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  • 1
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    Quantitative Comparison of Prone and Supine PERCIST Measurements in Breast Cancer
    MDPI AG ; 2020
    In:  Tomography Vol. 6, No. 2 ( 2020-06-01), p. 170-176
    Details
    In: Tomography, MDPI AG, Vol. 6, No. 2 ( 2020-06-01), p. 170-176
    Abstract: Positron emission tomography (PET) is typically performed in the supine position. However, breast magnetic resonance imaging (MRI) is performed in prone, as this improves visibility of deep breast tissues. With the emergence of hybrid scanners that integrate molecular information from PET and functional information from MRI, it is of great interest to determine if the prognostic utility of prone PET is equivalent to supine. We compared PERCIST (PET Response Criteria in Solid Tumors) measurements between prone and supine FDG-PET in patients with breast cancer and the effect of orientation on predicting pathologic complete response (pCR). In total, 47 patients were enrolled and received up to 6 cycles of neoadjuvant therapy. Prone and supine FDG-PET were performed at baseline (t0; n = 46), after cycle 1 (t1; n = 1) or 2 (t2; n = 10), or after all neoadjuvant therapy (t3; n = 19). FDG uptake was quantified by maximum and peak standardized uptake value (SUV) with and without normalization to lean body mass; that is, SUVmax, SUVpeak, SULmax, and SULpeak. PERCIST measurements were performed for each paired baseline and post-treatment scan. Receiver operating characteristic analysis for the prediction of pCR was performed using logistic regression that included age and tumor size as covariates. SUV and SUL metrics were significantly different between orientation (P 〈 .001), but were highly correlated (P 〉 .98). Importantly, no differences were observed with the PERCIST measurements (P 〉 .6). Overlapping 95% confidence intervals for the receiver operating characteristic analysis suggested no difference at predicting pCR. Therefore, prone and supine PERCIST in this data set were not statistically different.
    Type of Medium: Online Resource
    ISSN: 2379-139X
    URL: Article
    URL: Article
    DOI: 10.18383/j.tom.2020.00002
    DOI: 10.18383/j.tom.2020.00002.sup.01
    Language: English
    Publisher: MDPI AG
    Publication Date: 2020
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  • 2
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    TBCRC 032 IB/II Multicenter Study: Molecular Insights to AR Antagonist and PI3K Inhibitor Efficacy in Patients with AR+ Metastatic Triple-Negative Breast Cancer
    American Association for Cancer Research (AACR) ; 2020
    In:  Clinical Cancer Research Vol. 26, No. 9 ( 2020-05-01), p. 2111-2123
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 26, No. 9 ( 2020-05-01), p. 2111-2123
    Abstract: Preclinical data demonstrating androgen receptor (AR)–positive (AR+) triple-negative breast cancer (TNBC) cells are sensitive to AR antagonists, and PI3K inhibition catalyzed an investigator-initiated, multi-institutional phase Ib/II study TBCRC032. The trial investigated the safety and efficacy of the AR-antagonist enzalutamide alone or in combination with the PI3K inhibitor taselisib in patients with metastatic AR+ (≥10%) breast cancer. Patients and Methods: Phase Ib patients [estrogen receptor positive (ER+) or TNBC] with AR+ breast cancer received 160 mg enzalutamide in combination with taselisib to determine dose-limiting toxicities and the maximum tolerated dose (MTD). Phase II TNBC patients were randomized to receive either enzalutamide alone or in combination with 4 mg taselisib until disease progression. Primary endpoint was clin ical benefit rate (CBR) at 16 weeks. Results: The combination was tolerated, and the MTD was not reached. The adverse events were hyperglycemia and skin rash. Overall, CBR for evaluable patients receiving the combination was 35.7%, and median progression-free survival (PFS) was 3.4 months. Luminal AR (LAR) TNBC subtype patients trended toward better response compared with non-LAR (75.0% vs. 12.5%, P = 0.06), and increased PFS (4.6 vs. 2.0 months, P = 0.082). Genomic analyses revealed subtype-specific treatment response, and novel FGFR2 fusions and AR splice variants. Conclusions: The combination of enzalutamide and taselisib increased CBR in TNBC patients with AR+ tumors. Correlative analyses suggest AR protein expression alone is insufficient for identifying patients with AR-dependent tumors and knowledge of tumor LAR subtype and AR splice variants may identify patients more or less likely to benefit from AR antagonists.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-19-2170
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
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  • 3
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    Exploring homologous recombination deficiency thresholds for predicting response to platinum-based treatment in triple negative breast cancer.
