BACKGROUND:Hormone receptor-positive (HR+), human epidermal growth factor receptor 2 (HER2)-negative early-stage breast cancer (EBC) is a heterogenous disease. Identification of better clinical and molecular biomarkers is essential to guide optimal therapy for each patient. PATIENTS AND METHODS:We analyzed rates of pathologic complete response (pCR) and distant recurrence-free survival (DRFS) for patients with HR+/HER2-negative EBC in eight neoadjuvant arms in the I-SPY2 trial by clinical/molecular features: age, stage, histology, percentage estrogen receptor (ER) positivity, ER/progesterone receptor status, MammaPrint (MP)-High1 (0 to -0.57) versus MP-High2 (<-0.57), BluePrint (BP)-Luminal-type versus BP-Basal-type, and ImPrint immune signature. We quantified the clinical/molecular heterogeneity, assessed overlap among these biomarkers, and evaluated associations with pCR and DRFS. RESULTS:Three hundred and seventy-nine patients with HR+/HER2-negative EBC were included in this analysis, with an observed pCR rate of 17% across treatment arms. pCR rates were higher in patients with stage II versus III disease (21% versus 9%, P = 0.0013), ductal versus lobular histology (19% versus 11%, P = 0.049), lower %ER positivity (≤66% versus >66%) (35% versus 9%, P = 3.4E-09), MP-High2 versus MP-High1 disease (31% versus 11%, P = 1.1E-05), BP-Basal-type versus BP-Luminal-type disease (34% versus 10%, P = 1.62E-07), and ImPrint-positive versus -negative disease (38% versus 10%, P = 1.64E-09). Patients with lower %ER were more likely to have MP-High2 and BP-Basal-type disease. At a median follow-up of 4.8 years, patients who achieved pCR had excellent outcomes irrespective of clinical/molecular features. Among patients who did not achieve pCR, DRFS events were more frequent in patients with MP-High2 and BP-Basal-type disease than those with MP-High1 and BP-Luminal-type disease. CONCLUSIONS:Among patients with high molecular-risk HR+/HER2-negative EBC, the MP-High2, BP-Basal-type, and ImPrint-positive signatures identified a partially overlapping subset of patients who were more likely to achieve pCR in response to neoadjuvant chemotherapy ± targeted agents or immunotherapy compared to patients with MP-High1, BP-Luminal-type, and ImPrint-negative disease. I-SPY2.2 is incorporating the use of these biomarkers to molecularly define specific patient populations and optimize treatment selection.

102 Background: Previously, we showed that in our first PD1-inhibitor (PD1-inh) arm of I-SPY2, pCR associates with high STAT1/chemokine/dendritic signatures in TN and with high B-cell/low mast cell in HR+. From these results, we defined a research-grade Immune classifier incorporated into the RPS (PMID: 35623341), a schema designed to increase pCR if used to prioritize treatment. A clinical-grade version of the Immune (ImPrint) and other RPS biomarkers are now used in I-SPY2.2. Here we evaluate immune markers in 5 Immune-Oncology (IO) therapy arms (2 PD1-inh, 2 PD1-inh combinations, and 1 PDL1-inh combination). Methods: 343 patients with HER2-negative BC with information on pCR and mRNA in 5 IO arms (n 60-72 pts) plus controls (Ctr: 343) were considered. 32 continuous markers including 30 immune (7 checkpoint genes, 14 immune cell, 3 T/B-cell prognostic, 1 TGFB and 5 tumor-immune) and ESR1/PGR and proliferation signatures, were assessed for association with pCR using logistic regression. p-values were adjusted using the Benjamini-Hochberg method (BH p<0.05). Correlations to multiplex immunofluorescence (mIF) data from our initial arm (immune cell and spatial proximity markers) were calculated. Performance of ImPrint, developed with Agendia Inc, was characterized overall and within HR subsets. Results: A larger number of the research-grade immune markers predict response to IO in HR+ than in TN, with the most for HR+ in combination-IO arms (27/32 biomarkers). Tumor-immune signatures dominated