Abstract No. 
2020 San Antonio Breast Cancer Symposium
Dec 8-11

Pathologic features of the inter-regimen biopsy predict response to neoadjuvant therapy in the I-SPY2 trial

Carter JM, Klein ME, Venters SJ, Rabe K, Ocal IT, Singh K, Wolf DM, Sahoo S, Harada S, Khazai L, Harigopal M, Borowsky AD, Krings G, Balassanian R, Chen Y-Y, Cole K,Shad S, Delson A, Brown-Swigart L, I-SPY 2 TRIAL Consortium, Esserman L, van ‘t Veer L, Symmans WF

Background: The I-SPY 2 TRIAL is a neoadjuvant platform trial open to patients with locally advanced, molecular high-risk breast cancer. We are undertaking a concerted pursuit of mid-therapy response biomarkers, including evaluation of inter-regimen biopsies, to identify patients who may be candidates for treatment de-escalation. In a prior pilot study, we observed that absence of carcinoma in an inter-regimen biopsy was predictive of pathologic complete response (pCR). In this expanded study of 100 I-SPY 2 participants, we sought to confirm that finding and assess other pathologic features of the inter-regimen biopsy as predictors of tumor response to neoadjuvant therapy.

Methods: Digital H&E images of 100 inter-regimen (12 week) image-guided breast biopsies +/- ancillary immunohistochemistry (p63 +/- cytokeratin) were reviewed by 9 pathologists in the I-SPY pathology working group to record 1) tumor bed and 2) presence or absence of residual invasive carcinoma (IC) (with tumor cellularity scored as 0-100%). The data set included 393 cores (mean 3.9 (range 2-4) cores per biopsy). Interobserver percent agreement was calculated and Fisher’s exact t-test was used for association of presence/absence of IC with pCR, and tumoral HR status. Association between biopsy cellularity and RCB indices used Pearson’s correlation.

Results: In the 100 biopsy set, 84% had ≥80% inter-observer diagnostic agreement on both 1) presence of tumor bed (N= 84) and 2) presence or absence of IC (N=53 IC+ /31 IC-) and comprised the data set. There was no difference in the number of evaluable tissue cores between the IC+/IC- biopsies. The primary tumors were 63% HR+/37% HR-; and the presence of IC in the biopsy correlated with tumoral HR status (p=0.0014: 74%: HR+HER2-; 62%: TN; 60%: HR+HER2+; 10%: HR-HER2+). Of the 31 patients with IC-negative biopsies (14 HR+/17 HR-), 25 (80%) went on to pCR (9HR+/16 HR-) whereas only 7/53 (13%) of patients with IC+ biopsies had pCR (2 HR+/5 HR-). Overall, IC-negative biopsies had a calculated OR=26, Fisher p=7.5E-10 for pCR; yielding a positive predictive value (PPV) for pCR of 81% and a sensitivity of 78%; with a PPV for HR- tumors of 94% (15/16) vs. 67% (10/15) for HR+ tumors. In the 6 IC-negative biopsies from patients with non-pCR (“false-negatives”), most were HR+ (5 HR+/1HR-), and tumor bed size in the surgical specimen was smaller than that of IC+ biopsies with non-PCR: 276 mm2 (0.4-1000 mm2) vs. 1166 mm2 (1-11960 mm2). Overall, the 46/53 IC+ biopsies in patients with non-pCR (36 HR+/10 HR-) had a PPV of non-pCR of 86%, with a PPV for HR+ tumors of 94% and a PPV for HR- tumors of 66%. Tumor cellularity in the biopsy (mean 37%, [2.5-93%]) did not correlate with RCB index (p=0.57) or RCB breast-only index (p = 0.17) at surgery.

Conclusion: In this 100 biopsy set, we confirmed that the absence of residual carcinoma in inter-regimen biopsies was highly predictive of pathologic complete response, particularly for HR- tumors. The “false-negative” biopsies (IC-/non-pCR) were predominantly HR+ tumors with small residual tumor beds. Conversely, the presence of carcinoma in inter-regimen biopsies was highly predictive of non-pCR, particularly for HR+ tumors. These data demonstrate the utility, and the limitations, of the inter-regimen biopsy as one tool to identify patients who may benefit from therapeutic de-escalation.

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