In an extension of a basket trial focusing on triple-negative breast cancer, patients who received sacituzumab govitecan, an antibody–drug conjugate, had a 33.3% response rate for a median of 7.7 ...months. Myelotoxic effects and diarrhea were major adverse reactions.
Triple-negative breast cancer (TNBC) is a heterogeneous disease; gene expression analyses recently identified six distinct TNBC subtypes, each displaying a unique biology. Exploring novel approaches ...to treatment of these subtypes is critical because less than 30% of women with metastatic breast cancer survive five years and virtually all women with metastatic TNBC will ultimately die of their disease despite systemic therapy. To date, not a single targeted therapy has been approved for the treatment of TNBC and cytotoxic chemotherapy remains the standard treatment. We discuss the current and upcoming therapeutic strategies being explored in an attempt to "target" TNBC.
OBJECTIVESThe purpose of this study was to determine whether multiparametric magnetic resonance imaging (MRI) using dynamic contrast-enhanced MRI (DCE-MRI) and diffusion-weighted MRI (DWI), obtained ...before and after the first cycle of neoadjuvant chemotherapy (NAC), is superior to single-parameter measurements for predicting pathologic complete response (pCR) in patients with breast cancer.
MATERIALS AND METHODSPatients with stage II/III breast cancer were enrolled in an institutional review board–approved study in which 3-T DCE-MRI and DWI data were acquired before (n = 42) and after 1 cycle (n = 36) of NAC. Estimates of the volume transfer rate (K), extravascular extracellular volume fraction (ve), blood plasma volume fraction (vp), and the efflux rate constant (kep = K/ve) were generated from the DCE-MRI data using the Extended Tofts-Kety model. The apparent diffusion coefficient (ADC) was estimated from the DWI data. The derived parameter kep/ADC was compared with single-parameter measurements for its ability to predict pCR after the first cycle of NAC.
RESULTSThe kep/ADC after the first cycle of NAC discriminated patients who went on to achieve a pCR (P < 0.001) and achieved a sensitivity, specificity, positive predictive value, and area under the receiver operator curve (AUC) of 0.92, 0.78, 0.69, and 0.88, respectively. These values were superior to the single parameters kep (AUC, 0.76) and ADC (AUC, 0.82). The AUCs between kep/ADC and kep were significantly different on the basis of the bootstrapped 95% confidence intervals (0.018–0.23), whereas the AUCs between kep/ADC and ADC trended toward significance (−0.11 to 0.24).
CONCLUSIONSThe multiparametric analysis of DCE-MRI and DWI was superior to the single-parameter measurements for predicting pCR after the first cycle of NAC.
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.
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 clinical benefit rate (CBR) at 16 weeks.
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%,
= 0.06), and increased PFS (4.6 vs. 2.0 months,
= 0.082). Genomic analyses revealed subtype-specific treatment response, and novel
fusions and AR splice variants.
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.
mutations are common in breast cancer and promote tumor progression and treatment resistance. We conducted a phase I/II trial of alpelisib (α-specific PI3K inhibitor) plus nab-paclitaxel in patients ...with HER2-negative metastatic breast cancer (MBC).
Eligible patients had HER2-negative MBC with any number of prior chemotherapies. Phase I was 3+3 dose-escalation design with three dose levels of alpelisib (250, 300, and 350 mg) daily plus nab-paclitaxel 100 mg/m
administered on days 1, 8, and 15 every 28 days. Phase II was according to Simon's two-stage design.
mutations in tumor/circulating tumor DNA (ctDNA) were assessed. Primary endpoints were recommended phase II dose (RP2D) and objective response rate (ORR). Additional endpoints included safety, pharmacokinetics, progression-free survival (PFS), and association of
mutation with outcomes.