by chemokines/cytokines were most consistently associated with pCR across IO arms and across receptor status. Moreover, we found that these markers correlate to mIF spatial proximity measures reflecting high spatial co-localization of PD1+ immune and PDL1+ tumor cells, in TN especially (r=0.59; p=0.003). The ImPrint classifier was evaluated in the IO arms. In HR+, 28% were ImPrint+; and pCR rates were 76% in ImPrint+ vs. 16% in ImPrint-. In TN, 46% were ImPrint+; and pCR rates were 75% in ImPrint+ and 37% in ImPrint-. Overall (HR+ and TN, in all IO arms), pCR rates were 75% in ImPrint+ and 23% in ImPrint-. Performance varied by arm, with the highest pCR rates for HR+/ImPrint+ >90%; and for TN/ImPrint+ >81%. In contrast, pCR rates in the control arm were 34% for ImPrint+ (HR+:33%; TN: 34%) and 13% for ImPrint- (HR+: 21%; TN:8%). Conclusions: Tumor-immune signaling signatures predict response for IO drug class in both TN and HR+HER2-. The ImPrint single-sample classifier predicts response to a variety of IO regimens in both subsets and may inform prioritization of IO vs other treatments and best balance likely benefit vs risk of serious immune-related adverse events. Clinical trial information: NCT01042379 .

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The I-SPY2 Trial is a randomized phase II platform trial testing novel neoadjuvant therapies. Serial MRI and pathology are used to evaluate response. New agents (+/- taxane) are tested in a 12 week (wk) treatment block, followed by Adriamycin/Cytoxan (AC). We sought to determine whether MRI functional tumor volume (FTV)-based predictive models, in conjunction with breast core biopsy, could identify early responders who had reached pCR and thus proceed to surgery without receiving AC, sparing them additional toxicity. The “predicted Residual Cancer Burden” (preRCB) models were developed using retrospective I-SPY data and prospectively tested in I-SPY2. Eligible patients (pts) were required to be on preRCB-designated treatment arms and consented to participate in the optional preRCB process. PreRCB included breast MRI at baseline, wk 3 and wk 12 of the initial I-SPY2 treatment block and a clinical core biopsy of the tumor bed at 12-weeks. Pts who met combined preRCB criteria (predicted probability of pCR above threshold in a subtype specific FTV model and no invasive tumor on breast biopsy) were eligible to proceed to surgery without AC after return of results (ROR) and consultation with their clinician. From 1/20-6/22, 172 pts underwent preRCB and completed surgery. 51/172 (30%) met combined MRI/biopsy preRCB criteria and 40/51 proceeded to surgery without AC (Table). 96% (49/51) pts who met preRCB criteria had RCB0/1 vs. 48% (57/120) of pts who did not meet criteria (OR 27 [6.5-235]; Fisher’s exact test p=1.04E-10). Overall, preRCB led to a 24% reduction in AC use without significant difference in RCB0/1 rate between those with and without AC (p=1). Implementation of preRCB in I-SPY2 identified patients with pCR prior to AC. High uptake of early surgery recommendations led to reduced use of AC while maintaining optimal outcome. I-SPY 2.2 is testing next-generation models to enable further optimization.Table: 355PPreRCB met (n=51)PreRCB not met (n=120)No AC40/51 (78%)Received AC11/51 (22%)No AC22/120 (18%)Received AC98/120 (82% )RCB 0/1RCB 2/3RCB 0/1RCB 2/3RCB 0/1RCB 2/3RCB 0/1RCB 2/338 (95%)2 (5%)11 (100%)0 (0%)12 (55%)10 (45%)45 (46%)53 (54%) Open table in a new tab

