Quantum Leap Healthcare Collaborative

Abstract Introduction: The I-SPY2 neoadjuvant platform trial (NCT01042379) evaluates new therapies in high molecular risk, stage 2-3 breast cancer patients. Between 2010 and 2022, 24 therapies were tested in 2,117 patients. One-third of these patients had HER2-negative tumors with low expression of immune genes and no DNA repair deficiency (DRD) (HER2-/Immune-/DRD- subtype). These patients had very low pathologic complete response (pCR) rates (∼10% on average) across all treatment and control arms. We performed a high-throughput drug screen (n=386 compounds) in triple-negative (TN), immune-low, DRD-low breast cancer patient-derived organoids with confirmed in vitro resistance to platinum chemotherapy to identify effective treatments for this tumor type. HSP90 inhibitors, including ganetespib, were one of the most potent drug classes in the screen. HSP90 is an abundant chaperone protein involved in the folding of oncoproteins under basal conditions and during stress response. Neoadjuvant ganetespib was tested in I-SPY2 in combination with standard chemotherapy in HER2-negative breast cancer but did not meaningfully improve pCR rates (PMID 36456573). Here, we re-evaluate the ganetespib arm by Response Predictive Subtypes with 5-year median follow-up data, focused on patients with breast tumors of the HER2-/Immune-/DRD- subtype. Methods: HER2-/Immune-/DRD- patients (N=221; 79% HR+, 21% TN) and HER2-/Immune+ and/or DRD+ patients (N=219; 32% HR+, 68% TN) were randomized to neoadjuvant ganetespib (150 mg/m2 ganetespib every 3 weeks with paclitaxel, then doxorubicin plus cyclophosphamide (AC)) (n=38 HER2-/Immune-/DRD- and n=55 HER2-/Immune+ and/or DRD+), or standard neoadjuvant chemotherapy control (paclitaxel-AC) (n=183 HER2-/Immune-/DRD- and n=164 HER2-/Immune+ and/or DRD+). The primary endpoint, pCR, was defined as the absence of invasive disease in the breast and regional nodes at surgery. Distant relapse-free survival (DRFS) was assessed using Kaplan-Meier curves, with hazard ratios (HR) estimated by Cox regression. Residual cancer burden (RCB) and serial MRI-based functional tumor volume (FTV) were collected as investigational early measures of treatment efficacy in the neoadjuvant setting. Results: In HER2-/Immune-/DRD- patients, pCR rates were low in the ganetespib and control arms (13% vs. 9%), compared with 38% vs. 31%, respectively, in HER2-/Immune+ and/or DRD+ patients. In both subtypes, patients who achieved a pCR with either treatment had excellent DRFS (100% at 5 years). Interestingly, in HER2-/Immune-/DRD- patients treated with ganetespib with no pCR (n=32), we observed only 1 DRFS event, compared with 35 DRFS events in HER2-/Immune-/DRD- control-treated patients with no pCR (n=166); HR 0.12 (95% CI 0.02-0.90; p-value: 0.039). The respective DRFS at 5 years was 96% with ganetespib vs. 77% with control, showing a significantly improved DRFS with neoadjuvant ganetespib for HER2-/Immune-/DRD- patients, despite their non-pCR. This treatment effect remained significant when adjusted for hormone receptor status. Among non-pCR patients, RCB measure and FTV decrease explained a portion of ganetespib’s significant DRFS benefit. In contrast, ganetespib did not improve DRFS in HER2-/Immune+ and/or DRD+ patients compared with control. Conclusion: Our data suggest a promising role for ganetespib in improving long-term outcomes for patients with HER2-/Immune-/DRD- tumors, which account for 38% of all molecularly high-risk breast cancers, even in the absence of a pathologic complete response. Continuous measures of RCB and FTV may serve as early predictors of ganetespib’s long-term survival benefit in HER2-/Immune/-DRD- patients. Citation Format: T. B. V. Bui, D. M. Wolf, C. Yau, R. W. Sayaman, K. Chow, S. W. Choi, M. C. Bruck, K. Santos-Parker, A. M. Glas, J. E. Lang, A. Forero-Torres, L. Brown-Swigart, G. L. Hirst, E. F. Petricoin, J. Perlmutter, W. F. Symmans, P. R. Pohlmann, D. Yee, L. Pusztai, I-SPY investigators, N. M. Hylton, A. M. DeMichele, J. M. Rosenbluth, L. J. Esserman, L. J. Van 'T Veer. Neoadjuvant HSP90 inhibition with ganetespib significantly improves distant relapse-free survival in I-SPY2 patients with HER2-negative breast cancer with low expression of immune genes and no DNA repair deficiency [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS3-11-10.

