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Albain KS, Yau C, Petricoin EF, et al. Neoadjuvant Trebananib plus Paclitaxel-based Chemotherapy for Stage II/III Breast Cancer in the Adaptively Randomized I-SPY2 Trial—Efficacy and Biomarker Discovery. Clin Cancer Res30:729-740, 2024.

Kyalwazi B, Yau C, Campbell MJ, et al. Race, Gene Expression Signatures, and Clinical Outcomes of Patients With High-Risk Early Breast Cancer. JAMA Network Open6:e2349646, 2023.

Gallagher RI, Wulfkuhle J, Wolf DM, et al. Protein signaling and drug target activation signatures to guide therapy prioritization: Therapeutic resistance and sensitivity in the I-SPY 2 Trial. Cell Rep MedPublished online 2023:101312:, 2023.

Perlmutter J, Brain S, Brown T, et al. Advocate involvement in Clinical Trials: Lessons from the Patient-centric I-SPY2 Breast Cancer Trial. Med Res Arch11 (7.2):, 2023.

Boughey JC, Yu H, Dugan CL, et al. Changes in Surgical Management of the Axilla Over 11 Years – Report on More Than 1500 Breast Cancer Patients Treated with Neoadjuvant Chemotherapy on the Prospective I-SPY2 Trial. Ann Surg Oncol(published online):1-10, 2023.

Mukhtar RA, Chau H, Woriax H, et al. Breast Conservation Surgery and Mastectomy have Similar Locoregional Recurrence Following Neoadjuvant Chemotherapy: Results from 1,462 Patients on the Prospective, Randomized I-SPY2 Trial. Ann Surg(published ahead of print):, 2023.

Yu K, Basu A, Yau C, Wolf DM, Goodarzi H, Bandyopadhyay S, Korkola JE, Hirst GL, Asare S, DeMichele A, Hylton N, Yee D, Esserman L, van ‘t Veer L, Sirota M Computational drug repositioning for the identification of new agents to sensitize drug-resistant breast tumors across treatments and receptor subtypes. Frontiers in Oncol13:1192208, 2023.

Magbanua MGM, Brown-Swigart L, Ahmed Z, et al. Clinical significance and biology of circulating tumor DNA in high-risk early-stage HER2-negative breast cancer receiving neoadjuvant chemotherapy. Cancer Cell:, 2023.

Parker BA, Shatsky RA, Schwab RB, et al. Association of baseline ROR1 and ROR2 gene expression with clinical outcomes in the I-SPY2 neoadjuvant breast cancer trial. Breast Cancer Res Treat199:281–291, 2023.

Chitalia R, Miliotis M, Jahani N, et al. Radiomic tumor phenotypes augment molecular profiling in predicting recurrence free survival after breast neoadjuvant chemotherapy. Communications Med3:46, 2023.

Magbanua MGM, van ‘t Veer L, Clark AS, et al. Outcomes and clinicopathologic characteristics associated with disseminated tumor cells in bone marrow after neoadjuvant chemotherapy in high-risk early stage breast cancer: the I-SPY SURMOUNT study. Breast Cancer Res Treat198:383–390, 2023.

Lang JE, Forero-Torres A, Yee D, et al Safety and efficacy of HSP90 inhibitor ganetespib for neoadjuvant treatment of stage II/III breast cancer. npj Breast Cancer8:128, 2022.

Li W, Le NN, Onishi N, et al Diffusion-Weighted MRI for Predicting Pathologic Complete Response in Neoadjuvant Immunotherapy. Cancers14:4436-4448, 2022.

Osdoit M, Yau C, Symmans WF, et al. Association of Residual Ductal Carcinoma In Situ With Breast Cancer Recurrence in the Neoadjuvant I-SPY2 Trial. JAMA Surgery157:1034–1041, 2022.

Chitalia R, Pati S, Bhalerao M, et al. Expert tumor annotations and radiomics for locally advanced breast cancer in DCE-MRI for ACRIN 6657/I-SPY1. Scientific Data 9:440, 2022.

Wolf DM, Yau C, Wulfkuhle JD, et al. Redefining breast cancer subtypes to guide treatment prioritization and maximize response: Predictive biomarkers across 10 cancer therapies. Cancer Cell40:P609-623.E6, 2022.

