A randomized phase III double-blind placebo-controlled trial of first-line chemotherapy and trastuzumab with or without bevacizumab for patients with HER2/neu-positive metastatic breast cancer: a trial of the ECOG-ACRIN Cancer Research Group (E1105).

BACKGROUND: In 2008, bevacizumab received accelerated Food and Drug Administration (FDA) approval for use in human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC). Based on the pre-clinical and preliminary clinical activity of the trastuzumab and bevacizumab combination, ECOG-ACRIN E1105 trial was developed to determine if the addition of bevacizumab to a chemotherapy and trastuzumab combination for first-line therapy would improve progression-free survival (PFS) in patients with HER2-positive MBC. FINDINGS: 96 patients were randomized to receive standard first-line chemotherapy and trastuzumab with or without bevacizumab between November 2007 and October 2009, and 93 began protocol therapy. Induction therapy was given for 24 weeks, followed by maintenance trastuzumab with or without bevacizumab. 60% (56/93) began carboplatin and 74% (69/93) completed 6 cycles of induction therapy. Primary endpoint was PFS. Median PFS was 11.1 and 13.8 months for placebo and bevacizumab arms, respectively (hazard ratio [HR] 95%, Confidence Interval [Cl] for bevacizumab vs. placebo: 0.73 [0.43-1.23], p = 0.24), and at a median follow-up of 70.7 months, median survival was 49.1 and 63 months (HR [95% Cl] for OS: 1.09 [0.61-1.97], p = 0.75). The most common toxicities across both arms were neutropenia and hypertension, with left ventricular systolic dysfunction, fatigue, and sensory neuropathy reported more frequently with bevacizumab. CONCLUSIONS: In this trial, the addition of bevacizumab did not improve outcomes in patients with metastatic HER2-positive breast cancer. Although the trial was underpowered due to smaller than anticipated sample size, these findings corroborated other clinical trials during this time. CLINICAL TRIAL INFORMATION: NCT00520975.

Using the HER2/CEP17 FISH Ratio to Predict Pathologic Complete Response Following Neoadjuvant Anti-HER2 Doublet Therapy in HER2+ Breast Cancer.

BACKGROUND: Clinical trials of HER2-directed therapy that omit neoadjuvant conventional chemotherapy for HER+ breast cancer demonstrate that a subset of patients still obtains a pCR. Identifying tumor characteristics which predict pCR may help select patients for de-escalated neoadjuvant dual HER2-targeted treatment without chemotherapy. This is the first study evaluating the HER2/CEP17 ratio by FISH as a biomarker to predict pCR among patients who received neoadjuvant anti-HER2 regimens without chemotherapy. PATIENTS AND METHODS: Data from patients with locally advanced HER2+ breast cancer who received neoadjuvant dual HER2-targeted therapy without conventional chemotherapy from a single center was retrospectively reviewed. All patients were enrolled in one of 3 clinical trials evaluating chemotherapy de-escalation. Logistic regression modeling assessed for a relationship between the HER2/CEP17 FISH ratio obtained from baseline tissue biopsy and pCR based on pathology at the time of definitive breast surgery following neoadjuvant treatment. RESULTS: Following neoadjuvant treatment with dual HER2-targeted therapies in 56 patients, the probability of pCR was 73% among patients with a HER2 ratio of 13.1 compared to a probability of 38% among patients with HER2 ratio of 5.5 (OR 4.14, 95% CI 1.44-11.89; P = .012). This positive association persisted after controlling for different treatment regimens administered (OR 2.87, 95% CI 0.9-9.18, P = .020). CONCLUSIONS: These data found a positive association between the HER2/CEP17 FISH ratio and pCR following neoadjuvant dual HER2-targeted therapy without chemotherapy. Larger prospective studies are needed to validate the HER2 ratio as a biomarker to select patients for neoadjuvant dual anti-HER2 therapy without chemotherapy.

Identifying homologous recombination deficiency in breast cancer: genomic instability score distributions differ among breast cancer subtypes.

PURPOSE: 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.

Sacituzumab Govitecan-hziy in Refractory Metastatic Triple-Negative Breast Cancer.