Abstract Ductal carcinoma in situ (DCIS) of the breast is a heterogeneous, non-invasive condition characterized by the proliferation of malignant epithelial cells within the duct, with variable risk of progression to invasive disease. Current standard treatment involves surgical resection followed by possible adjuvant endocrine therapy and/or adjuvant radiation. However, a substantial proportion of DCIS may never progress to invasive disease and thus may be overtreated with the current standard of care. Consequently, active surveillance (AS) is emerging as a treatment option for patients with DCIS. DCIS is definitely a risk factor for breast cancer, and should be reframed as an opportunity for preventive intervention. RECAST (Re-evaluating Conditions for Active Surveillance Suitability as Treatment) is a Phase II adaptive platform trial studying the efficacy of up front endocrine therapy to identify appropriate candidates for long-term active surveillance versus those who would benefit from standard surgical treatment. Patients with hormone receptor positive DCIS of any grade undergo baseline breast MRI and are randomized to one of four hormonal therapy regimens, including standard endocrine therapy, z-endoxifen, elacestrant or HAV-008 with the potential to offer equivalent or improved benefit with less adverse effects. Serial MRI at 3 and 6 months is then used to evaluate change in background parenchymal enhancement (BPE) and DCIS lesion. Patients deemed low risk based on imaging response have the option to continue AS and avoid surgery and radiation and continue their endocrine therapy for 3 years. The primary endpoint of the trial is to determine whether novel endocrine therapy increases the fraction of patients who will be suitable for long-term AS as measured by the fraction of patients who remain on active surveillance at 7 months compared to control. To date, over 50 patients are enrolled in the trial. Our target accrual of 400 patients. A total of 17 (34%) patients have reported an AE, all grade 1 or 2, with no serious adverse events reported and no safety signals identified. Of the 50 patients currently on treatment, 25 have reached or gone beyond the 6-month mark and 22 (88%) of those patients remain on active surveillance with a median follow up of 351 days. At the 3 month point, one patient progressed on imaging and two chose to come off surveillance due to other reasons. At 6 months, 8% (2/25) progressed on imaging and one additional patient has proceeded to surgery at the 1 year point. One patient who went on to have surgery was found to have invasive disease (pT1bN0). Robust accrual continues at sixteen currently active sites with five more sites anticipated to open in the next few months. The shift to using hormonal therapy in the neoadjuvant setting allows investigators to assess response to endocrine therapy, characterize risk of progression to invasive cancer and helps to better inform treatment-making decisions before continuing AS or proceeding with surgery, and appropriately assesses the value of endocrine risk reduction prior to surgery to avoid it. The trial uses a patient-centered approach and gives all patients a window of opportunity to assess their response as well as medication tolerability to make an informed decision about treatment approach. Citation Format: K. C. Hewitt, C. Yau, R. Mukhtar, C. Thompson, J. Hui, K. Westbrook, J. Jackson, C. Carruthers, C. Farley, S. Bommakanti, K. Brownson, B. Fan, I. Meszoely, T. Balija, M. H. Mcnatt, P. Gilman, J. Marti, T. Li, S. Horton, A. Borowsky, J. Rosenbluth, L. Esserman. Initial results from RECAST DCIS: Multicenter platform trial testing active surveillance and novel endocrine therapy agents for DCIS management [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS3-03-08.