Marczyk M, Mrukwa A, Yau C, et al. Treatment Efficacy Score—continuous residual cancer burden-based metric to compare neoadjuvant chemotherapy efficacy between randomized trial arms in breast cancer trials. Annals of Oncology33:814–823, 2022.

Le NN, Li W, Onishi N, et al. Effect of Inter-Reader Variability on Diffusion-Weighted MRI Apparent Diffusion Coefficient Measurements and Prediction of Pathologic Complete Response for Breast Cancer. Tomography8:1208–1220, 2022.

Thakran S, Cohen E, Jahani N, et al. Impact of deformable registration methods for prediction of recurrence free survival response to neoadjuvant chemotherapy in breast cancer: Results from the ISPY 1/ACRIN 6657 trial. Translat Oncol20:101411, 2022.

Nguyen AA-T, Onishi N, Carmona-Bozo J, et al. Post-Processing Bias Field Inhomogeneity Correction for Assessing Background Parenchymal Enhancement on Breast MRI as a Quantitative Marker of Treatment Response. Tomography8:891–904, 2022.

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Clin Cancer Res 30: 729-740, 2024.

Neoadjuvant Trebananib plus Paclitaxel-based Chemotherapy for Stage II/III Breast Cancer in the Adaptively Randomized I-SPY2 Trial—Efficacy and Biomarker Discovery

Albain KS, Yau C, Petricoin EF, Wolf DM, Lang JE, Chien AJ, Haddad T, Forero-Torres A, Wallace AM, Kaplan H, Pusztai L, Euhus D, Nanda R, Elias AD, Clark AS, Godellas C, Boughey JC, Isaacs C, Tripathy D, Lu J, Yung RL, Gallagher RI, Wulfkuhle JD, Brown-Swigart L, Krings G, Chen YY, Potter DA, Stringer-Reasor E, Blair S, Asare SM, Wilson A, Hirst GL, Singhrao R, Buxton M, Clennell JL, Sanil A, Berry S, Asare AL, Matthews JB, DeMichele AM, Hylton NM, Melisko M, Perlmutter J, Rugo HS, Symmans WF, Veer LJ van’t, Yee D, Berry DA, Esserman LJ

Purpose: The neutralizing peptibody trebananib prevents angiopoietin-1 and angiopoietin-2 from binding with Tie2 receptors, inhibiting angiogenesis and proliferation. Trebananib was combined with paclitaxel±trastuzumab in the I-SPY2 breast cancer trial.

Patients and Methods: I-SPY2, a phase II neoadjuvant trial, adaptively randomizes patients with high-risk, early-stage breast cancer to one of several experimental therapies or control based on receptor subtypes as defined by hormone receptor (HR) and HER2 status and MammaPrint risk (MP1, MP2). The primary endpoint is pathologic complete response (pCR). A therapy “graduates” if/when it achieves 85% Bayesian probability of success in a phase III trial within a given subtype. Patients received weekly paclitaxel (plus trastuzumab if HER2-positive) without (control) or with weekly intravenous trebananib, followed by doxorubicin/cyclophosphamide and surgery. Pathway-specific biomarkers were assessed for response prediction.

Results: There were 134 participants randomized to trebananib and 133 to control. Although trebananib did not graduate in any signature [phase III probabilities: Hazard ratio (HR)-negative (78%), HR-negative/HER2-positive (74%), HR-negative/HER2-negative (77%), and MP2 (79%)], it demonstrated high probability of superior pCR rates over control (92%–99%) among these subtypes. Trebananib improved 3-year event-free survival (HR 0.67), with no significant increase in adverse events. Activation levels of the Tie2 receptor and downstream signaling partners predicted trebananib response in HER2-positive disease; high expression of a CD8 T-cell gene signature predicted response in HR-negative/HER2-negative disease.

Conclusions: The angiopoietin (Ang)/Tie2 axis inhibitor trebananib combined with standard neoadjuvant therapy increased estimated pCR rates across HR-negative and MP2 subtypes, with probabilities of superiority >90%. Further study of Ang/Tie2 receptor axis inhibitors in validated, biomarker-predicted sensitive subtypes is warranted.