    American Society of Clinical Oncology (ASCO) ; 2022
    In:  Journal of Clinical Oncology Vol. 40, No. 16_suppl ( 2022-06-01), p. 525-525
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 40, No. 16_suppl ( 2022-06-01), p. 525-525
    Abstract: 525 Background: Homologous recombination deficiency (HRD) status can be used to identify patients who are eligible for treatment with DNA damaging agents. Using a 3-biomarker Genomic Instability Score (GIS) threshold of ≥42, studies have previously examined the association between HRD status and outcomes in patients with triple negative breast cancer (TNBC). However, evidence suggests that a GIS threshold of ≥33 may be more appropriate. Here, we conducted an exploratory analysis evaluating the ability of ≥33 and ≥42 GIS thresholds to predict response to platinum-based treatment in patients with TNBC. Methods: Patients across 5 cohorts (TBCRC030 1 , TBCRC008 2 , NCT01372579 3 , PrECOG 0105 4 , combined cisplatin cohort 4 ) were included in this analysis if they had a primary TNBC diagnosis, received neoadjuvant platinum-based treatment, had a valid GIS, and had known pathologic complete response (pCR) status. GIS was determined by a combination of loss of heterozygosity, telomeric-allelic imbalance, and large-scale state transitions. 4,5 BRCA mutation status was defined by loss of function resulting from a pathogenic variant in BRCA1 or BRCA2. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV), were calculated by comparing binary threshold status and binary pCR status. Results: A total of 204 tumors (158 BRCAwt; 33 BRCAm; 13 unknown) were included; pCR to platinum-based treatment occurred in 55 cases (39 BRCAwt; 14 BRCAm; 2 unknown). Sensitivity, specificity, PPV, and NPV were comparable between the ≥33 and ≥42 GIS thresholds, with the ≥33 threshold producing higher sensitivity values. This was true when thresholds were applied to all samples and to BRCAwt samples only (Table). Among patients who achieved pCR in response to platinum-based treatment, 5.5% of patients in the full cohort and 7.7% of those in the BRCAwt cohort had a GIS between 33-41. Conclusions: To ensure that the majority of patients likely to benefit from treatment are identified, a GIS of ≥33 may be the most appropriate threshold to predict response to platinum-based treatment in patients with TNBC; however, a prospective trial will be needed to confirm these findings. Additional studies will be important to determine whether this threshold may be appropriate to determine eligibility for other DNA-damaging agents such as PARP inhibitors. 1. Ann Oncol. 2020;31(11):1518-25 2. J Nucl Med. 2015;56(1):31-7. 3. Breast Cancer Res Treat. 2015;151(3):629-38. 4. Clin Cancer Res. 2016;22(15):3764-73. 5. Breast Cancer Res Treat. 2014;16(6):1-9. [Table: see text]
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2022.40.16_suppl.525
    RVK:
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    RVK:
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2022
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  • 4
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    Impact of HER2 Heterogeneity on Treatment Response of Early-Stage HER2-Positive Breast Cancer: Phase II Neoadjuvant Clinical Trial of T-DM1 Combined with Pertuzumab
    American Association for Cancer Research (AACR) ; 2021
    In:  Cancer Discovery Vol. 11, No. 10 ( 2021-10-01), p. 2474-2487
    Details
    In: Cancer Discovery, American Association for Cancer Research (AACR), Vol. 11, No. 10 ( 2021-10-01), p. 2474-2487