BACKGROUND: Standard chemotherapy is associated with low response rates and short progression-free survival among patients with pretreated metastatic triple-negative breast cancer. Sacituzumab govitecan-hziy is an antibody-drug conjugate that combines a humanized monoclonal antibody, which targets the human trophoblast cell-surface antigen 2 (Trop-2), with SN-38, which is conjugated to the antibody by a cleavable linker. Sacituzumab govitecan-hziy enables delivery of high concentrations of SN-38 to tumors. METHODS: We conducted a phase 1/2 single-group, multicenter trial involving patients with advanced epithelial cancers who received sacituzumab govitecan-hziy intravenously on days 1 and 8 of each 21-day cycle until disease progression or unacceptable toxic effects. A total of 108 patients received sacituzumab govitecan-hziy at a dose of 10 mg per kilogram of body weight after receiving at least two previous anticancer therapies for metastatic triple-negative breast cancer. The end points included safety; the objective response rate (according to Response Evaluation Criteria in Solid Tumors, version 1.1), which was assessed locally; the duration of response; the clinical benefit rate (defined as a complete or partial response or stable disease for at least 6 months); progression-free survival; and overall survival. Post hoc analyses determined the response rate and duration, which were assessed by blinded independent central review. RESULTS: The 108 patients with triple-negative breast cancer had received a median of 3 previous therapies (range, 2 to 10). Four deaths occurred during treatment; 3 patients (2.8%) discontinued treatment because of adverse events. Grade 3 or 4 adverse events (in ≥10% of the patients) included anemia and neutropenia; 10 patients (9.3%) had febrile neutropenia. The response rate (3 complete and 33 partial responses) was 33.3% (95% confidence interval [CI], 24.6 to 43.1), and the median duration of response was 7.7 months (95% CI, 4.9 to 10.8); as assessed by independent central review, these values were 34.3% and 9.1 months, respectively. The clinical benefit rate was 45.4%. Median progression-free survival was 5.5 months (95% CI, 4.1 to 6.3), and overall survival was 13.0 months (95% CI, 11.2 to 13.7). CONCLUSIONS: Sacituzumab govitecan-hziy was associated with durable objective responses in patients with heavily pretreated metastatic triple-negative breast cancer. Myelotoxic effects were the main adverse reactions. (Funded by Immunomedics; IMMU-132-01 ClinicalTrials.gov number, NCT01631552.).

Effect of Metformin vs Placebo on Invasive Disease-Free Survival in Patients With Breast Cancer: The MA.32 Randomized Clinical Trial.

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 in Breast Cancer to Enhance Response to Immune Checkpoint Inhibitors in Breast Cancer.

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.

Clinical evaluation of germline polymorphisms associated with capecitabine toxicity in breast cancer: TBCRC-015.

PURPOSE: Capecitabine is important in breast cancer treatment but causes diarrhea and hand-foot syndrome (HFS), affecting adherence and quality of life. We sought to identify pharmacogenomic predictors of capecitabine toxicity using a novel monitoring tool. METHODS: Patients with metastatic breast cancer were prospectively treated with capecitabine (2000 mg/m2/day, 14 days on/7 off). Patients completed in-person toxicity questionnaires (day 1/cycle) and automated phone-in assessments (days 8, 15). Correlation of genotypes with early and overall toxicity was the primary endpoint. RESULTS: Two hundred and fifty-nine patients were enrolled (14 institutions). Diarrhea and HFS occurred in 52% (17% grade 3) and 69% (9% grade 3), respectively. Only 29% of patients completed four cycles without dose reduction/interruption. In 39%, the highest toxicity grade was captured via phone. Three single nucleotide polymorphisms (SNPs) associated with diarrhea-DPYD*5 (odds ratio [OR] 4.9; P = 0.0005), a MTHFR missense SNP (OR 3.3; P = 0.02), and a SNP upstream of MTRR (OR 3.0; P = 0.03). GWAS elucidated a novel HFS SNP (OR 3.0; P = 0.0007) near TNFSF4 (OX40L), a gene implicated in autoimmunity including autoimmune skin diseases never before implicated in HFS. Genotype-gene expression analyses of skin tissues identified rs11158568 (associated with HFS via GWAS) with expression of CHURC1, a transcriptional activator controlling fibroblast growth factor (beta = - 0.74; P = 1.46 × 10-23), representing a previously unidentified mechanism for HFS. CONCLUSIONS: This is the first cancer pharmacogenomic study to use phone-in self-reporting, permitting augmented toxicity characterization. Three germline toxicity SNPs were replicated, and several novel SNPs/genes having strong functional relevance were discovered. If further validated, these markers could permit personalized capecitabine dosing.

