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  • 1
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    Abstract P3-09-01: Characterization of residual disease after neoadjuvant selective estrogen receptor degrader (SERD) therapy using tumor organoids in the I-SPY Endocrine Optimization Protocol (EOP)
    American Association for Cancer Research (AACR) ; 2023
    In:  Cancer Research Vol. 83, No. 5_Supplement ( 2023-03-01), p. P3-09-01-P3-09-01
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 5_Supplement ( 2023-03-01), p. P3-09-01-P3-09-01
    Abstract: Background: Treatment of estrogen receptor (ER)-positive breast cancer with selective estrogen receptor degraders (SERDs) frequently results in the loss or reduction of ER expression. Whether these changes are due to on-target effects of SERDs degrading ER or arise as a mechanism of tumor resistance with associated changes in cellular phenotypes remains unknown. It is critical to distinguish between these possibilities to accurately assess treatment response and determine the most appropriate subsequent therapy. To this end, we created and conducted molecular analyses on patient-derived organoid cultures from post-treatment tissue in patients receiving neoadjuvant SERD therapy for early-stage ER+ breast cancer in the I-SPY2 Endocrine Optimization Protocol (EOP). Methods: The I-SPY2 EOP study is a prospective, randomized substudy within the I-SPY TRIAL testing the oral SERD amcenestrant alone or in combination with letrozole or abemaciclib in stage 2/3 ER+ Her2-negative breast cancer. Enrollment is ongoing, with patients receiving amcenestrant neoadjuvantly for 6 months until the day before surgery. Tumor tissue is collected at baseline, 3 weeks, and at surgery. Organoids were generated from post-treatment surgical samples. Organoid cultures were optimized based on established methods (Dekkers et al., Nature Protocols, 2021) to assess ER levels and activity. Pre- and post-treatment tissue samples were also assessed for ER, PR, Ki67, and GATA3, a luminal marker and transcription factor that is functionally linked with ER, via immunohistochemistry. Results: In 7 patients with both pre- and post-treatment tissue samples including fresh surgical samples for organoid generation, the ER in baseline tumor tissue was & gt;=90% in all patients, PR ranged from 40-90%, and Ki67 ranged from 5-30%. In post-treatment surgical tissue from these cases, ER ranged from 0-30%, PR from 0-50%, Ki67 from & lt; 1%-10%, and GATA3 was positive in 5 of 5 cases tested to-date. The creation of organoids from residual disease at surgery was attempted for these 7 patients, with organoids successfully propagated in 5 cases thus far. 3 of 5 organoid cultures were ready for analysis and in all cases strong ER and PR expression in organoids was observed after culture for & gt; 1 month in the absence of amcenestrant. Detailed gene expression profiling (including Mammaprint/Blueprint) and gene set enrichment analyses (GSEA) to assess for intrinsic breast cancer subtype and ER activity in each sample and corresponding organoid culture are in progress and will be reported with the full dataset. Conclusion: Patient-derived organoid culturing of residual disease after neoadjuvant endocrine therapy is feasible. Neoadjuvant treatment with a SERD can render ER and PR low or absent at the time of surgical resection, which does not necessarily imply the presence of endocrine therapy resistant disease. The use of organoids and additional IHC markers (GATA3) demonstrate that receptor negativity may be an indicator of the drug hitting its target, suggesting ER signaling is still intact. In general, patient-derived tumor organoid cultures modeling residual disease states can be a useful adjunct to existing methods used to monitor the effects of neoadjuvant endocrine therapy and is being explored in the I-SPY EOP trial. Citation Format: Jennifer Rosenbluth, Christopher J. Schwartz, Tam Binh Bui, Shruti Warhadpande, Pravin Phadatare, Sigal Eini, Michael Bruck, Julissa Molina-Vega, Kami Pullakhandam, Nicole Schindler, Lamorna A. Brown Swigart, Christina Yau, Gillian Hirst, Rita Mukhtar, Karthik V. Giridhar, Olufunmilayo I. Olopade, Kevin Kalinsky, Cheryl A. Ewing, Jasmine M. Wong, Michael D. Alvarado, Laura Van’t Veer, Laura J. Esserman, Jo Chien. Characterization of residual disease after neoadjuvant selective estrogen receptor degrader (SERD) therapy using tumor organoids in the I-SPY Endocrine Optimization Protocol (EOP) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-09-01.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.SABCS22-P3-09-01
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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  • 2