    Abstract: Intratumor heterogeneity is postulated to cause therapeutic resistance. To prospectively assess the impact of HER2 (ERBB2) heterogeneity on response to HER2-targeted therapy, we treated 164 patients with centrally confirmed HER2-positive early-stage breast cancer with neoadjuvant trastuzumab emtansine plus pertuzumab. HER2 heterogeneity was assessed on pretreatment biopsies from two locations of each tumor. HER2 heterogeneity, defined as an area with ERBB2 amplification in & gt;5% but & lt;50% of tumor cells, or a HER2-negative area by FISH, was detected in 10% (16/157) of evaluable cases. The pathologic complete response rate was 55% in the nonheterogeneous subgroup and 0% in the heterogeneous group (P & lt; 0.0001, adjusted for hormone receptor status). Single-cell ERBB2 FISH analysis of cellular heterogeneity identified the fraction of ERBB2 nonamplified cells as a driver of therapeutic resistance. These data suggest HER2 heterogeneity is associated with resistance to HER2-targeted therapy and should be considered in efforts to optimize treatment strategies. Significance: HER2-targeted therapies improve cure rates in HER2-positive breast cancer, suggesting chemotherapy can be avoided in a subset of patients. We show that HER2 heterogeneity, particularly the fraction of ERBB2 nonamplified cancer cells, is a strong predictor of resistance to HER2 therapies and could potentially be used to optimize treatment selection. See related commentary by Okines and Turner, p. 2369. This article is highlighted in the In This Issue feature, p. 2355
    Type of Medium: Online Resource
    ISSN: 2159-8274 , 2159-8290
    URL: Article
    DOI: 10.1158/2159-8290.CD-20-1557
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
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  • 5
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    Identifying homologous recombination deficiency in breast cancer: genomic instability score distributions differ among breast cancer subtypes
    Springer Science and Business Media LLC ; 2023
    In:  Breast Cancer Research and Treatment Vol. 202, No. 1 ( 2023-11), p. 191-201
    Details
    In: Breast Cancer Research and Treatment, Springer Science and Business Media LLC, Vol. 202, No. 1 ( 2023-11), p. 191-201
    Abstract: A 3-biomarker homologous recombination deficiency (HRD) score is a key component of a currently FDA-approved companion diagnostic assay to identify HRD in patients with ovarian cancer using a threshold score of ≥ 42, though recent studies have explored the utility of a lower threshold (GIS ≥ 33). The present study evaluated whether the ovarian cancer thresholds may also be appropriate for major breast cancer subtypes by comparing the genomic instability score (GIS) distributions of BRCA1/2 -deficient estrogen receptor–positive breast cancer (ER + BC) and triple-negative breast cancer (TNBC) to the GIS distribution of BRCA1/2- deficient ovarian cancer. Methods Ovarian cancer and breast cancer (ER + BC and TNBC) tumors from ten study cohorts were sequenced to identify pathogenic BRCA1/2 mutations, and GIS was calculated using a previously described algorithm. Pathologic complete response (pCR) to platinum therapy was evaluated in a subset of TNBC samples. For TNBC, a threshold was set and threshold validity was assessed relative to clinical outcomes. Results A total of 560 ovarian cancer, 805 ER + BC, and 443 TNBC tumors were included. Compared to ovarian cancer, the GIS distribution of BRCA1/2 -deficient samples was shifted lower for ER + BC (p = 0.015), but not TNBC (p = 0.35). In the subset of TNBC samples, univariable logistic regression models revealed that GIS status using thresholds of ≥ 42 and ≥ 33 were significant predictors of response to platinum therapy. Conclusions This study demonstrated that the GIS thresholds used for ovarian cancer may also be appropriate for TNBC, but not ER + BC. GIS thresholds in TNBC were validated using clinical response data to platinum therapy.
    Type of Medium: Online Resource
    ISSN: 0167-6806 , 1573-7217
    URL: Article
    DOI: 10.1007/s10549-023-07046-3
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2023
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  • 6
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    Changes in Peripheral and Local Tumor Immunity after Neoadjuvant Chemotherapy Reshape Clinical Outcomes in Patients with Breast Cancer
    American Association for Cancer Research (AACR) ; 2020
    In:  Clinical Cancer Research Vol. 26, No. 21 ( 2020-11-01), p. 5668-5681
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 26, No. 21 ( 2020-11-01), p. 5668-5681