JAMA Network Open 6:e 2349646, 2023.

Race, Gene Expression Signatures, and Clinical Outcomes of Patients With High-Risk Early Breast Cancer

Kyalwazi B, Yau C, Campbell MJ, Yoshimatsu TF, Chien AJ, Wallace AM, Forero-Torres A, Pusztai L, Ellis ED, Albain KS, Blaes AH, Haley BB, Boughey JC, Elias AD, Clark AS, Isaacs CJ, Nanda R, Han HS, Yung RL, Tripathy D, Edmiston KK, Viscusi RK, Northfelt DW, Khan QJ, Asare SM, Wilson A, Hirst GL, Lu R, Symmans WF, Yee D, DeMichele AM, Veer LJ van ’t, Esserman LJ, Olopade OI.

Importance There has been little consideration of genomic risk of recurrence by breast cancer subtype despite evidence of racial disparities in breast cancer outcomes.

Objective To evaluate associations between clinical trial end points, namely pathologic complete response (pCR) and distant recurrence–free survival (DRFS), and race and examine whether gene expression signatures are associated with outcomes by race.

Design, Setting, and Participants This retrospective cohort study used data from the Investigation of Serial Studies to Predict Your Therapeutic Response With Imaging and Molecular Analysis 2 (I-SPY 2) multicenter clinical trial of neoadjuvant chemotherapy with novel agents and combinations for patients with previously untreated stage II/III breast cancer. Analyses were conducted of associations between race and short- and long-term outcomes, overall and by receptor subtypes, and their association with 28 expression biomarkers. The trial enrolled 990 female patients between March 30, 2010, and November 5, 2016, with a primary tumor size of 2.5 cm or greater and clinical or molecular high risk based on MammaPrint or hormone receptor (HR)-negative/ERBB2 (formerly HER2 or HER2/neu)–positive subtyping across 9 arms. This data analysis was performed between June 10, 2021, and October 20, 2022.

Exposure Race, tumor receptor subtypes, and genomic biomarker expression of early breast cancer.

Main Outcomes and Measures The primary outcomes were pCR and DRFS assessed by race, overall, and by tumor subtype using logistic regression and Cox proportional hazards regression models. The interaction between 28 expression biomarkers and race, considering pCR and DRFS overall and within subtypes, was also evaluated.

Results The analytic sample included 974 participants (excluding 16 self-reporting as American Indian or Alaska Native, Native Hawaiian or Other Pacific Islander, or multiple races due to small sample sizes), including 68 Asian (7%), 120 Black (12%), and 786 White (81%) patients. Median (range) age at diagnosis was 47 (25-71) years for Asian, 49 (25-77) for Black, and 49 (23-73) years for White patients. The pCR rates were 32% (n = 22) for Asian, 30% for Black (n = 36), and 32% for White (n = 255) patients (P = .87). Black patients with HR-positive/ERBB2-negative tumors not achieving pCR had significantly worse DRFS than their White counterparts (hazard ratio, 2.28; 95% CI, 1.24-4.21; P = .01), with 5-year DRFS rates of 55% (n = 32) and 77% (n = 247), respectively. Black patients with HR-positive/ERBB2-negative tumors, compared with White patients, had higher expression of an interferon signature (mean [SD], 0.39 [0.87] and −0.10 [0.99]; P = .007) and, compared with Asian patients, had a higher mitotic score (mean [SD], 0.07 [1.08] and −0.69 [1.06]; P = .01) and lower estrogen receptor/progesterone receptor signature (mean [SD], 0.31 [0.90] and 1.08 [0.95]; P = .008). A transforming growth factor β signature had a significant association with race relative to pCR and DRFS, with a higher signature associated with lower pCR and worse DRFS outcomes among Black patients only.

Conclusions and Relevance The findings show that women with early high-risk breast cancer who achieve pCR have similarly good outcomes regardless of race, but Black women with HR-positive/ERBB2-negative tumors without pCR may have worse DRFS than White women, highlighting the need to develop and test novel biomarker-informed therapies in diverse populations.