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    Abstract P5-05-05: Monitoring for response and recurrence in neoadjuvant-treated hormone receptor-positive HER2-negative breast cancer by personalized circulating tumor DNA testing
    American Association for Cancer Research (AACR) ; 2023
    In:  Cancer Research Vol. 83, No. 5_Supplement ( 2023-03-01), p. P5-05-05-P5-05-05
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 5_Supplement ( 2023-03-01), p. P5-05-05-P5-05-05
    Abstract: Background: The detection of circulating tumor DNA (ctDNA) may serve as an early predictor of response and recurrence. In this study, we used a tumor-informed ctDNA test to monitor clinical outcomes in patients with high-risk hormone receptor-positive HER2-negative (HR+HER2-) tumors who received neoadjuvant chemotherapy (NAC) on the I-SPY 2 trial (NCT01042379). Methods: We collected blood samples at pretreatment, during (at 3 and 12 weeks after initiation of paclitaxel-based treatment with or without an investigational drug), after NAC prior to surgery, 4 weeks after surgery, and annually until clinical diagnosis of recurrence. Cell-free DNA was isolated from plasma (N=329 samples) and ctDNA was detected using a personalized, tumor-informed multiplex polymerase chain reaction next generation sequencing-based test (SignateraTM). All patients were at high risk for recurrence by MammaPrint. The response endpoints were pathologic complete response (pCR) and residual cancer burden (RCB), and the survival endpoint was event-free survival (EFS). Results: This analysis included 66 patients with HR+HER2- breast cancer who had blood samples collected before, during, after NAC and had at least one blood sample after surgery with sufficient plasma for analysis. 57.1% (32/56) had grade III disease; 72.4% (42/58) were node-positive; 36.2% (21/58) had T3/T4 disease; and 33.3% (22/66) were MammaPrint High 2. The percent ctDNA positivity rates at pretreatment, after NAC prior to surgery, and 4 weeks after surgery were 79.7% (47/59), 6.5% (4/62), and 2% (1/50), respectively. Significantly higher ctDNA positivity rates at pretreatment were observed in patients with larger tumors (95% in T3/T4 vs. 69% in T1/T2, Fisher’s exact p=0.0387), higher grade tumors (94% in Grade III vs. 67% in Grade I/II, p=0.0147) and by MammaPrint score (100% in High 2 vs. 71% in High 1, p=0.0052). In this high-risk HR+/HER2- cohort, 10/66 (15.2%) achieved pCR/RCB 0, who were all ctDNA-negative at surgery. 56/66 (84.8%) had no-PCR, with RCB I (limited residual cancer), II (moderate) and III (extensive) in 7 (10.6%), 31 (47.0%) and 18 (27.3%), respectively. ctDNA-positivity after paclitaxel-based treatment was significantly associated with RCB II/III status (Fisher’s exact p=0.01). All patients in this cohort with persistent ctDNA subsequently had RCB II or III at surgery. 47 patients had paired samples collected after NAC prior to surgery and at 4 weeks after surgery. Of the 47, 91.5% (43/47) were ctDNA-negative at both time points and 8.5% (4/47) were discordant; 1 was ctDNA-negative and later tested ctDNA-positive, while 3 were ctDNA-positive and later tested ctDNA-negative. 61/66 patients had EFS data with a median of 1.6 years of follow up (range: 0.6 to 5.6). 5 tested ctDNA-positive in at least one time point after surgery. Of these, 2 experienced a recurrence (one local relapse and one distant metastasis) and both tested positive at the time of recurrence. For the patient who developed a distant recurrence it was the only blood sample available at a follow-up time point; for the patient who developed a local recurrence, blood from two earlier follow-up time points had tested negative. To date, no recurrences have been observed in those whose test(s) after surgery were negative for ctDNA. Conclusions: The persistence of ctDNA during neoadjuvant therapy is associated with the extent of residual disease in a cohort of patients with HR+HER2- breast cancer in the I-SPY 2 trial and thus may be useful in identifying patients who are not having an optimal response to therapy. I-SPY 2.2 will test whether ctDNA has utility in redirecting therapy to improve surgical outcome and subsequent prognosis. Citation Format: Mark Jesus M. Magbanua, Hope Rugo, Lamorna A. Brown Swigart, Ziad Ahmed, Gillian L. Hirst, Denise M. Wolf, Ruixiao Lu, Ekaterina Kalashnikova, Derrick Renner, Angel Rodriguez, Minetta C. Liu, Christina Yau, Laura J. Esserman, Laura Van ’t Veer, Angela DeMichele. Monitoring for response and recurrence in neoadjuvant-treated hormone receptor-positive HER2-negative breast cancer by personalized circulating tumor DNA testing [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P5-05-05.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.SABCS22-P5-05-05
