Effect of Pembrolizumab Plus Neoadjuvant Chemotherapy on Pathologic Complete Response in Women With Early-Stage Breast Cancer: An Analysis of the Ongoing Phase 2 Adaptively Randomized I-SPY2 Trial.

Importance: Approximately 25% of patients with early-stage breast cancer who receive (neo)adjuvant chemotherapy experience a recurrence within 5 years. Improvements in therapy are greatly needed. Objective: To determine if pembrolizumab plus neoadjuvant chemotherapy (NACT) in early-stage breast cancer is likely to be successful in a 300-patient, confirmatory randomized phase 3 neoadjuvant clinical trial. Design, Setting, and Participants: The I-SPY2 study is an ongoing open-label, multicenter, adaptively randomized phase 2 platform trial for high-risk, stage II/III breast cancer, evaluating multiple investigational arms in parallel. Standard NACT serves as the common control arm; investigational agent(s) are added to this backbone. Patients with ERBB2 (formerly HER2)-negative breast cancer were eligible for randomization to pembrolizumab between November 2015 and November 2016. Interventions: Participants were randomized to receive taxane- and anthracycline-based NACT with or without pembrolizumab, followed by definitive surgery. Main Outcomes and Measures: The primary end point was pathologic complete response (pCR). Secondary end points were residual cancer burden (RCB) and 3-year event-free and distant recurrence-free survival. Investigational arms graduated when demonstrating an 85% predictive probability of success in a hypothetical confirmatory phase 3 trial. Results: Of the 250 women included in the final analysis, 181 were randomized to the standard NACT control group (median [range] age, 47 [24.77] years). Sixty-nine women (median [range] age, 50 [27-71] years) were randomized to 4 cycles of pembrolizumab in combination with weekly paclitaxel followed by AC; 40 hormone receptor (HR)-positive and 29 triple-negative. Pembrolizumab graduated in all 3 biomarker signatures studied. Final estimated pCR rates, evaluated in March 2017, were 44% vs 17%, 30% vs 13%, and 60% vs 22% for pembrolizumab vs control in the ERBB2-negative, HR-positive/ERBB2-negative, and triple-negative cohorts, respectively. Pembrolizumab shifted the RCB distribution to a lower disease burden for each cohort evaluated. Adverse events included immune-related endocrinopathies, notably thyroid abnormalities (13.0%) and adrenal insufficiency (8.7%). Achieving a pCR appeared predictive of long-term outcome, where patients with pCR following pembrolizumab plus chemotherapy had high event-free survival rates (93% at 3 years with 2.8 years\u27 median follow-up). Conclusions and Relevance: When added to standard neoadjuvant chemotherapy, pembrolizumab more than doubled the estimated pCR rates for both HR-positive/ERBB2-negative and triple-negative breast cancer, indicating that checkpoint blockade in women with early-stage, high-risk, ERBB2-negative breast cancer is highly likely to succeed in a phase 3 trial. Pembrolizumab was the first of 10 agents to graduate in the HR-positive/ERBB2-negative signature. Trial Registration: ClinicalTrials.gov Identifier: NCT01042379

PRoBE the cloud toolkit: finding the best biomarkers of drug response within a breast cancer clinical trial.

Objectives: In this paper, we discuss leveraging cloud-based platforms to collect, visualize, analyze, and share data in the context of a clinical trial. Our cloud-based infrastructure, Patient Repository of Biomolecular Entities (PRoBE), has given us the opportunity for uniform data structure, more efficient analysis of valuable data, and increased collaboration between researchers. Materials and Methods: We utilize a multi-cloud platform to manage and analyze data generated from the clinical Investigation of Serial Studies to Predict Your Therapeutic Response with Imaging And moLecular Analysis 2 (I-SPY 2 TRIAL). A collaboration with the Institute for Systems Biology Cancer Gateway in the Cloud has additionally given us access to public genomic databases. Applications to I-SPY 2 data have been built using R Shiny, while leveraging Google\u27s BigQuery tables and SQL commands for data mining. Results: We highlight the implementation of PRoBE in several unique case studies including prediction of biomarkers associated with clinical response, access to the Pan-Cancer Atlas, and integrating pathology images within the cloud. Our data integration pipelines, documentation, and all codebase will be placed in a Github repository. Discussion and conclusion: We are hoping to develop risk stratification diagnostics by integrating additional molecular, magnetic resonance imaging, and pathology markers into PRoBE to better predict drug response. A robust cloud infrastructure and tool set can help integrate these large datasets to make valuable predictions of response to multiple agents. For that reason, we are continuously improving PRoBE to advance the way data is stored, accessed, and analyzed in the I-SPY 2 clinical trial