    Abstract: The recent approval of anti-programmed death-ligand 1 immunotherapy in combination with nab-paclitaxel for metastatic triple-negative breast cancer (TNBC) highlights the need to understand the role of chemotherapy in modulating the tumor immune microenvironment (TIME). Experimental Design: We examined immune-related gene expression patterns before and after neoadjuvant chemotherapy (NAC) in a series of 83 breast tumors, including 44 TNBCs, from patients with residual disease (RD). Changes in gene expression patterns in the TIME were tested for association with recurrence-free (RFS) and overall survival (OS). In addition, we sought to characterize the systemic effects of NAC through single-cell analysis (RNAseq and cytokine secretion) of programmed death-1–high (PD-1HI) CD8+ peripheral T cells and examination of a cytolytic gene signature in whole blood. Results: In non-TNBC, no change in expression of any single gene was associated with RFS or OS, while in TNBC upregulation of multiple immune-related genes and gene sets were associated with improved long-term outcome. High cytotoxic T-cell signatures present in the peripheral blood of patients with breast cancer at surgery were associated with persistent disease and recurrence, suggesting active antitumor immunity that may indicate ongoing disease burden. Conclusions: We have characterized the effects of NAC on the TIME, finding that TNBC is uniquely sensitive to the immunologic effects of NAC, and local increases in immune genes/sets are associated with improved outcomes. However, expression of cytotoxic genes in the peripheral blood, as opposed to the TIME, may be a minimally invasive biomarker of persistent micrometastatic disease ultimately leading to recurrence.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-19-3685
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
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  • 7
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    Abstract PD1-03: A phase Ib trial of fulvestrant + CDK4/6 inhibitor (CDK4/6i) palbociclib + pan-FGFR tyrosine kinase inhibitor (TKI) erdafitinib in FGFR -amplified/ ER+/ HER2-negative metastatic breast cancer (MBC)
    American Association for Cancer Research (AACR) ; 2021
    In:  Cancer Research Vol. 81, No. 4_Supplement ( 2021-02-15), p. PD1-03-PD1-03
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 81, No. 4_Supplement ( 2021-02-15), p. PD1-03-PD1-03
    Abstract: Background: Somatic alterations in the FGFR pathway (mainly FGFR1, amplified in about 15% of ER+ BC) have been implicated in resistance to endocrine therapy (ET), and more recently, to CDK4/6i as well. Based on our preclinical data showing that the FGFR pan-inhibitor erdafitinib when added to fulvestrant/palbociclib resulted in marked PDX regressions, we initiated a phase Ib trial combining erdafitinib with fulvestrant/palbociclib in patients with ER+/HER2-/FGFR-amplified MBC (NCT03238196) to determine safety, tolerability and anti-tumor activity of this combination. Methods: Patients with evaluable ER+/HER2- MBC with FGFR1-4 amplification (detected on tumor next generation sequencing or plasma ctDNA) exposed to at least one ET regimen (but no more than 2 lines of chemotherapy) in the metastatic setting, were treated with fulvestrant, palbociclib (standard of care dosing/ schedule) and oral erdafitinib, tested in 4 doses ranging from 4 mg to 8 mg daily. Once MTD reached, we planned to enroll 20 patients in the expansion portion of the trial. Tumor blocks were collected for FGFR1 FISH amplification analysis, and plasma ctDNA was collected at baseline, 4 weeks and at treatment discontinuation. Tumor assessments were performed every 8 weeks. Results: Since August 2017, 26 eligible patients with evaluable ER+/HER2-/FGFR-amplified MBC were enrolled across 4 institutions. Patient characteristics are summarized in Table 1. Main grade 1 and 2 adverse events (AE) were consistent with on-target toxicities of erdafitinib and/or palbociclib: mucositis (67%), hyperphosphatemia (61%), dysgeusia (52%), diarrhea (48%), fatigue (48%), neutropenia (47%), hand-foot syndrome (38%), anemia (29%), and onycholysis (14%). Febrile neutropenia occurred in 5% patients, no cases of central serous retinopathy were seen. Serious AE were rare: one grade 4 elevation of transaminases (DLT; attributed to fulvestrant), one grade 3 colitis (attributed to erdafitinib), and one thromboembolic event (attributed to palbociclib). In combination with fulvestrant/ palbociclib, the MTD of erdafitinib was 6 mg. No drug-drug interaction was seen. 8 patients were deemed non-evaluable for anti-tumor effect as treatment discontinuation (mainly due to AE) occurred prior to first tumor assessment. Of the 18 evaluable patients: 7 had disease progression, 8 had stable disease (4 of which discontinued treatment due to AE), 3 have not completed their first tumor assessment, 4 are still on treatment; median PFS was 3 months and CBR at 6 months was 28%. However, higher PFS (6 months) was seen in 6/8 patients with high levels of FGFR1 amplification (FISH FGFR1:CEP8 ratio & gt;5; gene copy number & gt;10) and in both patients with FGFR3 amplification. Conclusion: To our knowledge, this is the first time an FGFR inhibitor has been tested in combination with ET and CDK4/6i in patients with MBC harboring FGFR alterations. Erdafitinib-related side effects appeared to be on target, leading to treatment discontinuation in several patients despite optimal medical treatment. Clinical activity was seen in heavily pre-treated patients with molecular evidence of high FGFR amplification despite 100% prior exposure to ET and CDK4/6i. Full clinical and correlative work will be presented at the meeting, and a future phase II trial is being planned. Table 126 / 35 patients accrued13 in escalation, 13 in expansion(ongoing)Median age53 (35 - 75)Race/ ethnicityWhite 22Black 1Asian 2Hispanic 1Median number of lines of treatment in the metastatic setting4 (1 - 5)Prior lines of treatment in the metastatic settingEndocrine therapy 100%Fulvestrant 28%CDK4/6i 100%PI3K pathway inhibitor 80%1 line chemo 65%2 lines chemo 45%FGFR1 amplification23FGFR3 amplification2FGFR4 amplification1 Citation Format: Ingrid A. Mayer, Barbara B. Haley, Vandana G. Abramson, Adam Brufsky, Brent Rexer, Erica Stringer-Reasor, Komal L. Jhaveri, Melinda Sanders, Paula I. Ericsson-Gonzalez, Fei Ye, Carlos L. Arteaga. A phase Ib trial of fulvestrant + CDK4/6 inhibitor (CDK4/6i) palbociclib + pan-FGFR tyrosine kinase inhibitor (TKI) erdafitinib in FGFR-amplified/ ER+/ HER2-negative metastatic breast cancer (MBC) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD1-03.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.SABCS20-PD1-03
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
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  • 8
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    Abstract GS1-08: CCTGMA.32, a phase III randomized double-blind placebo controlled adjuvant trial of metformin (MET) vs placebo (PLAC) in early breast cancer (BC): Results of the primary efficacy analysis (clinical trials.gov NCT01101438)
    American Association for Cancer Research (AACR) ; 2022
    In:  Cancer Research Vol. 82, No. 4_Supplement ( 2022-02-15), p. GS1-08-GS1-08
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 4_Supplement ( 2022-02-15), p. GS1-08-GS1-08
    Abstract: Background: MET has been associated with beneficial anti-cancer effects in epidemiologic and preclinical research. It may act indirectly by reversing obesity associated physiologic changes or directly via mitochondrial mediated effects on LKB1/AMPK/mTOR and other mechanisms. MA.32 investigated the effect of MET vs PLAC (in addition to standard therapy) on adjuvant BC outcomes. Design: Randomized, placebo-controlled double-blind Phase III clinical trial conducted within the NCI US National Clinical Trials Network, NCRI (UK) BG, IBCSG. Methods: Between 2010-2013 BC patients & lt; 75 yo without diabetes (DM) with high risk T1-3, N0-3 M0 BC regardless of ER, PgR, HER2 and with adequate cardiac, renal and