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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  • 3
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    Abstract PD5-04: PD5-04 Characterizing the HER2-/Immune-/DNA repair (DRD-) response predictive breast cancer subtype: the hunt for new protein targets in a high-needs population with low response to all I-SPY2 agents
    American Association for Cancer Research (AACR) ; 2023
    In:  Cancer Research Vol. 83, No. 5_Supplement ( 2023-03-01), p. PD5-04-PD5-04
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 5_Supplement ( 2023-03-01), p. PD5-04-PD5-04
    Abstract: Background: In previous work we leveraged the I-SPY2 trial to create treatment response predictive subtypes (RPS) incorporating tumor biology beyond clinical HR/HER2, to better predict drug responses in an expanded treatment landscape that includes platinum agents, dual HER2-targeting regimens and immunotherapy [1]. We showed that best performing schemas incorporate Immune, DRD and HER2/Luminal phenotypes, and that treatment allocation based on these would increase the overall pCR rate to 63% from 51% using HR/HER2-based treatment selection. The RPS schema has been selected for prospective evaluation in I-SPY2. Using the RPS, one would prioritize platinum-based therapy for HER2-/Immune-/DRD+, immunotherapy for HER2-/Immune+, and dual-anti-HER2 for HER2+ that are not luminal. HER2+/Luminal patients have low response rates to dual-anti-HER2 therapy but may respond better to anti-AKT. However, there is still a considerable ‘biomarker-negative’ group of resistant cancers (HER2-/Immune-/DRD-) with very low pCR rates to all tested agents, that require a new therapeutic approach. Here we characterize the protein signaling architecture of these tumors to identify new target candidates. Methods: 987 I-SPY 2 patients from 10 arms of the trial were considered for this analysis. All have gene expression, pCR and RPS; 944 have distant recurrence free survival (DRFS) data; and 736 have reverse phase protein array (RPPA) data from laser capture microdissected tumor epithelium. These data – known collectively as the I-SPY2-990 mRNA/RPPA Data Resource - were recently made public on NCBI’s Gene Expression Omnibus [GEO: GSE196096] . We focus on HER2-/Immune-/DRD- tumors, applying Wilcoxon and t-tests to identify phosphoproteins that differ between HR+HER2-/Immune-/DRD- and other HR+HER2- tumors; and between TN/Immune-/DRD- and other TNs. The Benjamini-Hochberg (BH) method is used to adjust p-values for multiple hypothesis testing. In addition, the Kaplan-Meier method is used to estimate DRFS. Results: 201/736 I-SPY 2 patients with RPPA data are classified HER2-/Immune-/DRD- (HR+HER2-: n=138; TN: n=63). Of these, 8.5% (17/201) achieved pCR. Non-responding HER2-/Immune-DRD- had worse outcomes than responders (~75% vs. ~95% DRFS at 5 years). 60/139 phospho-proteins differ significantly between HR+HER2-/Immune-/DRD- and other HR+HER2- tumors (n=122). These tumors are relatively ‘cold’, in that 90% (54/60) of the phosphoprotein activities characterizing this group are at lower levels than in the overall HR+HER2- population; including immune (e.g. pPDL1, pJAK/STAT) and proliferation (e.g., Ki67, CyclinB1, pAURK) endpoints. Phosphoproteins showing higher levels in this subset include ERBB2 (BH p=1.7E-06), Cyclin D1 (BH p=1.4E-05), pAR (BH p=1.4E-05), and ER (BH p=3E-04). Within the TN subset, only 3/139 phospho-proteins differed significantly between TN/Immune-/DRD- and other TN tumors (n=189). These were all immune-related (pPDL1, pSTAT1, and HLA DR), with lower expression in the TN/Immune-/DRD- group. Conclusion: HR+HER2- and TN patients who are Immune-Low and DRD-Low have very low pCR rates to all tested therapeutics in I-SPY2 including standard chemotherapy, platinum, and immunotherapy. Senolytics (possibly targeting Cyclin D1), HER2low agents, and AR modulators may overcome resistance in HR+HER2-/Immune-/DRD-, whereas an immune activator beyond checkpoint inhibition is suggested for TN/Immune-/DRD- patients. [1] Wolf et. al., Redefining Breast Cancer Subtypes to Guide Treatment Prioritization and Maximize Response: Predictive Biomarkers across 10 Cancer Therapies. Cancer Cell 2022 Citation Format: Denise M. Wolf, Christina Yau, Julia Wulfkuhle, Rosa I. Gallagher, Lamorna A. Brown Swigart, Gillian L. Hirst, Jean-Philippe Coppe, Mark Jesus M. Magbanua, Rosalyn Sayaman, I-SPY2 Investigators, Laura Sit, Nola M. Hylton, Angela DeMichele, Donald A. Berry, Lajos Pusztai, Douglas Yee, Laura J. Esserman, Emanuel F. Petricoin, Laura Van ’t Veer. PD5-04 Characterizing the HER2-/Immune-/DNA repair (DRD-) response predictive breast cancer subtype: the hunt for new protein targets in a high-needs population with low response to all I-SPY2 agents [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD5-04.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.SABCS22-PD5-04