A phase Ib, open-label, dose-escalation study of the safety and pharmacology of taselisib (GDC-0032) in combination with either docetaxel or paclitaxel in patients with HER2-negative, locally advanced, or metastatic breast cancer.

PURPOSE: This open-label, phase Ib, dose-escalation, and dose-expansion study (NCT01862081) evaluated taselisib with a taxane in locally advanced or metastatic breast cancer (BC) and/or non-small cell lung cancer (NSCLC). METHODS: Patients received taselisib (2-6 mg tablet or 3-6 mg capsule) plus docetaxel or paclitaxel. Primary endpoints were safety, dose-limiting toxicities, maximum tolerated dose, and identification of a recommended phase II dose. Secondary endpoints included pharmacokinetics and antitumor activity assessment. RESULTS: Eighty patients (BC: 72; NSCLC: 7; BC/NSCLC: 1) were enrolled (docetaxel-receiving arms: 21; paclitaxel-receiving arms: 59). Grade ≥ 3 adverse events (AEs), serious AEs, and AEs leading to death were reported in 90.5%, 42.9%, and 14.3% of patients, respectively (docetaxel-receiving arms), and 78.9%, 40.4%, and 3.5% of patients, respectively (paclitaxel-receiving arms). Eight patients experienced dose-limiting toxicities. The maximum tolerated dose was exceeded with 3 mg taselisib (capsule) for 21 consecutive days plus 75 mg/m2 docetaxel and not exceeded with 6 mg taselisib (tablet) for 5 days on/2 days off plus 80 mg/m2 paclitaxel. Objective response rates and clinical benefit rates were 35.0% and 45.0%, respectively (docetaxel-receiving arms), and 20.4% and 27.8%, respectively (paclitaxel-receiving arms). Exposure for paclitaxel or docetaxel plus taselisib was consistent with the single agents. CONCLUSIONS: Taselisib in combination with a taxane has a challenging safety profile. Despite evidence of antitumor activity, the benefit-risk profile was deemed not advantageous. Further development is not planned.

Surgical Findings and Outcomes in Premenopausal Breast Cancer Patients Undergoing Oophorectomy: A Multicenter Review From the Society of Gynecologic Surgeons Fellows Pelvic Research Network.

STUDY OBJECTIVE: To describe the procedures performed, intra-abdominal findings, and surgical pathology in a cohort of women with premenopausal breast cancer who underwent oopherectomy. DESIGN: Multicenter retrospective chart review (Canadian Task Force classification II-3). SETTING: Nine US academic medical centers participating in the Fellows' Pelvic Research Network (FPRN). PATIENTS: One hundred twenty-seven women with premenopausal breast cancer undergoing oophorectomy between January 2013 and March 2016. INTERVENTION: Surgical castration. MEASUREMENTS AND MAIN RESULTS: The mean patient age was 45.8 years. Fourteen patients (11%) carried a BRCA mutations, and 22 (17%) carried another germline or acquired mutation, including multiple variants of uncertain significance. There was wide variation in surgical approach. Sixty-five patients (51%) underwent pelvic washings, and 43 (35%) underwent concurrent hysterectomy. Other concomitant procedures included midurethral sling placement, appendectomy, and hysteroscopy. Three patients experienced complications (transfusion, wound cellulitis, and vaginal cuff dehiscence). Thirteen patients (10%) had ovarian pathology detected on analysis of the surgical specimen, including metastatic tumor, serous cystadenomas, endometriomas, and Brenner tumor. Eight patients (6%) had Fallopian tube pathology, including 3 serous tubal intraepithelial cancers. Among the 44 uterine specimens, 1 endometrial adenocarcinoma and 1 multifocal endometrial intraepithelial neoplasia were noted. Regarding the entire study population, the number of patients meeting our study criteria and seen by gynecologic surgeons in the FPRN for oophorectomy increased by nearly 400% from 2013 to 2015. CONCLUSION: Since publication of the Suppression of Ovarian Function Trial data, bilateral oophorectomy has been recommended for some women with premenopausal breast cancer to facilitate breast cancer treatment with aromatase inhibitors. These women may be at elevated risk for occult abdominal pathology compared with the general population. Gynecologic surgeons often perform castration oophorectomy in patients with breast cancer as an increasing number of oncologists are using aromatase inhibitors to treat premenopausal breast cancer. Our data suggest that other abdominal/pelvic cancers, precancerous conditions, and previously unrecognized metastatic disease are not uncommon findings in this patient population. Gynecologists serving this patient population may consider a careful abdominal survey, pelvic washings, endometrial sampling, and serial sectioning of fallopian tube specimens for a thorough evaluation.