There has been little consideration of genomic risk of recurrence by breast cancer subtype despite evidence of racial disparities in breast cancer outcomes. 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. 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. Race, tumor receptor subtypes, and genomic biomarker expression of early breast cancer. 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. 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. 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.

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. 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. 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). 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.

Abstract Background: We compared the predictive and prognostic value of ctDNA dynamics in high-risk hormone receptor-positive/HER2-negative (HR+/HER2-) and triple negative breast cancer (TNBC) receiving neoadjuvant chemotherapy (NAC) enrolled in the I-SPY 2 trial (NCT01042379). To our knowledge, this is the largest ctDNA study in breast cancer in the neoadjuvant setting. Methods: Blood samples were collected at pre-treatment (T0), during treatment (T1 at 3 weeks, and T2 at 12 weeks) and after NAC (T3 at 24 weeks) from 106 HR+/HER2- and 97 TNBC patients. Plasma samples (n=734) were analyzed using a personalized and tumor-informed mPCR NGS-based ctDNA test (SignateraTM). Patients, all high risk for recurrence by MammaPrint, received paclitaxel-based treatment +/- experimental therapy followed by anthracycline. The median follow-up was 3.0 years (0.5 to 6.5). The predictive and prognostic value of ctDNA dynamics and status at different timepoints were examined. Our analysis is exploratory and does not adjust for other biomarkers. Results: Pretreatment ctDNA positivity (Fisher p&amp;lt;0.0001) and levels (mean tumor molecules/mL, MTM/mL, t test p=0.0062) were significantly higher in TNBC (90.7%, 14.7 MTM/mL) than in high risk HR+/HER2- (66.0%, 5.5 MTM/mL). Early and late ctDNA clearance during treatment (3 and 12 weeks of NAC) was predictive of pathologic complete response (pCR) and residual cancer burden (RCB), class 0-III, in TNBC but not HR+/HER2- (Table). In both subtypes: (1) ctDNA was a significant negative prognostic factor for distant recurrence-free survival (DRFS) at all timepoints (p&amp;lt;0.05) except at pretreatment; (2) all patients who achieved pCR were ctDNA-negative after NAC; (3) among non-responding patients, ctDNA-negativity after NAC was associated with improved DRFS (Table). Conclusions: The predictive value of ctDNA for prediction of pCR and RCB differed between subtypes (HR+/HER2- vs. TNBC), while similar prognostic value was observed. In TNBC, early clearance of ctDNA at 3 weeks was a significant predictor of favorable response to NAC. Compared to patients who were ctDNA-positive after NAC, ctDNA-negative status in both subtypes was associated with improved DRFS even in patients with residual cancer (no pCR or RCB-II/III). These findings could inform on the design of future studies that seek to demonstrate the utility of ctDNA in the curative setting. Predictive and prognostic significance of ctDNA in early breast cancer in the neoadjuvant setting HR+HER2- (n=106) TNBC (n=97) Predictive value for prediction of pCR and RCB Fisher p-value Fisher p-value Early ctDNA clearance (between T0 and T1) and pCR 0.4521 &amp;lt;0.0001 Late ctDNA clearance (between T0 and T2) and pCR 0.8071 0.0004 Early ctDNA clearance (between T0 and T1) and RCB (0-III) 0.1360 &amp;lt;0.0001 Late ctDNA clearance (between T0 and T2) and RCB (0-III) 0.4869 0.0004 Early ctDNA clearance at T1 and pCR rates pCR rate pCR rate ctDNA clearance (ctDNA+ at T0/ctDNA- at T1) 21% 67% Late ctDNA clearance (betweeNo early clearance (ctDNA+ at T0/ctDNA+ at T1) 13% 14% Prognostic value for prediction of DRFS Log rank p-value Log rank p-value ctDNA at T3 and pCR vs no PCR 0.0002 &amp;lt;0.0001 ctDNA at T3 and RCB (0-I vs II-III) 0.0110 &amp;lt;0.0001 Timepoints: T0 - pretreatment; T1 - three weeks after treatment initiation; T2 - at 12 weeks, between paclitaxel-based and anthracycline regimens; T3- after neoadjuvant chemotherapy prior to surgery Citation Format: Mark Jesus Mendoza Magbanua, Lamorna Brown Swigart, Derrick Renner, Svetlana Shchegrova, Gillian L. Hirst, Christina Yau, Denise M. Wolf, Hsin-Ta Wu, Ekaterina Kalashnikova, Amy L. Delson, A. Jo Chien, Debu Tripathy, Smita Asare, Raheleh Salari, Angel Rodriguez, Bernhard Zimmermann, Himanshu Sethi, Alexey Aleshin, Paul Billings, Rita Nanda, Hope S. Rugo, Laura J. Esserman, Minetta C. Liu, Angela DeMichele, Laura van 't Veer. Comparison of the predictive and prognostic significance of circulating tumor DNA in patients with high risk HER2-negative breast cancer receiving neoadjuvant chemotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB111.