hepatic function were randomized (stratified for ER/PgR + vs -, BMI & lt; vs & gt; 30 kg/m2, HER2 +ve vs -ve, any vs no chemo) within 1 year of BC diagnosis to MET 850 mg po bid or PLAC bid for 5 years. Dose was reduced for toxicity with re-escalation when possible. Subjects were followed for Invasive Disease-Free Survival (IDFS primary outcome; events included invasive local/regional recurrences, distant recurrences, new ipsilateral/contralateral invasive BCs, new non-breast primary cancers, any death), Overall Survival (OS), Distant Relapse Free Survival (DRFS), BC Specific Survival (BCSS), BC Free Interval (BCFI), contralateral BC and cardiovascular (CV) events/new DM. 3582 subjects were required for 80% power to detect HR 0.76 (431 events). In 2011, entry was restricted to higher risk BC, leading to 80% power to detect HR 0.785 (544 events). In 2016, after the 2nd interim analysis at 29.5 months median F/U, the DSMB recommended (i) the intervention be continued with primary analysis triggered at 544 events be conducted in ER/PgR +ve (any HER2) subjects only and (ii) ER/PgR -ve subjects stop study drug for futility but blinding and follow-up continue. In 2021, a time driven analysis in ER/PgR +ve BC was approved (465 events providing 80% power to detect the original HR 0.76). Time to event survival described by the Kaplan-Meier method. Two-sided log-rank tests adjusting for stratification factors were primarily used to compare IDFS between arms. Cox proportional hazards models were used to identify and adjust for factors significantly related to IDFS. Results: 3649 subjects were enrolled. In the 2533 ER/PgR +ve subjects included in the primary analysis, baseline mean (± SD) age was 52.7 (±9.9 yrs); mean BMI 28.8 (±6.4) kg/m2. Baseline tumor characteristics were balanced: T stage 1/2/3/4 = 832/1351/349/1; N stage 0/1/2/3 = 964/1097/449/23; HER2+ 429. 1901 (75%) received XRT. 2150 (84.9%) received (neo)adj chemo, 2223 (87.8%) (neo)adj hormones and 434 (17.1%) HER2 targeted therapy. Any Grade ≥ 3 toxicity was similar in MET and PLAC arms (21.7% and 18.7%, P = 0.06). Median follow-up was 96.2 (range 0.2-121.0) months with 465 IDFS events (234 MET, 231 PLAC, 76% due to BC). Efficacy results are shown below. MET vs PLACMET vs PLACIDFSOSPopulation Included# subjectsHR (95% CI)HR (95% CI)PRIMARY ANALYSISER/PgR +ve (any HER2)*25331.01 (0.84-1.21). P=0.920.89 (0.64-1.23). P=0.46ER/PgR -ve (any HER211161.01 (0.79-1.30. P=0.92)0.89 (0.64-1.23). P=0.46Exploratory. AnalysisHER2 +ve (any ER/PgR)6200.64 (0.43-0.95. P=0.0260.53 (0.30-0.98. P=0.0398**in ER/PgR pos BC HRs were similar for BCFI, DRFS, BCSS (ranging from 0.98-1.09)Conclusions: MET did not improve IDFS or other BC outcomes in ER/PgR positive or ER/PgR negative BC and should not be used as adjuvant treatment. Exploratory findings suggesting benefit in HER2+ve BC should be further investigated. Funded by: CCSRI, NCI (US), CBCF, BCRF, CRUK, Hold’Em for Life Charity, Apotex (Canada) Citation Format: Pamela J. Goodwin, Bingshu E Chen, Karen A Gelmon, Timothy J Whelan, Marguerite Ennis, Julie Lemieux, Jennifer A Ligibel, Dawn L Hershman, Ingrid A Mayer, Timothy J Hobday, Judith M Bliss, Priya Rastogi, Manuela Rabaglio-Poretti, Som D. Mukherjee, Robert R Mackey, Vandana G Abramson, Conrad Oja, Robert Wesolowski, Alastair M Thompson, Daniel W Rea, Paul M Stos, Lois E Shepherd, Vuk Stambolic, Wendy R Parulekar. CCTGMA.32, a phase III randomized double-blind placebo controlled adjuvant trial of metformin (MET) vs placebo (PLAC) in early breast cancer (BC): Results of the primary efficacy analysis (clinical trials.gov NCT01101438) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr GS1-08.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.SABCS21-GS1-08
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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  • 9
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    Tucatinib versus placebo added to trastuzumab and capecitabine for patients with previously treated HER2+ metastatic breast cancer with brain metastases (HER2CLIMB).