Ann Surg Oncol (published online) :1-10, 2023

Changes in Surgical Management of the Axilla Over 11 Years – Report on More Than 1500 Breast Cancer Patients Treated with Neoadjuvant Chemotherapy on the Prospective I-SPY2 Trial

Boughey JC, Yu H, Dugan CL, Piltin MA, Postlewait L, Son JD, Edmiston KK, Godellas CV, Lee MC, Carr MJ, Tonneson JE, Crown A, Lancaster RB, Woriax HE, Ewing CA, Chau HS, Patterson AK, Wong JM, Alvarado MD, Yang RL, Chan TW, Sheade JB, Ahrendt GM, Larson KE, Switalla K, Tuttle TM, Tchou JC, Rao R, Tamirisa N, Singh P, Gould RE, Terando A, Sauder C, Hewitt K, Chiba A, Esserman LJ, Mukhtar RA.

Background: Axillary surgery after neoadjuvant chemotherapy (NAC) is becoming less extensive. We evaluated the evolution of axillary surgery after NAC on the multi-institutional I-SPY2 prospective trial.

Methods: We examined annual rates of sentinel lymph node (SLN) surgery with resection of clipped node, if present), axillary lymph node dissection (ALND), and SLN and ALND in patients enrolled in I-SPY2 from January 1, 2011 to December 31, 2021 by clinical N status at diagnosis and pathologic N status at surgery. Cochran-Armitage trend tests were calculated to evaluate patterns over time.

Results: Of 1578 patients, 973 patients (61.7%) had SLN-only, 136 (8.6%) had SLN and ALND, and 469 (29.7%) had ALND-only. In the cN0 group, ALND-only decreased from 20% in 2011 to 6.25% in 2021 (p = 0.0078) and SLN-only increased from 70.0% to 87.5% (p = 0.0020). This was even more striking in patients with clinically node-positive (cN+) disease at diagnosis, where ALND-only decreased from 70.7% to 29.4% (p < 0.0001) and SLN-only significantly increased from 14.6% to 56.5% (p < 0.0001). This change was significant across subtypes (HR-/HER2-, HR+/HER2-, and HER2+). Among pathologically node-positive (pN+) patients after NAC (n = 525) ALND-only decreased from 69.0% to 39.2% (p < 0.0001) and SLN-only increased from 6.9% to 39.2% (p < 0.0001).

Conclusions: Use of ALND after NAC has significantly decreased over the past decade. This is most pronounced in cN+ disease at diagnosis with an increase in the use of SLN surgery after NAC. Additionally, in pN+ disease after NAC, there has been a decrease in use of completion ALND, a practice pattern change that precedes results from clinical trials.

Frontiers in Oncol 13: 1192208, 2023

Computational drug repositioning for the identification of new agents to sensitize drug-resistant breast tumors across treatments and receptor subtypes

Yu K, Basu A, Yau C, et al.

Introduction: Drug resistance is a major obstacle in cancer treatment and can involve a variety of different factors. Identifying effective therapies for drug resistant tumors is integral for improving patient outcomes.

Methods: In this study, we applied a computational drug repositioning approach to identify potential agents to sensitize primary drug resistant breast cancers. We extracted drug resistance profiles from the I-SPY 2 TRIAL, a neoadjuvant trial for early stage breast cancer, by comparing gene expression profiles of responder and non-responder patients stratified into treatments within HR/HER2 receptor subtypes, yielding 17 treatment-subtype pairs. We then used a rank-based pattern-matching strategy to identify compounds in the Connectivity Map, a database of cell line derived drug perturbation profiles, that can reverse these signatures in a breast cancer cell line. We hypothesize that reversing these drug resistance signatures will sensitize tumors to treatment and prolong survival.

Results: We found that few individual genes are shared among the drug resistance profiles of different agents. At the pathway level, however, we found enrichment of immune pathways in the responders in 8 treatments within the HR+HER2+, HR+HER2-, and HR-HER2- receptor subtypes. We also found enrichment of estrogen response pathways in the non-responders in 10 treatments primarily within the hormone receptor positive subtypes. Although most of our drug predictions are unique to treatment arms and receptor subtypes, our drug repositioning pipeline identified the estrogen receptor antagonist fulvestrant as a compound that can potentially reverse resistance across 13/17 of the treatments and receptor subtypes including HR+ and triple negative. While fulvestrant showed limited efficacy when tested in a panel of 5 paclitaxel resistant breast cancer cell lines, it did increase drug response in combination with paclitaxel in HCC-1937, a triple negative breast cancer cell line.