Towards real-time topical detection and characterization of FDG dose infiltration prior to PET imaging.

PURPOSE: To dynamically detect and characterize 18F-fluorodeoxyglucose (FDG) dose infiltrations and evaluate their effects on positron emission tomography (PET) standardized uptake values (SUV) at the injection site and in control tissue. METHODS: Investigational gamma scintillation sensors were topically applied to patients with locally advanced breast cancer scheduled to undergo limited whole-body FDG-PET as part of an ongoing clinical study. Relative to the affected breast, sensors were placed on the contralateral injection arm and ipsilateral control arm during the resting uptake phase prior to each patient's PET scan. Time-activity curves (TACs) from the sensors were integrated at varying intervals (0-10, 0-20, 0-30, 0-40, and 30-40 min) post-FDG and the resulting areas under the curve (AUCs) were compared to SUVs obtained from PET. RESULTS: In cases of infiltration, observed in three sensor recordings (30 %), the injection arm TAC shape varied depending on the extent and severity of infiltration. In two of these cases, TAC characteristics suggested the infiltration was partially resolving prior to image acquisition, although it was still apparent on subsequent PET. Areas under the TAC 0-10 and 0-20 min post-FDG were significantly different in infiltrated versus non-infiltrated cases (Mann-Whitney, p < 0.05). When normalized to control, all TAC integration intervals from the injection arm were significantly correlated with SUVpeak and SUVmax measured over the infiltration site (Spearman ρ ≥ 0.77, p < 0.05). Receiver operating characteristic (ROC) analyses, testing the ability of the first 10 min of post-FDG sensor data to predict infiltration visibility on the ensuing PET, yielded an area under the ROC curve of 0.92. CONCLUSIONS: Topical sensors applied near the injection site provide dynamic information from the time of FDG administration through the uptake period and may be useful in detecting infiltrations regardless of PET image field of view. This dynamic information may also complement the static PET image to better characterize the true extent of infiltrations.

Subtyping of triple-negative breast cancer: implications for therapy.

Triple-negative breast cancer (TNBC) is a heterogeneous disease; gene expression analyses recently identified 6 distinct TNBC subtypes, each of which displays a unique biology. Exploring novel approaches for the treatment of these subtypes is critical, especially because the median survival for women with metastatic TNBC is less than 12 months, and virtually all women with metastatic TNBC ultimately will 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. In this review, the authors discuss recent developments in subtyping TNBC and the current and upcoming therapeutic strategies being explored in an attempt to target TNBC.

Enabling a genetically informed approach to cancer medicine: a retrospective evaluation of the impact of comprehensive tumor profiling using a targeted next-generation sequencing panel.

BACKGROUND: Oncogenic genetic alterations "drive" neoplastic cell proliferation. Small molecule inhibitors and antibodies are being developed that target an increasing number of these altered gene products. Next-generation sequencing (NGS) is a powerful tool to identify tumor-specific genetic changes. To determine the clinical impact of extensive genetic analysis, we reviewed our experience using a targeted NGS platform (FoundationOne) in advanced cancer patients. PATIENTS AND METHODS: We retrospectively assessed demographics, NGS results, and therapies received for patients undergoing targeted NGS (exonic sequencing of 236 genes and selective intronic sequencing from 19 genes) between April 2012 and August 2013. Coprimary endpoints were the percentage of patients with targeted therapy options uncovered by mutational profiling and the percentage who received genotype-directed therapy. RESULTS: Samples from 103 patients were tested, most frequently breast carcinoma (26%), head and neck cancers (23%), and melanoma (10%). Most patients (83%) were found to harbor potentially actionable genetic alterations, involving cell-cycle regulation (44%), phosphatidylinositol 3-kinase-AKT (31%), and mitogen-activated protein kinase (19%) pathways. With median follow-up of 4.1 months, 21% received genotype-directed treatments, most in clinical trials (61%), leading to significant benefit in several cases. The most common reasons for not receiving genotype-directed therapy were selection of standard therapy (35%) and clinical deterioration (13%). CONCLUSION: Mutational profiling using a targeted NGS panel identified potentially actionable alterations in a majority of advanced cancer patients. The assay identified additional therapeutic options and facilitated clinical trial enrollment. As time progresses, NGS results will be used to guide therapy in an increasing proportion of patients.