A total of 43 patients were enrolled (phase I,
= 13 and phase II,
= 30). A total of 84% had visceral disease and 84% had prior taxane. No dose-limiting toxicities occurred in phase I. RP2D was alpelisib 350 mg daily plus nab-paclitaxel 100 mg/m
on days 1, 8, and 15. Hyperglycemia (grade 3, 26% and grade 4, 0%), neutropenia (grade 3, 23% and grade 4, 7%), diarrhea (grade 3, 5% and grade 4, 0%), and rash (grade 3, 7% and grade 4, 0%) were the most common adverse events. Among 42 evaluable patients, ORR was 59% (complete response, 7% and partial response, 52%), 21% of whom had response lasting >12 months; median PFS was 8.7 months. A total of 40% of patients demonstrated tumor and/or ctDNA
mutation; patients with tumor/ctDNA mutation demonstrated better PFS compared with those without mutation (11.9 vs. 7.5 months; HR, 0.44;
= 0.027). Patients with normal metabolic status had longer PFS compared with prediabetic/diabetic patients (12 vs. 7.5 months;
= 0.014). No pharmacokinetics interactions were detected.
The alpelisib plus nab-paclitaxel combination was well tolerated and shows encouraging efficacy, especially in patients with
-mutated tumor/ctDNA. The impact of metabolic status on response to this combination merits further investigation.
IMPORTANCE: Metformin, a biguanide commonly used to treat type 2 diabetes, has been associated with potential beneficial effects across breast cancer subtypes in observational and preclinical ...studies. OBJECTIVE: To determine whether the administration of adjuvant metformin (vs placebo) to patients with breast cancer without diabetes improves outcomes. DESIGN, SETTING, AND PARTICIPANTS: MA.32, a phase 3 randomized, placebo-controlled, double-blind trial, conducted in Canada, Switzerland, US, and UK, enrolled 3649 patients with high-risk nonmetastatic breast cancer receiving standard therapy between August 2010 and March 2013, with follow-up to October 2020. INTERVENTIONS: Patients were randomized (stratified for hormone receptor estrogen receptor and/or progesterone receptor {ER/PgR} status, positive vs negative; body mass index, ≤30 vs >30; human epidermal growth factor receptor 2 ERBB2, formerly HER2 or HER2/neu, positive vs negative; and any vs no chemotherapy) to 850 mg of oral metformin twice a day (n = 1824) or oral placebo twice a day (n = 1825) for 5 years. MAIN OUTCOMES AND MEASURES: The primary outcome was invasive disease–free survival in hormone receptor–positive breast cancer. Of the 8 secondary outcomes, overall survival, distant relapse–free survival, and breast cancer–free interval were analyzed. RESULTS: Of the 3649 randomized patients (mean age, 52.4 years; 3643 women 99.8%), all (100%) were included in analyses. After a second interim analysis, futility was declared for patients who were ER/PgR−, so the primary analysis was conducted for 2533 patients who were ER/PgR+. The median duration of follow-up in the ER/PgR+ group was 96.2 months (range, 0.2-121 months). Invasive disease–free survival events occurred in 465 patients who were ER/PgR+. The incidence rates for invasive disease–free survival events were 2.78 per 100 patient-years in the metformin group vs 2.74 per 100 patient-years in the placebo group (hazard ratio HR, 1.01; 95% CI, 0.84-1.21; P = .93), and the incidence rates for death were 1.46 per 100 patient-years in the metformin group vs 1.32 per 100 patient-years in the placebo group (HR, 1.10; 95% CI, 0.86-1.41; P = .47). Among patients who were ER/PgR−, followed up for a median of 94.1 months, incidence of invasive disease–free survival events was 3.58 vs 3.60 per 100 patient-years, respectively (HR, 1.01; 95% CI, 0.79-1.30; P = .92). None of the 3 secondary outcomes analyzed in the ER/PgR+ group had statistically significant differences. Grade 3 nonhematological toxic events occurred more frequently in patients taking metformin than in patients taking placebo (21.5% vs 17.5%, respectively, P = .003). The most common grade 3 or higher adverse events in the metformin vs placebo groups were hypertension (2.4% vs 1.9%), irregular menses (1.5% vs 1.4%), and diarrhea (1.9% vs 7.0%). CONCLUSIONS AND RELEVANCE: Among patients with high-risk operable breast cancer without diabetes, the addition of metformin vs placebo to standard breast cancer treatment did not significantly improve invasive disease–free survival. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01101438
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.
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.
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.
PI3K/mTOR inhibition plus PTX heightens response to ICI and may provide a viable therapeutic approach for treatment of metastatic BC.
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