Identification and characterization of novel associations in the casp8/als2cr12 region on chromosome 2 with breast cancer risk

Previous studies have suggested that polymorphisms in CASP8 on chromosome 2 are associated with breast cancer risk. To clarify the role of CASP8 in breast cancer susceptibility, we carried out dense genotyping of this region in the Breast Cancer Association Consortium (BCAC). Single-nucleotide polymorphisms (SNPs) spanning a 1 Mb region around CASP8 were genotyped in 46 450 breast cancer cases and 42 600 controls of European origin from 41 studies participating in the BCAC as part of a custom genotyping array experiment (iCOGS). Missing genotypes and SNPs were imputed and, after quality exclusions, 501 typed and 1232 imputed SNPs were included in logistic regression models adjusting for study and ancestry principal components. The SNPs retained in the final model were investigated further in data from nine genome-wide association studies (GWAS) comprising in total 10 052 case and 12 575 control subjects. The most significant association signal observed in European subjects was for the imputed intronic SNP rs1830298 in ALS2CR12 (telomeric to CASP8), with per allele odds ratio and 95% confidence interval [OR (95% confidence interval, Cl)] for the minor allele of 1.05(1.03-1.07), P = 1 x 10(-5). Three additional independent signals from intronic SNPs were identified, in CASP8 (rs36043647), ALS2CR11 (rs59278883) and CFLAR (rs7558475). The association with rs1830298 was replicated in the imputed results from the combined GWAS (P = 3 x 10(-6)), yielding a combined OR (95% Cl) of 1.06(1.04-1.08), P = 1 x 10(-9). Analyses of gene expression associations in peripheral blood and normal breast tissue indicate that CASP8 might be the target gene, suggesting a mechanism involving apoptosis

Associations of common variants at 1p11.2 and 14q24.1 (rad51l1) with breast cancer risk and heterogeneity by tumor subtype: findings from the breast cancer association consortium†

A genome-wide association study (GWAS) identified single-nucleotide polymorphisms (SNPs) at 1p11.2 and 14q24.1 (RAD51L1) as breast cancer susceptibility loci. The initial GWAS suggested stronger effects for both loci for estrogen receptor (ER)-positive tumors. Using data from the Breast Cancer Association Consortium (BCAC), we sought to determine whether risks differ by ER, progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), grade, node status, tumor size, and ductal or lobular morphology. We genotyped rs11249433 at 1p.11.2, and two highly correlated SNPs rs999737 and rs10483813 (r(2) = 0.98) at 14q24.1 (RAD51L1), for up to 46 036 invasive breast cancer cases and 46 930 controls from 39 studies. Analyses by tumor characteristics focused on subjects reporting to be white women of European ancestry and were based on 25 458 cases, of which 87% had ER data. The SNP at 1p11.2 showed significantly stronger associations with ER-positive tumors [per-allele odds ratio (OR) for ER-positive tumors was 1.13, 95% CI = 1.10-1.16 and, for ER-negative tumors, OR was 1.03, 95% CI = 0.98-1.07, case-only P-heterogeneity = 7.6 x 10 25]. The association with ER-positive tumors was stronger for tumors of lower grade (case-only P = 6.7 x 10 23) and lobular histology (case-only P = 0.01). SNPs at 14q24.1 were associated with risk for most tumor subtypes evaluated, including triple-negative breast cancers, which has not been described previously. Our results underscore the need for large pooling efforts with tumor pathology data to help refine risk estimates for SNP associations with susceptibility to different subtypes of breast cancer

MK-2206 and Standard Neoadjuvant Chemotherapy Improves Response in Patients With Human Epidermal Growth Factor Receptor 2-Positive and/or Hormone Receptor-Negative Breast Cancers in the I-SPY 2 Trial.