Conclusion: We applied a computational drug repurposing approach to identify potential agents to sensitize drug resistant breast cancers in the I-SPY 2 TRIAL. We identified fulvestrant as a potential drug hit and showed that it increased response in a paclitaxel-resistant triple negative breast cancer cell line, HCC-1937, when treated in combination with paclitaxel.

Breast Cancer Res Treat 198: 383–390, 2023.

Outcomes and clinicopathologic characteristics associated with disseminated tumor cells in bone marrow after neoadjuvant chemotherapy in high-risk early stage breast cancer: the I-SPY SURMOUNT study

Magbanua MGM, van ‘t Veer L, Clark AS, Chien AJ, Boughey JC, Han HS, Wallace A, Beckwith H, Liu MC, Yau C, Wileyto EP, Ordonez A, Solanki TI, Hsiao F, Lee JC, Basu A, Brown-Swigart L, Perlmutter J, Delson AL, Bayne L, Deluca S, Yee SS, Carpenter EL, Esserman LJ, Park JW, Chodosh LA, DeMichele A

Purpose: Disseminated tumor cells (DTCs) expressing epithelial markers in the bone marrow are associated with recurrence and death, but little is known about risk factors predicting their occurrence. We detected EPCAM+/CD45− cells in bone marrow from early stage breast cancer patients after neoadjuvant chemotherapy (NAC) in the I-SPY 2 Trial and examined clinicopathologic factors and outcomes.

Methods: Patients who signed consent for SURMOUNT, a sub-study of the I-SPY 2 Trial (NCT01042379), had bone marrow collected after NAC at the time of surgery. EPCAM+CD45− cells in 4 mLs of bone marrow aspirate were enumerated using immunomagnetic enrichment/flow cytometry (IE/FC). Patients with > 4.16 EPCAM+CD45− cells per mL of bone marrow were classified as DTC-positive. Tumor response was assessed using the residual cancer burden (RCB), a standardized approach to quantitate the extent of residual invasive cancer present in the breast and the axillary lymph nodes after NAC. Association of DTC-positivity with clinicopathologic variables and survival was examined.

Results: A total of 73 patients were enrolled, 51 of whom had successful EPCAM+CD45− cell enumeration. Twenty-four of 51 (47.1%) were DTC-positive. The DTC-positivity rate was similar across receptor subtypes, but DTC-positive patients were significantly younger (p = 0.0239) and had larger pretreatment tumors compared to DTC-negative patients (p = 0.0319). Twenty of 51 (39.2%) achieved a pathologic complete response (pCR). While DTC-positivity was not associated with achieving pCR, it was significantly associated with higher RCB class (RCB-II/III, 62.5% vs. RCB-0/I; 33.3%; Chi-squared p = 0.0373). No significant correlation was observed between DTC-positivity and distant recurrence-free survival (p = 0.38, median follow-up = 3.2 years).

Conclusion: DTC-positivity at surgery after NAC was higher in younger patients, those with larger tumors, and those with residual disease at surgery.

npj Breast Cancer 8: 128, 2022.

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

Nguyen AA-T, Onishi N, Carmona-Bozo J, Li W, aaLang JE, Forero-Torres A, Yee D, Yau C, Wolf D, Park J, Parker BA, Chien AJ, Wallace AM, Murthy R, Albain KS, Ellis ED, Beckwith H, Haley BB, Elias AD, Boughey JC, Yung RL, Isaacs C, Clark AS, Han HS, Nanda R, Khan QJ, Edmiston KK, Stringer-Reasor E, Price E, Joe B, Liu MC, Brown-Swigart L, Petricoin EF, Wulfkuhle JD, Buxton M, Clennell JL, Sanil A, Berry S, Asare SM, Wilson A, Hirst GL, Singhrao R, Asare AL, Matthews JB, Melisko M, Perlmutter J, Rugo HS, Symmans WF, van ‘t Veer LJ, Hylton NM, DeMichele AM, Berry DA, Esserman LJKornak J, Newitt DC, Hylton NM

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.