Abstract Background: I-SPY2 is a multicenter, phase 2 trial using response-adaptive randomization within molecular subtypes defined by receptor status and MammaPrint risk to evaluate novel agents as neoadjuvant therapy for breast cancer. The primary endpoint is pathologic complete response (pCR, ypT0/is ypN0)). DNA repair deficiency in cancer cells can lead to immunogenic neoantigens, activation of the STING pathway, and PARP inhibition can also upregulate PD-L1 expression. Based on these rationales we tested the combination of durvalumab (anti-PDL1), olaparib (PARP inhibitor) and paclitaxel in I-SPY2. Methods: Women with tumors ≥ 2.5 cm were eligible for screening. Only HER2 negative (HER2-) patients were eligible for this treatment, hormone receptor positive (HR+) patients had to have MammaPrint high molecular profile. Treatment included durvalumab 1500 mg every 4 weeks x 3, olaparib 100 mg twice daily through weeks 1-11 concurrent with paclitaxel 80 mg/m2 weekly x 12 (DOP) followed by doxorubicin/cyclophosphamide (AC) x 4. The control arm was weekly paclitaxel x 12 followed by AC x 4. All patients undergo serial MRI imaging and imaging response at 3 &amp; 12 weeks combined with accumulating pCR data are used to estimate, and continuously update, predicted pCR rate for the trial arm. Regimens “graduation with success” when the Bayesian predictive probability of success in a 300-patient phase 3 neoadjuvant trial in the appropriate biomarker groups reaches &amp;gt; 85%. Results: A total of 73 patients received DOP treatment including 21 HR- tumors (i.e. triple-negative breast cancer, TNBC) and 52 HR+ tumors between May 2018 - June 2019. The control group included 299 patients with HER2- tumors. The DOP arm graduated in June 2019, 13 months after enrollment had started, for all HER2- negative and the HR+/HER2- cohorts with &amp;gt; 0.85% predictive probabilities of success. 72 patient completed surgery and evaluable for pCR, the final predicted probabilities of success in a future phase III trial to demonstrate higher pCR rate with DOP compared to control are 81% for all HER2- cancers (estimated pCR rate 37%), 80% for TNBC (estimated pCR rate 47%) and 74.5% for HR+/HER2- patients (estimated pCR rate 28%). Association between pCR and germline BRCA status and immune gene expression including PDL1 will be presented at the meeting. No unexpected toxicities were seen, but 10 patients (14%) had possibly immune or olaparib related grade 2/3 AEs (3 pneumonitis, 2 adrenal insufficiency, 1 colitis, 1 pancreatitis, 2 elevated LFT, 1 skin toxicity, 2 hypothyroidism, 1 hyperthyroidism, 1 esophagitis). Conclusion: I-SPY2 demonstrated a significant improvement in pCR with durvalumab and olaparib included with paclitaxel compared to chemotherapy alone in women with stage II/III high-risk, HER2-negative breast cancer, improvement was seen in both the HR+ and TNBC subsets. Citation Format: Lajos Pusztai, Hyo S. Han, Christina Yau, Denise Wolf, Anne M. Wallace, Rebecca Shatsky, Teresa Helsten, Judy C. Boughey, Tufia Haddad, Erica Stringer-Reasor, Carla Falkson, A. Jo Chien, Rita Mukhtar, Anthony Elias, Borges Virginia, Rita Nanda, Douglas Yee, Kevin Kalinsky, Kathy S. Albain, Aixa Soyano Muller, Kathleen Kemmer, Amy S. Clark, Claudine Isaacs, Alexandra Thomas, Nola Hylton, W. Fraser Symmans, Jane Perlmutter, Michelle Melisko, Hope S. Rugo, Richard Schwab, Amy Wilson, Amy Wilson, Ruby Singhrao, Smita Asare, Laura J. van't Veer, Angela M. DeMichele, Ashish Sanil, Donald A. Berry, Laura J. Esserman, Trial Consortium I-SPY 2. Evaluation of durvalumab in combination with olaparib and paclitaxel in high-risk HER2 negative stage II/III breast cancer: Results from the I-SPY 2 TRIAL [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT011.