PURPOSE: The phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin is a key pathway of survival and therapeutic resistance in breast cancer. We evaluated the pan-Akt inhibitor MK-2206 in combination with standard therapy in patients with high-risk early-stage breast cancer. PATIENTS AND METHODS: I-SPY 2 is a multicenter, phase II, open-label, adaptively randomized neoadjuvant platform trial that screens experimental therapies and efficiently identifies potential predictive biomarker signatures. Patients are categorized by human epidermal growth factor receptor 2 (HER2), hormone receptor (HR), and MammaPrint statuses in a 2 × 2 × 2 layout. Patients within each of these 8 biomarker subtypes are adaptively randomly assigned to one of several experimental therapies, including MK-2206, or control. Therapies are evaluated for 10 biomarker signatures, each of which is a combination of these subtypes. The primary end point is pathologic complete response (pCR). A therapy graduates with one or more of these signatures if and when it has an 85% Bayesian predictive probability of success in a hypothetical phase III trial, adjusting for biomarker covariates. Patients in the current report received standard taxane- and anthracycline-based neoadjuvant therapy without (control) or with oral MK-2206 135 mg/week. RESULTS: MK-2206 graduated with 94 patients and 57 concurrently randomly assigned controls in 3 graduation signatures: HR-negative/HER2-positive, HR-negative, and HER2-positive. Respective Bayesian mean covariate-adjusted pCR rates and percentage probability that MK-2206 is superior to control were 0.48:0.29 (97%), 0.62:0.36 (99%), and 0.46:0.26 (94%). In exploratory analyses, MK-2206 evinced a numerical improvement in event-free survival in its graduating signatures. The most significant grade 3-4 toxicity was rash (14% maculopapular, 8.6% acneiform). CONCLUSION: The Akt inhibitor MK-2206 combined with standard neoadjuvant therapy resulted in higher estimated pCR rates in HR-negative and HER2-positive breast cancer. Although MK-2206 is not being further developed at this time, this class of agents remains of clinical interest

Neoadjuvant T-DM1/pertuzumab and paclitaxel/trastuzumab/pertuzumab for HER2

HER2-targeted therapy dramatically improves outcomes in early breast cancer. Here we report the results of two HER2-targeted combinations in the neoadjuvant I-SPY2 phase 2 adaptive platform trial for early breast cancer at high risk of recurrence: ado-trastuzumab emtansine plus pertuzumab (T-DM1/P) and paclitaxel, trastuzumab and pertuzumab (THP). Eligible women have \u3e2.5 cm clinical stage II/III HER2+ breast cancer, adaptively randomized to T-DM1/P, THP, or a common control arm of paclitaxel/trastuzumab (TH), followed by doxorubicin/cyclophosphamide, then surgery. Both T-DM1/P and THP arms \u27graduate\u27 in all subtypes: predicted pCR rates are 63%, 72% and 33% for T-DM1/P (n = 52), THP (n = 45) and TH (n = 31) respectively. Toxicity burden is similar between arms. Degree of HER2 pathway signaling and phosphorylation in pretreatment biopsy specimens are associated with response to both T-DM1/P and THP and can further identify highly responsive HER2+ tumors to HER2-directed therapy. This may help identify patients who can safely de-escalate cytotoxic chemotherapy without compromising excellent outcome

Safety and efficacy of HSP90 inhibitor ganetespib for neoadjuvant treatment of stage II/III breast cancer.