Characterization of breast cancers with PI3K mutations in an academic practice setting using SNaPshot profiling.

Mutations in the PIK3CA gene are common in breast cancer and represent a clinically useful therapeutic target. Several larger, population-based studies have shown a positive prognostic significance associated with these mutations. This study aims to further identify characteristics of patients harboring PIK3CA mutations while evaluating the clinical impact of genomic testing for these mutations. Tumors from 312 patients at Vanderbilt-Ingram Cancer Center were analyzed for PIK3CA mutations using a multiplex screening assay (SNaPshot). Mutation rates, receptor status, histopathologic characteristics, and time to recurrence were assessed. The number of patients participating in clinical trials, specifically trials relating to the PIK3CA mutation, was examined. Statistically significant differences between wild-type and mutated tumors were determined using the Wilcoxon, Pearson, and Fischer exact tests. The PIK3CA mutation was found in 25 % of tumors tested. Patients with PIK3CA mutations were significantly more likely to express hormone receptors, be of lower combined histological grade, and have a reduced time to recurrence. Patients found to have a PIK3CA mutation were significantly more likely to enter a PIK3CA-specific clinical trial. In addition to confirming previously established positive prognostic characteristics of tumors harboring PIK3CA mutations, this study demonstrates the feasibility and utility of mutation profiling in a clinical setting. PIK3CA mutation testing impacted treatment and resulted in more patients entering mutation-specific clinical trials.

DCE-MRI analysis methods for predicting the response of breast cancer to neoadjuvant chemotherapy: pilot study findings.

PURPOSE: The purpose of this pilot study is to determine (1) if early changes in both semiquantitative and quantitative DCE-MRI parameters, observed after the first cycle of neoadjuvant chemotherapy in breast cancer patients, show significant difference between responders and nonresponders and (2) if these parameters can be used as a prognostic indicator of the eventual response. METHODS: Twenty-eight patients were examined using DCE-MRI pre-, post-one cycle, and just prior to surgery. The semiquantitative parameters included longest dimension, tumor volume, initial area under the curve, and signal enhancement ratio related parameters, while quantitative parameters included K(trans), v(e), k(ep), v(p), and τ(i) estimated using the standard Tofts-Kety, extended Tofts-Kety, and fast exchange regime models. RESULTS: Our preliminary results indicated that the signal enhancement ratio washout volume and k(ep) were significantly different between pathologic complete responders from nonresponders (P < 0.05) after a single cycle of chemotherapy. Receiver operator characteristic analysis showed that the AUC of the signal enhancement ratio washout volume was 0.75, and the AUCs of k(ep) estimated by three models were 0.78, 0.76, and 0.73, respectively. CONCLUSION: In summary, the signal enhancement ratio washout volume and k(ep) appear to predict breast cancer response after one cycle of neoadjuvant chemotherapy. This observation should be confirmed with additional prospective studies.

Feasibility and Tolerability of Adjuvant Capecitabine-Based Chemoradiation in Patients With Breast Cancer and Residual Disease After Neoadjuvant Chemotherapy: A Prospective Clinical Trial.