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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  • 4
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    Abstract PD5-02: PD5-02 An Organoid Model System to Study Resistance Mechanisms, Predictive Biomarkers, and New Strategies to Overcome Therapeutic Resistance in Early-Stage Triple-Negative Breast Cancer
    American Association for Cancer Research (AACR) ; 2023
    In:  Cancer Research Vol. 83, No. 5_Supplement ( 2023-03-01), p. PD5-02-PD5-02
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 5_Supplement ( 2023-03-01), p. PD5-02-PD5-02
    Abstract: Background: While new treatments and improved subtyping schemas are anticipated to improve treatment response in triple-negative breast cancer (TNBC) patients, therapeutic resistance remains a significant challenge. Moreover, there is an urgent need for additional research model systems to study resistance and residual disease in breast cancer, including aggressive subtypes of breast cancer. Organoid culture is a promising technology used for growing breast cancer cells with high efficiency; however, the extent to which treatment resistance can be modeled using this system is unknown. This research used patient-derived organoid cultures in the context of computational analyses of large molecular and clinical datasets to study resistance mechanisms, biomarkers, and alternative treatment strategies to overcome drug resistance in early-stage TNBC. Methods: Organoid cultures were derived from breast tumor samples (taken from lumpectomy, mastectomy, or core biopsy samples), digested to the organoid level using collagenase, and grown in three dimensional cultures using a basement membrane extract and a fully-defined organoid medium (Dekkers et al. Nat Protoc 2021). An evaluation of all available I-SPY2 biomarker data (Wolf et al. Cancer Cell 2022) was performed focusing on genes, proteins, and pathways associated with resistance. These were then used to study whether resistance biomarkers identified in patient tumors are also present in organoids propagated from breast cancer post-treatment residual disease. To this end, bulk RNA sequencing data of organoids were normalized and merged with the TCGA dataset (Hoadley et al. Cell 2018) to enable analysis in a larger context, and immunofluorescence staining of organoids was performed. A high-throughput 386 anti-cancer drug compound screen and subsequent synergy testing with the most promising compounds were performed to identify and predict alternative treatment strategies. Additional assays to explore kinome activity in this organoid model are in progress. Results: A TNBC organoid biobank was established (n=31), which was enriched for inflammatory breast cancer (IBC; n=15), an aggressive form of breast cancer. Most organoids were derived from residual disease after neoadjuvant therapy. Bulk RNA sequencing analysis performed on 10 TNBC organoids revealed 3 subsets that were characterized predominantly by either normal-like/luminal androgen receptor or basal-like features or expressed distinct gene expression profiles, with IBC cases present in all 3 subsets. Intriguingly, the IBC organoids were characterized by higher expression of a number of immune-related signatures, despite an absence of clear immune cells in culture. A residual disease IBC/TNBC organoid resistant to chemotherapy was used to perform the 386-drug compound screen. The organoid model showed resistance to veliparib-cisplatin, consistent with the expression of gene/protein biomarkers predictive of drug resistance found in I-SPY2 (low PARPi7 levels and high pFOXO1 and pMEK1/2 expression). In addition, the screen identified multiple classes of inhibitors as promising synergistic/additive candidates for overcoming resistance to cisplatin. Conclusion: In this proof-of-principle study, we demonstrated the utility of matching I-SPY2 resistance biomarkers and signatures to residual disease tumor organoid cultures. We show that tumor organoid cultures modeling drug resistance states are a useful complement to existing research models of breast cancer and can be used for compound testing. We have developed a pipeline to propagate residual tumors from patients enrolled in I-SPY2 into organoid cultures to create a broader platform for preclinical drug testing informed by tumor biology with the ultimate goal of enabling faster, more successful translational studies and increased treatment options for resistant disease. Citation Format: Tam Binh V. Bui, Denise M. Wolf, Kaitlin Moore, Isaac S. Harris, Pravin Phadatare, Christina Yau, Lamorna A. Brown Swigart, Laura J. Esserman, Jean-Philippe Coppe, Julia Wulfkuhle, Emanuel F. Petricoin, Michael Campbell, Laura M. Selfors, Deborah A. Dillon, Beth Overmoyer, Filipa Lynce, Laura Van ’t Veer, Jennifer Rosenbluth. PD5-02 An Organoid Model System to Study Resistance Mechanisms, Predictive Biomarkers, and New Strategies to Overcome Therapeutic Resistance in Early-Stage Triple-Negative Breast Cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD5-02.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.SABCS22-PD5-02
