes/trials are being collected for combined analysis. The association between the continuous RCB index and event-free survival (EFS), and distant recurrence free survival (DRFS) were assessed using mixed effect Cox models with the incorporation of random RCB coefficients to account for between-study heterogeneity. We will also allow for differences in baseline hazard across biological BC subtypes and, if needed, across studies as well. In addition to this stratified mixed effect model, a multivariate analysis adjusting for age, T-category, nodal status and grade was performed within each subtype. In addition, mixed effect Cox models will be employed to evaluate association between RCB index with EFS and DRFS within each HR/HER2 subtype. Kaplan Meier estimates of EFS and DRFS at 5 and 10 years were computed for each RCB class within subtype. Results: We analyzed subject-level data from 9 institutes/trials representing 4077 patients currently available from an anticipated final total of 4,800 patients (to be presented at the meeting). There were 950 EFS and 876 DRFS events during follow up (median 65 months, IQR: 70 months). RCB index (continuous) was independently prognostic within each subtype: HR+/HER2- (EFS HR (per unit increase in RCB index) =1.64, 95%CI 1.48-1.82; DRFS HR=1.68, 1.51-1.87), HR+/HER2+ (EFS HR=1.80, 1.57-2.05; DRFS HR=1.93, 1.67-2.24), HR-/HER2+ (EFS HR=2.15, 1.76-2.62; DRFS HR=2.10, 1.77-2.50), and HR-/HER2- (EFS HR=2.05, 1.89-2.22; DRFS HR=2.16, 1.90-2.46); and remained prognostic in multivariate models adjusting for age, grade, and clinical T and N stage at diagnosis. Table 1 contains the response rate and estimated EFS at 5 years and 10 years for each RCB class within each HR/HER2 phenotype (DRFS results were similar). Conclusions: Long-term prognosis after pCR was similarly excellent in all phenotypic subtypes. RCB index and classification was independently and strongly prognostic in all subtypes, and generalizable to multiple practice settings. Prognostic differences by RCB class occurred within 5 years in HR- BC, but extended to 10 years in HR+ BC. RCB-I had slightly worse EFS than pCR in HR- BC and HR+/HER2+ BC (after 5 years), but the same EFS as pCR in HR+/HER2- BC. Complete analysis of all subjects, including neoadjuvant treatments, will be presented at the meeting. PhenotypeOutcomepCRRCB-IRCB-IIRCB-IIIHR+/HER2-Frequency (%)11%10%52%27%(N=1467)5 yr EFS (95% CI)91% (86-96)93% (89-98)82% (79-85)70% (65-75)10 yr EFS (95% CI)84% (75-93)88% (82-95)71% (67-75)52% (46-58)HR+/HER2+Frequency (%)38%18%35%9%(N=762)5 yr EFS (95% CI)94% (91-97)93% (88-98)78% (73-84)49% (37-65)10 yr EFS (95% CI)91% (86-96)79% (70-90)65% (59-73)42% (29-60)HR-/HER2+Frequency (%)66%11%18%5%(N=550)5 yr EFS (95% CI)93% (90-96)88% (79-97)60% (50-71)45% (30-69)10 yr EFS (95% CI)90% (86-94)84% (74-95)56% (46-68)45% (30-69)HR-/HER2-Frequency (%)41%13%33%13%(N=1293)5 yr EFS (95% CI)92% (90-94)85% (79-91)68% (63-72)28% (21-36)10 yr EFS (95% CI)87% (82-91)80% (72-88)63% (58-68)24% (18-33) Citation Format: Christina Yau, Marieke van der Noordaa, Jane Wei, Marie Osdoit, Fabien Reyal, Anne-Sophie Hamy, Marick Lae, Miguel Martin, Maria del Monte, I-SPY 2 TRIAL Consortium, Judy C Boughey, Rebekah Gould, Jelle Wesseling, Tessa Steenbruggen, Maartje van Seijen, Gabe Sonke, Stephen Edge, Stephen-John Sammut, Elena Provenzano, Jean Abraham, Peter Hall, Ashley Graham, Lorna Mackintosh, David Cameron, Alice Wang, Priyanka Sharma, Kimberly Cole, Lajos Pusztai, Mi-Ok Kim, Laura van ‘t Veer, Laura Esserman, W. Fraser Symmans. Residual cancer burden after neoadjuvant therapy and long-term survival outcomes in breast cancer: A multi-center pooled analysis [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 GS5-01.