The COVID-19 pandemic has rapidly changed delivery of cancer care. Many nonurgent surgeries are delayed to preserve hospital resources, and patient visits to health care settings are limited to reduce exposure to SARS-CoV-2. Providers must carefully weigh risks and benefits of delivering immunosuppressive therapy during the pandemic. For breast cancer, a key difference is increased use of neoadjuvant systemic therapy due to deferral of many breast surgeries during the pandemic. In some cases, this necessitates increased use of genomic tumor profiling on core biopsy specimens to guide neoadjuvant therapy decisions. Breast cancer treatment during the pandemic requires multidisciplinary input and varies according to stage, tumor biology, comorbidities, age, patient preferences, and available hospital resources. We present here the Johns Hopkins Women's Malignancies Program approach to breast cancer management during the COVID-19 pandemic. We include algorithms based on tumor biology and extent of disease that guide management decisions during the pandemic. These algorithms emphasize medical oncology treatment decisions and demonstrate how we have operationalized the general treatment recommendations during the pandemic proposed by national groups, such as the COVID-19 Pandemic Breast Cancer Consortium. Our recommendations can be adapted by other institutions and medical oncology practices in accordance with local conditions and resources. Guidelines such as these will be important as we continue to balance treatment of breast cancer against risk of SARS-CoV-2 exposure and infection until approval of a vaccine.

In this work, we address the problem of fast and accurate non-blind motion deblurring of a sequence of frames. We propose an approach based on single image non-blind deconvolution methods by extending them from two spatial dimensions onto a 2D+ time space. The resulted algorithms utilize recent advances of deep learning and heavily rely on learning the spatial and time correlations of frames from data which allows to perform the deblurring in an end-to-end fashion without the manual tuning of parameters. Developed algorithms were trained and tested on blurred video sequences, and as a result an improvement in restoration quality by around 1dB in terms of PSNR was achieved, comparing to a single-frame deconvolution. The proposed algorithms perform video restoration in a close to real-time speed, having potential for real applications in both portable consumer electronics and machine vision systems.

We present a method of memory footprint reduction for FFT-based, electromagnetic (EM) volume integral equation (VIE) formulations. The arising Green's function tensors have low multilinear rank, which allows Tucker decomposition to be employed for their compression, thereby greatly reducing the required memory storage for numerical simulations. Consequently, the compressed components are able to fit inside a graphical processing unit (GPU) on which highly parallelized computations can vastly accelerate the iterative solution of the arising linear system. In addition, the element-wise products throughout the iterative solver's process require additional flops, thus, we provide a variety of novel and efficient methods that maintain the linear complexity of the classic element-wise product with an additional multiplicative small constant. We demonstrate the utility of our approach via its application to VIE simulations for the Magnetic Resonance Imaging (MRI) of a human head. For these simulations we report an order of magnitude acceleration over standard techniques.