HSP90 inhibitors destabilize oncoproteins associated with cell cycle, angiogenesis, RAS-MAPK activity, histone modification, kinases and growth factors. We evaluated the HSP90-inhibitor ganetespib in combination with standard chemotherapy in patients with high-risk early-stage breast cancer. I-SPY2 is a multicenter, phase II adaptively randomized neoadjuvant (NAC) clinical trial enrolling patients with stage II-III breast cancer with tumors 2.5 cm or larger on the basis of hormone receptors (HR), HER2 and Mammaprint status. Multiple novel investigational agents plus standard chemotherapy are evaluated in parallel for the primary endpoint of pathologic complete response (pCR). Patients with HER2-negative breast cancer were eligible for randomization to ganetespib from October 2014 to October 2015. Of 233 women included in the final analysis, 140 were randomized to the standard NAC control; 93 were randomized to receive 150 mg/m2 ganetespib every 3 weeks with weekly paclitaxel over 12 weeks, followed by AC. Arms were balanced for hormone receptor status (51-52% HR-positive). Ganetespib did not graduate in any of the biomarker signatures studied before reaching maximum enrollment. Final estimated pCR rates were 26% vs. 18% HER2-negative, 38% vs. 22% HR-negative/HER2-negative, and 15% vs. 14% HR-positive/HER2-negative for ganetespib vs control, respectively. The predicted probability of success in phase 3 testing was 47% HER2-negative, 72% HR-negative/HER2-negative, and 19% HR-positive/HER2-negative. Ganetespib added to standard therapy is unlikely to yield substantially higher pCR rates in HER2-negative breast cancer compared to standard NAC, and neither HSP90 pathway nor replicative stress expression markers predicted response. HSP90 inhibitors remain of limited clinical interest in breast cancer, potentially in other clinical settings such as HER2-positive disease or in combination with anti-PD1 neoadjuvant chemotherapy in triple negative breast cancer.Trial registration: www.clinicaltrials.gov/ct2/show/NCT01042379

Ganitumab and metformin plus standard neoadjuvant therapy in stage 2/3 breast cancer.

I-SPY2 is an adaptively randomized phase 2 clinical trial evaluating novel agents in combination with standard-of-care paclitaxel followed by doxorubicin and cyclophosphamide in the neoadjuvant treatment of breast cancer. Ganitumab is a monoclonal antibody designed to bind and inhibit function of the type I insulin-like growth factor receptor (IGF-1R). Ganitumab was tested in combination with metformin and paclitaxel (PGM) followed by AC compared to standard-of-care alone. While pathologic complete response (pCR) rates were numerically higher in the PGM treatment arm for hormone receptor-negative, HER2-negative breast cancer (32% versus 21%), this small increase did not meet I-SPY\u27s prespecified threshold for graduation. PGM was associated with increased hyperglycemia and elevated hemoglobin A1c (HbA1c), despite the use of metformin in combination with ganitumab. We evaluated several putative predictive biomarkers of ganitumab response (e.g., IGF-1 ligand score, IGF-1R signature, IGFBP5 expression, baseline HbA1c). None were specific predictors of response to PGM, although several signatures were associated with pCR in both arms. Any further development of anti-IGF-1R therapy will require better control of anti-IGF-1R drug-induced hyperglycemia and the development of more predictive biomarkers

Assessment of Residual Cancer Burden and Event-Free Survival in Neoadjuvant Treatment for High-risk Breast Cancer: An Analysis of Data From the I-SPY2 Randomized Clinical Trial.