    American Society of Clinical Oncology (ASCO) ; 2020
    In:  Journal of Clinical Oncology Vol. 38, No. 15_suppl ( 2020-05-20), p. 1005-1005
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 38, No. 15_suppl ( 2020-05-20), p. 1005-1005
    Abstract: 1005 Background: Tucatinib (TUC) is an investigational, highly selective HER2 kinase inhibitor. HER2CLIMB (NCT02614794) showed clinically meaningful and statistically significant improvements in overall survival (OS) and progression free survival (PFS) in all pts, prolongation of PFS in pts with brain metastases (BM), and objective response rate (ORR) when TUC was added to trastuzumab (T) and capecitabine (C). Primary methods and outcomes have been reported previously (Murthy NEJM 2019). We report the results of exploratory efficacy analyses in pts with BM. Methods: All pts with HER2+ metastatic breast cancer (MBC) enrolled in HER2CLIMB had a baseline brain MRI. Pts with BM were eligible and classified as untreated, treated stable, or treated and progressing. Pts were randomized 2:1 to receive TUC or placebo, in combination with T and C. Efficacy analyses in pts with BM at baseline were performed by applying RECIST 1.1 to the brain based on investigator evaluation. CNS-PFS (progression in the brain or death) and OS were evaluated in BM pts overall. Intracranial (IC) confirmed ORR (ORR-IC) and IC duration of response (DOR-IC) were evaluated in BM pts with measurable IC disease. After isolated brain progression, pts could continue study therapy after local treatment until second progression, and time from randomization to second progression or death was evaluated. Results: Overall, 291 pts (48%) had BM at baseline: 198 (48%) in the TUC arm and 93 (46%) in the control arm. There was a 68% reduction in risk of CNS-PFS in the TUC arm (HR: 0.32; 95% CI: 0.22, 0.48; P 〈 0.0001). Median CNS-PFS was 9.9 mo in the TUC arm vs 4.2 mo in the control arm. Risk of death overall was reduced by 42% in the TUC arm (OS HR: 0.58; 95% CI: 0.40, 0.85; P = 0.005). Median OS was 18.1 mo vs 12.0 mo. ORR-IC was higher in the TUC arm (47.3%; 95% CI: 33.7, 61.2) vs the control arm (20.0%; 95% CI: 5.7, 43.7). Median DOR-IC was 6.8 mo (95% CI: 5.5, 16.4) vs 3.0 mo (95% CI: 3.0, 10.3). In pts with isolated brain progression who continued study therapy after local treatment (n = 30), risk of second progression or death was reduced by 67% (HR: 0.33; 95% CI: 0.11, 1.02), and median PFS from randomization was 15.9 mo vs 9.7 mo, favoring the TUC arm. Conclusions: In pts with heavily previously treated HER2+ MBC with BM, TUC in combination with T and C doubled the ORR-IC, reduced risk of IC progression or death by two thirds and reduced risk of death by nearly half. If approved, TUC in combination with T and C has the potential to become a new standard of care in pts with HER2+ MBC with and without BM. Clinical trial information: NCT02614794 .
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2020.38.15_suppl.1005
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2020
    detail.hit.zdb_id: 2005181-5
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  • 10
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    Inhibition of the PI3K/mTOR Pathway in Breast Cancer to Enhance Response to Immune Checkpoint Inhibitors in Breast Cancer
    MDPI AG ; 2021
    In:  International Journal of Molecular Sciences Vol. 22, No. 10 ( 2021-05-14), p. 5207-
    Details
    In: International Journal of Molecular Sciences, MDPI AG, Vol. 22, No. 10 ( 2021-05-14), p. 5207-
    Abstract: Objectives: Inhibition of the PI3K/mTOR pathway suppresses breast cancer (BC) growth, enhances anti-tumor immune responses, and works synergistically with immune checkpoint inhibitors (ICI). The objective here was to identify a subclass of PI3K inhibitors that, when combined with paclitaxel, is effective in enhancing response to ICI. Methods: C57BL/6 mice were orthotopically implanted with syngeneic luminal/triple-negative-like PyMT cells exhibiting high endogenous PI3K activity. Tumor growth in response to treatment with anti-PD-1 + anti-CTLA-4 (ICI), paclitaxel (PTX), and either the PI3Kα-specific inhibitor alpelisib, the pan-PI3K inhibitor copanlisib, or the broad spectrum PI3K/mTOR inhibitor gedatolisib was evaluated in reference to monotherapy or combinations of these therapies. Effects of these therapeutics on intratumoral immune populations were determined by multicolor FACS. Results: Treatment with alpelisib + PTX inhibited PyMT tumor growth and increased tumor-infiltrating granulocytes but did not significantly affect the number of tumor-infiltrating CD8+ T cells and did not synergize with ICI. Copanlisib + PTX + ICI significantly inhibited PyMT growth and increased activation of intratumoral CD8+ T cells as compared to ICI alone, yet did not inhibit tumor growth more than ICI alone. In contrast, gedatolisib + ICI resulted in significantly greater inhibition of tumor growth compared to ICI alone and induced durable dendritic-cell, CD8+ T-cell, and NK-cell responses. Adding PTX to this regimen yielded complete regression in 60% of tumors. Conclusion: PI3K/mTOR inhibition plus PTX heightens response to ICI and may provide a viable therapeutic approach for treatment of metastatic BC.
    Type of Medium: Online Resource
    ISSN: 1422-0067
    URL: Article
    DOI: 10.3390/ijms22105207
    Language: English
    Publisher: MDPI AG
    Publication Date: 2021
    detail.hit.zdb_id: 2019364-6
    SSG: 12
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