BACKGROUND:Difference in pathologic complete response (pCR) rate after neoadjuvant chemotherapy does not capture the impact of treatment on downstaging of residual cancer in the experimental arm. We developed a method to compare the entire distribution of residual cancer burden (RCB) values between clinical trial arms to better quantify the differences in cytotoxic efficacy of treatments. PATIENTS AND METHODS:The Treatment Efficacy Score (TES) reflects the area between the weighted cumulative distribution functions of RCB values from two trial arms. TES is based on a modified Kolmogorov-Smirnov test with added weight function to capture the importance of high RCB values and uses the area under the difference between two distribution functions as a statistical metric. The higher the TES the greater the shift to lower RCB values in the experimental arm. We developed TES from the durvalumab + olaparib arm (n = 72) and corresponding controls (n = 282) of the I-SPY2 trial. The 11 other experimental arms and control cohorts (n = 947) were used as validation sets to assess the performance of TES. We compared TES to Kolmogorov-Smirnov, Mann-Whitney, and Fisher's exact tests to identify trial arms with higher cytotoxic efficacy and assessed associations with trial arm level survival differences. Significance was assessed with a permutation test. RESULTS:In the validation set, TES identified arms with a higher pCR rate but was more accurate to identify regimens as less effective if treatment did not reduce the frequency of high RCB values, even if the pCR rate improved. The correlation between TES and survival was higher than the correlation between the pCR rate difference and survival. CONCLUSIONS:TES quantifies the difference between the entire distribution of pathologic responses observed in trial arms and could serve as a better early surrogate to predict trial arm level survival differences than pCR rate difference alone.

BACKGROUND:We proposed that a test for sensitivity to the adjuvant endocrine therapy component of treatment for patients with stage II-III breast cancer (SET2,3) should measure transcription related to estrogen and progesterone receptors (SETER/PR index) adjusted for a baseline prognostic index (BPI) combining clinical tumor and nodal stage with molecular subtype by RNA4 (ESR1, PGR, ERBB2, and AURKA). PATIENTS AND METHODS:Patients with clinically high-risk, hormone receptor-positive (HR+), human epidermal growth factor receptor 2 (HER2)-negative (HR+/HER2-) breast cancer received neoadjuvant taxane-anthracycline chemotherapy, surgery with measurement of residual cancer burden (RCB), and then adjuvant endocrine therapy. SET2,3 was measured from pre-treatment tumor biopsies, evaluated first in an MD Anderson Cancer Center (MDACC) cohort (n = 307, 11 years' follow-up, U133A microarrays), cut point was determined, and then independent, blinded evaluation was carried out in the I-SPY2 trial (n = 268, high-risk MammaPrint result, 3.8 years' follow-up, Agilent-44K microarrays, NCI Clinical Trials ID: NCT01042379). Primary outcome measure was distant relapse-free survival. Multivariate Cox regression models tested prognostic independence of SET2,3 relative to RCB and other molecular prognostic signatures, and whether other prognostic signatures could substitute for SETER/PR or RNA4 components of SET2,3. RESULTS:SET2,3 added independent prognostic information to RCB in the MDACC cohort: SET2,3 [hazard ratio (HR) 0.23, P = 0.004] and RCB (HR 1.77, P < 0.001); and the I-SPY2 trial: SET2,3 (HR 0.27, P = 0.031) and RCB (HR 1.68, P = 0.008). SET2,3 provided similar prognostic information irrespective of whether RCB-II or RCB-III after chemotherapy, and in both luminal subtypes. Conversely, RCB was most strongly prognostic in cancers with low SET2,3 status (MDACC P < 0.001, I-SPY2 P < 0.001). Other molecular signatures were not independently prognostic; they could effectively substitute for RNA4 subtype within the BPI component of SET2,3, but they could not effectively substitute for SETER/PR index. CONCLUSIONS:SET2,3 added independent prognostic information to chemotherapy response (RCB) and baseline prognostic score or subtype. Approximately 40% of patients with clinically high-risk HR+/HER2- disease had high SET2,3 and could be considered for clinical trials of neoadjuvant endocrine-based treatment.