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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  • 5
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    Ganitumab and metformin plus standard neoadjuvant therapy in stage 2/3 breast cancer
    Springer Science and Business Media LLC ; 2021
    In:  npj Breast Cancer Vol. 7, No. 1 ( 2021-10-05)
    Details
    In: npj Breast Cancer, Springer Science and Business Media LLC, Vol. 7, No. 1 ( 2021-10-05)
    Abstract: 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’s 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.
    Type of Medium: Online Resource
    ISSN: 2374-4677
    URL: Article
    DOI: 10.1038/s41523-021-00337-2
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2021
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  • 6
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    Report of the first seven agents in the I-SPY COVID trial: a phase 2, open label, adaptive platform randomised controlled trial
    Elsevier BV ; 2023
    In:  eClinicalMedicine Vol. 58 ( 2023-04), p. 101889-
    Details
    In: eClinicalMedicine, Elsevier BV, Vol. 58 ( 2023-04), p. 101889-
    Type of Medium: Online Resource
    ISSN: 2589-5370
    URL: Article
    DOI: 10.1016/j.eclinm.2023.101889
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2023
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  • 7
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    Safety and efficacy of HSP90 inhibitor ganetespib for neoadjuvant treatment of stage II/III breast cancer
    Springer Science and Business Media LLC ; 2022
    In:  npj Breast Cancer Vol. 8, No. 1 ( 2022-12-01)
    Details
    In: npj Breast Cancer, Springer Science and Business Media LLC, Vol. 8, No. 1 ( 2022-12-01)
    Abstract: 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/m 2 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
    Type of Medium: Online Resource
    ISSN: 2374-4677
    URL: Article
    DOI: 10.1038/s41523-022-00493-z
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2022
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  • 8
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    Neoadjuvant T-DM1/pertuzumab and paclitaxel/trastuzumab/pertuzumab for HER2+ breast cancer in the adaptively randomized I-SPY2 trial
    Springer Science and Business Media LLC ; 2021
    In:  Nature Communications Vol. 12, No. 1 ( 2021-11-05)
    Details
    In: Nature Communications, Springer Science and Business Media LLC, Vol. 12, No. 1 ( 2021-11-05)
    Abstract: 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 〉 2.5 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 ‘graduate’ 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.
    Type of Medium: Online Resource
    ISSN: 2041-1723
    URL: Article
    DOI: 10.1038/s41467-021-26019-y
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2021
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  • 9
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    Durvalumab With Olaparib and Paclitaxel for High-Risk HER2-Negative Stage II/III Breast Cancer: Results From the Adaptively Randomized I-SPY2 Platform Trial
    Elsevier BV ; 2020
    In:  SSRN Electronic Journal
    Details
    In: SSRN Electronic Journal, Elsevier BV
    Type of Medium: Online Resource
    ISSN: 1556-5068
    URL: Article
    DOI: 10.2139/ssrn.3751802
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2020
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  • 10
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    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
    Springer Science and Business Media LLC ; 2023
    In:  Breast Cancer Research and Treatment Vol. 198, No. 2 ( 2023-04), p. 383-390
    Details
    In: Breast Cancer Research and Treatment, Springer Science and Business Media LLC, Vol. 198, No. 2 ( 2023-04), p. 383-390
    Type of Medium: Online Resource
    ISSN: 0167-6806 , 1573-7217
    URL: Article
    DOI: 10.1007/s10549-022-06803-0
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2023
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