Cancers 14: 4436-4448, 2022.

Diffusion-Weighted MRI for Predicting Pathologic Complete Response in Neoadjuvant Immunotherapy

Li W, Le NN, Onishi N, Newitt DC, Wilmes LJ, Gibbs JE, Carmona-Bozo J, Liang J, Partridge SC, Price ER, Joe BN, Kornak J, Magbanua MJM, Nanda R, LeStage B, Esserman LJ, I-SPY Imaging Working Group, I-SPY Investigator Network, van’t Veer LJ, Hylton NM

Immunotherapy targets patients’ immune systems to fight cancer. The aim of this retrospective study is to assess tumor response to pre-operative immunotherapy and predict pathologic complete response using MRI at an early treatment time- point. Based on our analysis with a cohort from the multi-center I-SPY 2 clinical trial, we found diffusion-weighted MRI is superior to dynamic contrast-enhanced MRI, where the latter is a standard and most-commonly used MRI modality, in assessing immunotherapy, while no significant difference was observed in the control cohort where only standard chemotherapy was provided. This study tested the hypothesis that a change in the apparent diffusion coefficient (ADC) measured in diffusion-weighted MRI (DWI) is an independent imaging marker, and ADC performs better than functional tumor volume (FTV) for assessing treatment response in patients with locally advanced breast cancer receiving neoadjuvant immunotherapy. A total of 249 patients were randomized to standard neoadjuvant chemotherapy with pembrolizumab (pembro) or without pembrolizumab (control). DCE-MRI and DWI, performed prior to and 3 weeks after the start of treatment, were analyzed. Percent changes of tumor ADC metrics (mean, 5th to 95th percentiles of ADC histogram) and FTV were evaluated for the prediction of pathologic complete response (pCR) using a logistic regression model. The area under the ROC curve (AUC) estimated for the percent change in mean ADC was higher in the pembro cohort (0.73, 95% confidence interval [CI]: 0.52 to 0.93) than in the control cohort (0.63, 95% CI: 0.43 to 0.83). In the control cohort, the percent change of the 95th percentile ADC achieved the highest AUC, 0.69 (95% CI: 0.52 to 0.85). In the pembro cohort, the percent change of the 25th percentile ADC achieved the highest AUC, 0.75 (95% CI: 0.55 to 0.95). AUCs estimated for percent change of FTV were 0.61 (95% CI: 0.39 to 0.83) and 0.66 (95% CI: 0.47 to 0.85) for the pembro and control cohorts, respectively. Tumor ADC may perform better than FTV to predict pCR at an early treatment time-point during neoadjuvant immunotherapy.

JAMA Surgery 157:1034–1041, 2022.

Association of Residual Ductal Carcinoma In Situ With Breast Cancer Recurrence in the Neoadjuvant I-SPY2 Trial

Osdoit M, Yau C, Symmans WF, Boughey JC, Ewing CA, Balassanian R, Chen Y-Y, Krings G, Wallace AM, Zare S, Fadare O, Lancaster R, Wei S, Godellas CV, Tang P, Tuttle TM, Klein M, Sahoo S, Hieken TJ, Carter JM, Chen B, Ahrendt G, Tchou J, Feldman M, Tousimis E, Zeck J, Jaskowiak N, Sattar H, Naik AM, Lee MC, Rosa M, Khazai L, Rendi MH, Lang JE, Lu J, Tawfik O, Asare SM, Esserman LJ, Mukhtar RA

Importance: Pathologic complete response (pCR) after neoadjuvant chemotherapy (NAC) in breast cancer strongly correlates with overall survival and has become the standard end point in neoadjuvant trials. However, there is controversy regarding whether the definition of pCR should exclude or permit the presence of residual ductal carcinoma in situ (DCIS).

Objective: To examine the association of residual DCIS in surgical specimens after neoadjuvant chemotherapy for breast cancer with survival end points to inform standards for the assessment of pathologic complete response.