PURPOSE: Addition of adjuvant capecitabine improves overall survival for patients with breast cancer lacking pathologic complete response to standard-of-care neoadjuvant chemotherapy. Combining radiosensitizing capecitabine concurrent with radiation may further improve disease control, although the feasibility and tolerability of chemoradiation in this setting is unknown. This study aimed to determine the feasibility of this combination. Secondary objectives included the effect of chemoradiation on physician-reported toxicity, patient-reported skin dermatitis, and patient-reported quality of life compared with patients with breast cancer treated with adjuvant radiation. METHODS AND MATERIALS: Twenty patients with residual disease following standard neoadjuvant chemotherapy were enrolled in a prospective single-arm trial and treated with adjuvant capecitabine-based chemoradiation. Feasibility was defined as ≥75% of patients completing chemoradiation as planned. Toxicity was assessed using Common Terminology Criteria for Adverse Events version 5.0 and the patient-reported radiation-induced skin reaction scale. Quality of life was measured using the RAND Short-Form 36-Item Health Survey. RESULTS: Eighteen patients (90%) completed chemoradiation without interruption or dose reduction. The incidence of grade ≥3 radiation dermatitis was 5% (1 of 20 patients). Patient-reported radiation dermatitis did not show a clinically meaningful difference following chemoradiation (mean increase, 55 points) compared with published reports of patients with breast cancer treated with adjuvant radiation alone (mean increase, 47 points). On the other hand, patient-reported quality of life demonstrated a clinically meaningful decline at the end of chemoradiation (mean, 46; SD, 7) compared with the reference population of patients treated with adjuvant radiation alone (mean, 50; SD, 6). CONCLUSIONS: Adjuvant chemoradiation with capecitabine is feasible and tolerable in patients with breast cancer. Although current studies using adjuvant capecitabine for residual disease following neoadjuvant chemotherapy have specified sequential treatment of capecitabine and radiation, these results support the conduct of randomized trials in this setting to investigate the efficacy of concurrent radiation with capecitabine and provide patient-reported toxicity estimates for trial design.

Atezolizumab in Combination With Carboplatin and Survival Outcomes in Patients With Metastatic Triple-Negative Breast Cancer: The TBCRC 043 Phase 2 Randomized Clinical Trial.

Importance: Agents targeting programmed death ligand 1 (PD-L1) have demonstrated efficacy in triple-negative breast cancer (TNBC) when combined with chemotherapy and are now the standard of care in patients with PD-L1-positive metastatic disease. In contrast to microtubule-targeting agents, the effect of combining platinum compounds with programmed cell death 1 (PD-1)/PD-L1 immunotherapy has not been extensively determined. Objective: To evaluate the efficacy of atezolizumab with carboplatin in patients with metastatic TNBC. Design, Setting, and Participants: This phase 2 randomized clinical trial was conducted in 6 centers from August 2017 to June 2021. Interventions: Patients with metastatic TNBC were randomized to receive carboplatin area under the curve (AUC) 6 alone or with atezolizumab, 1200 mg, every 3 weeks until disease progression or unacceptable toxic effects with a 3-year duration of follow-up. Main Outcome and Measures: The primary end point was investigator-assessed progression-free survival (PFS). Secondary end points included overall response rate (ORR), clinical benefit rate (CBR), and overall survival (OS). Other objectives included correlation of response with tumor PD-L1 levels, tumor-infiltrating lymphocytes (TILs), tumor DNA- and RNA-sequenced biomarkers, TNBC subtyping, and multiplex analyses of immune markers. Results: All 106 patients with metastatic TNBC who were enrolled were female with a mean (range) age of 55 (27-79) years, of which 12 (19%) identified as African American/Black, 1 (1%) as Asian, 73 (69%) as White, and 11 (10%) as unknown. Patients were randomized and received either carboplatin (n = 50) or carboplatin and atezolizumab (n = 56). The combination improved PFS (hazard ratio [HR], 0.66; 95% CI, 0.44-1.01; P = .05) from a median of 2.2 to 4.1 months, increased ORR from 8.0% (95% CI, 3.2%-18.8%) to 30.4% (95% CI, 19.9%-43.3%), increased CBR at 6 months from 18.0% (95% CI, 9.8%-30.1%) to 37.5% (95% CI, 26.0%-50.6%), and improved OS (HR, 0.60; 95% CI, 0.37-0.96; P = .03) from a median of 8.6 to 12.6 months. Subgroup analysis showed PD-L1-positive tumors did not benefit more from adding atezolizumab (HR, 0.62; 95% CI, 0.23-1.65; P = .35). Patients with high TILs (HR, 0.12; 95% CI, 0.30-0.50), high mutation burden (HR, 0.50; 95% CI, 0.23-1.06), and prior chemotherapy (HR, 0.59; 95% CI, 0.36-0.95) received greater benefit on the combination. Patients with obesity and patients with more than 125 mg/dL on-treatment blood glucose levels were associated with better PFS (HR, 0.35; 95% CI, 0.10-1.80) on the combination. TNBC subtypes benefited from adding atezolizumab, except the luminal androgen receptor subtype. Conclusions and Relevance: In this randomized clinical trial, the addition of atezolizumab to carboplatin significantly improved survival of patients with metastatic TNBC regardless of PD-L1 status. Further, lower risk of disease progression was associated with increased TILs, higher mutation burden, obesity, and uncontrolled blood glucose levels. Trial Registration: ClinicalTrials.gov Identifier: NCT03206203.