IMPORTANCE: Residual cancer burden (RCB) distributions may improve the interpretation of efficacy in neoadjuvant breast cancer trials. OBJECTIVE: To compare RCB distributions between randomized control and investigational treatments within subtypes of breast cancer and explore the relationship with survival. DESIGN, SETTING, AND PARTICIPANTS: The I-SPY2 is a multicenter, platform adaptive, randomized clinical trial in the US that compares, by subtype, investigational agents in combination with chemotherapy vs chemotherapy alone in adult women with stage 2/3 breast cancer at high risk of early recurrence. Investigational treatments graduated in a prespecified subtype if there was 85% or greater predicted probability of higher rate of pathologic complete response (pCR) in a confirmatory, 300-patient, 1:1 randomized, neoadjuvant trial in that subtype. Evaluation of a secondary end point was reported from the 10 investigational agents tested in the I-SPY2 trial from March 200 through 2016, and analyzed as of September 9, 2020. The analysis plan included modeling of RCB within subtypes defined by hormone receptor (HR) and ERBB2 status and compared control treatments with investigational treatments that graduated and those that did not graduate. INTERVENTIONS: Neoadjuvant paclitaxel plus/minus 1 of several investigational agents for 12 weeks, then 12 weeks of cyclophosphamide/doxorubicin chemotherapy followed by surgery. MAIN OUTCOMES AND MEASURES: Residual cancer burden (pathological measure of residual disease) and event-free survival (EFS). RESULTS: A total of 938 women (mean [SD] age, 49 [11] years; 66 [7%] Asian, 103 [11%] Black, and 750 [80%] White individuals) from the first 10 investigational agents were included, with a median follow-up of 52 months (IQR, 29 months). Event-free survival worsened significantly per unit of RCB in every subtype of breast cancer (HR-positive/ERBB2-negative: hazard ratio [HZR], 1.75; 95% CI, 1.45-2.16; HR-positive/ERBB2-positive: HZR, 1.55; 95% CI, 1.18-2.05; HR-negative/ERBB2-positive: HZR, 2.39; 95% CI, 1.64-3.49; HR-negative/ERBB2-negative: HZR, 1.99; 95% CI, 1.71-2.31). Prognostic information from RCB was similar from treatments that graduated (HZR, 2.00; 95% CI, 1.57-2.55; 254 [27%]), did not graduate (HZR, 1.87; 95% CI, 1.61-2.17; 486 [52%]), or were control (HZR, 1.79; 95% CI, 1.42-2.26; 198 [21%]). Investigational treatments significantly lowered RCB in HR-negative/ERBB2-negative (graduated and nongraduated treatments) and ERBB2-positive subtypes (graduated treatments), with improved EFS (HZR, 0.61; 95% CI, 0.41-0.93) in the exploratory analysis. CONCLUSIONS AND RELEVANCE: In this randomized clinical trial, the prognostic significance of RCB was consistent regardless of subtype and treatment. Effective neoadjuvant treatments shifted the distribution of RCB in addition to increasing pCR rate and appeared to improve EFS. Using a standardized quantitative method to measure response advances the interpretation of efficacy. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01042379

Association of Event-Free and Distant Recurrence-Free Survival With Individual-Level Pathologic Complete Response in Neoadjuvant Treatment of Stages 2 and 3 Breast Cancer: Three-Year Follow-up Analysis for the I-SPY2 Adaptively Randomized Clinical Trial.

Importance: Pathologic complete response (pCR) is a known prognostic biomarker for long-term outcomes. The I-SPY2 trial evaluated if the strength of this clinical association persists in the context of a phase 2 neoadjuvant platform trial. Objective: To evaluate the association of pCR with event-free survival (EFS) and pCR with distant recurrence-free survival (DRFS) in subpopulations of women with high-risk operable breast cancer treated with standard therapy or one of several novel agents. Design, Setting, and Participants: Multicenter platform trial of women with operable clinical stage 2 or 3 breast cancer with no prior surgery or systemic therapy for breast cancer; primary tumors were 2.5 cm or larger. Women with tumors that were ERBB2 negative/hormone receptor (HR) positive with low 70-gene assay score were excluded. Participants were adaptively randomized to one of several different investigational regimens or control therapy within molecular subtypes from March 2010 through 2016. The analysis included participants with follow-up data available as of February 26, 2019. Interventions: Standard-of-care neoadjuvant therapy consisting of taxane treatment with or without (as control) one of several investigational agents or combinations followed by doxorubicin and cyclophosphamide. Main Outcomes and Measures: Pathologic complete response and 3-year EFS and DRFS. Results: Of the 950 participants (median [range] age, 49 [23-77] years), 330 (34.7%) achieved pCR. Three-year EFS and DRFS for patients who achieved pCR were both 95%. Hazard ratios for pCR vs non-pCR were 0.19 for EFS (95% CI, 0.12-0.31) and 0.21 for DRFS (95% CI, 0.13-0.34) and were similar across molecular subtypes, varying from 0.14 to 0.18 for EFS and 0.10 to 0.20 for DRFS. Conclusions and Relevance: The 3-year outcomes from the I-SPY2 trial show that, regardless of subtype and/or treatment regimen, including 9 novel therapeutic combinations, achieving pCR after neoadjuvant therapy implies approximately an 80% reduction in recurrence rate. The goal of the I-SPY2 trial is to rapidly identify investigational therapies that may improve pCR when validated in a phase 3 confirmatory trial. Whether pCR is a validated surrogate in the sense that a therapy that improves pCR rate can be assumed to also improve long-term outcome requires further study. Trial Registration: ClinicalTrials.gov Identifier: NCT01042379