Design, Setting, and Participants: The study team analyzed the association of residual DCIS after NAC with 3-year event-free survival (EFS), distant recurrence-free survival (DRFS), and local-regional recurrence (LRR) in the I-SPY2 trial, an adaptive neoadjuvant platform trial for patients with breast cancer at high risk of recurrence. This is a retrospective analysis of clinical specimens and data from the ongoing I-SPY2 adaptive platform trial of novel therapeutics on a background of standard of care for early breast cancer. I-SPY2 participants are adult women diagnosed with stage II/III breast cancer at high risk of recurrence.

Interventions: Participants were randomized to receive taxane and anthracycline-based neoadjuvant therapy with or without 1 of 10 investigational agents, followed by definitive surgery.

Main Outcomes and Measures: The presence of DCIS and EFS, DRFS, and LRR.

Results: The study team identified 933 I-SPY2 participants (aged 24 to 77 years) with complete pathology and follow-up data. Median follow-up time was 3.9 years; 337 participants (36%) had no residual invasive disease (residual cancer burden 0, or pCR). Of the 337 participants with pCR, 70 (21%) had residual DCIS, which varied significantly by tumor-receptor subtype; residual DCIS was present in 8.5% of triple negative tumors, 15.6% of hormone-receptor positive tumors, and 36.6% of ERBB2-positive tumors. Among those participants with pCR, there was no significant difference in EFS, DRFS, or LRR based on presence or absence of residual DCIS.

Conclusions and Relevance: The analysis supports the definition of pCR as the absence of invasive disease after NAC regardless of the presence or absence of DCIS.

Annals of Oncology 33: 814–823, 2022.

Treatment Efficacy Score—continuous residual cancer burden-based metric to compare neoadjuvant chemotherapy efficacy between randomized trial arms in breast cancer trials

Marczyk M, Mrukwa A, Yau C, Wolf D, Chen Y-Y, Balassanian R, Nanda R, Parker BA, Krings G, Sattar H, Zeck JC, Albain KS, Boughey JC, Liu MC, Elias AD, Clark AS, Venters SJ, Shad S, Basu A, Asare SM, Buxton M, Asare AL, Rugo HS, Perlmutter J, DeMichele AM, Yee D, Berry DA, Veer L van’t, Symmans WF, Esserman L, Pusztai L, I-SPY Consortium

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.

Translat Oncol 20: 101411, 2022.

Impact of deformable registration methods for prediction of recurrence free survival response to neoadjuvant chemotherapy in breast cancer: Results from the ISPY 1/ACRIN 6657 trial

Thakran S, Cohen E, Jahani N, Weinstein SP, Pantalone L, Hylton N, Newitt D, DeMichele A, Davatzikos C, Kontos D

Purpose: Image registration plays a vital role in spatially aligning multiple MRI scans for better longitudinal assessment of tumor morphological features. The objective was to evaluate the effect of registration accuracy of six established deformable registration methods(ANTs, DRAMMS, ART, NiftyReg, SSD-FFD, and NMI-FFD) on the predictive value of extracted radiomic features when modeling recurrence-free-survival(RFS) for women after neoadjuvant chemotherapy(NAC) for locally advanced breast cancer.

Methods: 130 women had DCE-MRI scans available from the first two visits in the ISPY1/ACRIN-6657 cohort. We calculated the transformation field from each of the different deformable registration methods, and used it to compute voxel-wise parametric-response-maps(PRM) for established four kinetic features.104-radiomic features were computed from each PRM map to characterize intra-tumor heterogeneity. We evaluated performance for RFS using Cox-regression, C-statistic, and Kaplan-Meier(KM) plots.

Results: A baseline model(F1:Age, Race, and Hormone-receptor-status) had a 0.54 C-statistic, and model F2(baseline + functional-tumor-volume at early treatment visit(FTV2)) had 0.63. The F2+ANTs had the highest C-statistic(0.72) with the smallest landmark differences(5.40±4.40mm) as compared to other models. The KM curve for model F2 gave p=0.004 for separation between women above and below the median hazard compared to the model F1(p=0.31). A models augmented with radiomic features, also achieved significant KM curve separation(p<0.001) except the F2+ART model.

Conclusion: Incorporating image registration in quantifying changes in tumor heterogeneity during NAC can improve prediction of RFS. Radiomic features of PRM maps derived from warping the DCE-MRI kinetic maps using ANTs registration method further improved the early prediction of RFS as compared to other methods.