NKG2A Is a Therapeutic Vulnerability in Immunotherapy Resistant MHC-I Heterogeneous Triple-Negative Breast Cancer.

Despite the success of immune checkpoint inhibition (ICI) in treating cancer, patients with triple-negative breast cancer (TNBC) often develop resistance to therapy, and the underlying mechanisms are unclear. MHC-I expression is essential for antigen presentation and T-cell-directed immunotherapy responses. This study demonstrates that TNBC patients display intratumor heterogeneity in regional MHC-I expression. In murine models, loss of MHC-I negates antitumor immunity and ICI response, whereas intratumor MHC-I heterogeneity leads to increased infiltration of natural killer (NK) cells in an IFNγ-dependent manner. Using spatial technologies, MHC-I heterogeneity is associated with clinical resistance to anti-programmed death (PD) L1 therapy and increased NK:T-cell ratios in human breast tumors. MHC-I heterogeneous tumors require NKG2A to suppress NK-cell function. Combining anti-NKG2A and anti-PD-L1 therapies restores complete response in heterogeneous MHC-I murine models, dependent on the presence of activated, tumor-infiltrating NK and CD8+ T cells. These results suggest that similar strategies may enhance patient benefit in clinical trials. SIGNIFICANCE: Clinical resistance to immunotherapy is common in breast cancer, and many patients will likely require combination therapy to maximize immunotherapeutic benefit. This study demonstrates that heterogeneous MHC-I expression drives resistance to anti-PD-L1 therapy and exposes NKG2A on NK cells as a target to overcome resistance. This article is featured in Selected Articles from This Issue, p. 201.

A randomized phase III double-blind placebo-controlled trial of first line chemotherapy and trastuzumab with or without bevacizumab for patients with HER2/neu-positive metastatic breast cancer: a trial of the ECOG-ACRIN Cancer Research Group (E1105).

Background: In 2008, bevacizumab received accelerated Food and Drug Administration (FDA) approval for use in human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC). Based on the preclinical and preliminary clinical activity of the trastuzumab and bevacizumab combination, ECOG-ACRIN E1105 trial was developed to determine if the addition of bevacizumab to a chemotherapy and trastuzumab combination for first-line therapy would improve progression-free survival (PFS) in patients with HER2-positive MBC. Findings: 96 patients were randomized to receive standard first-line chemotherapy and trastuzumab with or without bevacizumab between November 2007 and October 2009, and 93 began protocol therapy. Induction therapy was given for 24 weeks, followed by maintenance trastuzumab with or without bevacizumab. 60% (56/93) began carboplatin and 74% (69/93) completed 6 cycles of induction therapy. Primary endpoint was PFS. Median PFS was 11.1 and 13.8 months for placebo and bevacizumab arms, respectively (hazard ratio [HR] 95%, Confidence Interval [Cl] for bevacizumab vs. placebo: 0.73 [0.43-1.23], p = 0.24), and at a median follow-up of 70.7 months, median survival was 49.1 and 63 months (HR [95% Cl] for OS: 1.09 [0.61-1.97], p = 0.75). The most common toxicities across both arms were neutropenia and hypertension, with left ventricular systolic dysfunction, fatigue, and sensory neuropathy reported more frequently with bevacizumab. Conclusions: In this trial, the addition of bevacizumab did not improve outcomes in patients with metastatic HER2-positive breast cancer. Although the trial was underpowered due to smaller than anticipated sample size, these findings corroborated other clinical trials during this time.

Subcutaneous vs Intravenous Trastuzumab/Pertuzumab: A Time and Motion Substudy of a Phase II Trial of Adjuvant Trastuzumab/Pertuzumab for Stage I HER2+ Breast Cancer (ADEPT trial).

PURPOSE: The time required for in-clinic drug administration can substantially affect breast cancer patients' quality of life. Subcutaneous (SC) drug administration, as opposed to intravenous (IV), may reduce this time commitment. This study sought to estimate the difference in time burden between IV and SC administration of trastuzumab and pertuzumab (HP). METHODS: We prospectively enrolled a subcohort of patients participating in the ADEPT trial (ClinicalTrials.gov identifier: NCT04569747, investigating adjuvant HP plus endocrine therapy for stage I human epidermal growth factor receptor 2-positive breast cancer) to this single-arm crossover time and motion substudy. Patients received two cycles of IV HP followed by two cycles of SC HP. During each cycle, time points in drug preparation and administration were captured. The primary end point was total patient time in the treatment chair. Additional end points included total patient treatment experience time and total pharmacy workflow time. A sample size of 22 patients was estimated to provide 90.7% power with two-sided alpha .05 to detect a difference of 70 minutes in the primary end point by treatment arm (IV v SC). RESULTS: Twenty-two patients were enrolled. The mean total patient time in the treatment chair was 61.8 minutes shorter with SC versus IV HP (22.5 v 84.3 minutes; P < .0001). The mean total patient treatment experience time (incorporating time spent waiting for treatment initiation and time spent in the treatment chair) was 81.8 minutes shorter for SC administration (96 v 177.8 minutes; P < .0001). The pharmacy workflow time was 78.2 minutes shorter for SC versus IV formulation (41 v 119.2 minutes; P < .0001). CONCLUSION: SC administration of HP shortened patient time burden by approximately 1 hour. SC drug administration can facilitate faster workflows for health care professionals and improve patients' breast cancer treatment experience.

Epithelial Expressed B7-H4 Drives Differential Immunotherapy Response in Murine and Human Breast Cancer.

Combinations of immune checkpoint inhibitors (ICI, including anti-PD-1/PD-L1) and chemotherapy have been FDA approved for metastatic and early-stage triple-negative breast cancer (TNBC), but most patients do not benefit. B7-H4 is a B7 family ligand with proposed immunosuppressive functions being explored as a cancer immunotherapy target and may be associated with anti-PD-L1 resistance. However, little is known about its regulation and effect on immune cell function in breast cancers. We assessed murine and human breast cancer cells to identify regulation mechanisms of B7-H4 in vitro. We used an immunocompetent anti-PD-L1-sensitive orthotopic mammary cancer model and induced ectopic expression of B7-H4. We assessed therapy response and transcriptional changes at baseline and under treatment with anti-PD-L1. We observed B7-H4 was highly associated with epithelial cell status and transcription factors and found to be regulated by PI3K activity. EMT6 tumors with cell-surface B7-H4 expression were more resistant to immunotherapy. In addition, tumor-infiltrating immune cells had reduced immune activation signaling based on transcriptomic analysis. Paradoxically, in human breast cancer, B7-H4 expression was associated with survival benefit for patients with metastatic TNBC treated with carboplatin plus anti-PD-L1 and was associated with no change in response or survival for patients with early breast cancer receiving chemotherapy plus anti-PD-1. While B7-H4 induces tumor resistance to anti-PD-L1 in murine models, there are alternative mechanisms of signaling and function in human cancers. In addition, the strong correlation of B7-H4 to epithelial cell markers suggests a potential regulatory mechanism of B7-H4 independent of PD-L1. SIGNIFICANCE: This translational study confirms the association of B7-H4 expression with a cold immune microenvironment in breast cancer and offers preclinical studies demonstrating a potential role for B7-H4 in suppressing response to checkpoint therapy. However, analysis of two clinical trials with checkpoint inhibitors in the early and metastatic settings argue against B7-H4 as being a mechanism of clinical resistance to checkpoints, with clear implications for its candidacy as a therapeutic target.