Hope for Others: Research Results from the University of Pittsburgh Rapid Autopsy Program for Breast Cancer.

Breast cancer affects 1/8 of women throughout their lifetimes, with 90% of cancer deaths being caused by metastasis. However, metastasis poses unique challenges to research, as complex changes in the microenvironment in different metastatic sites and difficulty obtaining tissue for study hinder the ability to examine in depth the changes that occur during metastasis. Rapid autopsy programs thus fill a unique need in advancing metastasis research.

NSABP FB-10: a phase Ib/II trial evaluating ado-trastuzumab emtansine (T-DM1) with neratinib in women with metastatic HER2-positive breast cancer.

Background: We previously reported our phase Ib trial, testing the safety, tolerability, and efficacy of T-DM1 + neratinib in HER2-positive metastatic breast cancer patients. Patients with ERBB2 amplification in ctDNA had deeper and more durable responses. This study extends these observations with in-depth analysis of molecular markers and mechanisms of resistance in additional patients.

Research autopsy programmes in oncology: shared experience from 14 centres across the world.

While there is a great clinical need to understand the biology of metastatic cancer in order to treat it more effectively, research is hampered by limited sample availability. Research autopsy programmes can crucially advance the field through synchronous, extensive, and high-volume sample collection. However, it remains an underused strategy in translational research.

Long-Term Follow-Up of the Anthracyclines in Early Breast Cancer Trials (USOR 06-090, NSABP B-46-I/USOR 07132, and NSABP B-49 [NRG Oncology]).

JCO The primary joint efficacy analysis of the Anthracyclines in Early Breast Cancer (ABC) trials reported in 2017 failed to demonstrate nonanthracycline adjuvant therapy was noninferior to anthracycline-based regimens in high-risk, early breast cancer. Full analyses of the studies had proceeded when the prespecified futility boundary was crossed at a planned futility analysis for the ability to demonstrate noninferiority of a nonanthracycline regimen with continued follow-up. These results were presented with 3.

Veliparib with carboplatin and paclitaxel in BRCA-mutated advanced breast cancer (BROCADE3): Final overall survival results from a randomized phase 3 trial.

Background: In the BROCADE3 study, the addition of veliparib to carboplatin plus paclitaxel resulted in a significant improvement in progression-free survival (PFS) compared with placebo plus carboplatin and paclitaxel, in patients with germline BRCA1 or BRCA2 (BRCA1/2)-mutated, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer. We now report final overall survival (OS) data.

Methods: BROCADE3 is a randomized phase 3 study that enrolled patients with BRCA1/2-mutated, HER2-negative advanced breast cancer who received ≤ 2 prior lines of chemotherapy for metastatic disease.

WCRC-25: A novel luminal Invasive Lobular Carcinoma cell line model.

Unlabelled: Breast cancer is categorized by the molecular and histologic presentation of the tumor, with the major histologic subtypes being No Special Type (NST) and Invasive Lobular Carcinoma (ILC). ILC are characterized by growth in a single file discohesive manner with stromal infiltration attributed to their hallmark pathognomonic loss of E-cadherin ( ). Few ILC cell line models are available to researchers.

A phase 1 study of veliparib (ABT-888) plus weekly carboplatin and paclitaxel in advanced solid malignancies, with an expansion cohort in triple negative breast cancer (TNBC) (ETCTN 8620).

Background: Veliparib is a poly-ADP-ribose polymerase (PARP) inhibitor, and it has clinical activity with every 3 weeks carboplatin and paclitaxel. In breast cancer, weekly paclitaxel is associated with improved overall survival. We aimed to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of veliparib with weekly carboplatin and paclitaxel as well as safety, pharmacokinetics, and preliminary clinical activity in triple negative breast cancer (TNBC).

Cisplatin with veliparib or placebo in metastatic triple-negative breast cancer and BRCA mutation-associated breast cancer (S1416): a randomised, double-blind, placebo-controlled, phase 2 trial.

Background: Poly(ADP-ribose) polymerase (PARP) inhibitors are effective in germline BRCA1 or BRCA2 (BRCA1/2) mutation-associated metastatic breast cancer. However, studies evaluating PARP inhibitors plus platinum-based chemotherapy in germline BRCA1/2-wildtype triple-negative breast cancer are scarce. A large proportion of germline BRCA1/2-wildtype triple-negative breast cancer shows homologous recombination deficiency (HRD), resulting in a BRCA-like phenotype that might render sensitivity to PARP inhibitors.

A phase 1 and pharmacodynamic study of chronically-dosed, single-agent veliparib (ABT-888) in patients with BRCA1- or BRCA2-mutated cancer or platinum-refractory ovarian or triple-negative breast cancer.

Purpose: BRCA1 or BRCA2 mutated cancers (BRCAmut) have intrinsic sensitivity to PARP inhibitors due to deficiency in homologous recombination-mediated DNA repair. There are similarities between BRCAmut and BRCAwt ovarian and basal-like breast cancers. This phase I study determined the recommended phase II dose (RP2D) and preliminary efficacy of the PARP inhibitor, veliparib (ABT-888), in these patients.

Abemaciclib in Combination With Endocrine Therapy for Patients With Hormone Receptor-Positive, HER2-Negative Metastatic Breast Cancer: A Phase 1b Study.

Background: Cyclin-dependent kinases (CDK) 4 and 6 regulate G1 to S cell cycle progression and are often altered in cancers. Abemaciclib is a selective inhibitor of CDK4 and CDK6 approved for administration on a continuous dosing schedule as monotherapy or as combination therapy with an aromatase inhibitor or fulvestrant in patients with advanced or metastatic breast cancer. This Phase 1b study evaluated the safety and tolerability, pharmacokinetics, and antitumor activity of abemaciclib in combination with endocrine therapy for metastatic breast cancer (MBC), including aromatase inhibitors (letrozole, anastrozole, or exemestane) or tamoxifen.

Safety and efficacy of veliparib plus carboplatin/paclitaxel in patients with HER2-negative metastatic or locally advanced breast cancer: subgroup analyses by germline / mutations and hormone receptor status from the phase-3 BROCADE3 trial.

Purpose: To evaluate efficacy and safety of veliparib combined with carboplatin/paclitaxel in patients with advanced human epidermal growth factor receptor 2 (HER2)-negative, germline (g)-associated breast cancer defined by hormone receptor (HR) and g/ mutation status.

Patients And Methods: In this phase-3, double-blind, placebo-controlled trial, patients ( = 509) with advanced HER2-negative breast cancer and g mutations were randomized 2:1 to receive veliparib plus carboplatin/paclitaxel or placebo plus carboplatin/paclitaxel. Patients who discontinued chemotherapy prior to disease progression continued receiving blinded veliparib/placebo monotherapy.

Biomarkers of Response and Resistance to Palbociclib Plus Letrozole in Patients With ER/HER2 Breast Cancer.

Purpose: To determine (i) the relationship between candidate biomarkers of the antiproliferative (Ki67) response to letrozole and palbociclib alone and combined in ER/HER2 breast cancer; and (ii) the pharmacodynamic effect of the agents on the biomarkers.

Experimental Design: 307 postmenopausal women with ER/HER2 primary breast cancer were randomly assigned to neoadjuvant treatment with letrozole for 14 weeks; letrozole for 2 weeks, then letrozole+palbociclib to 14 weeks; palbociclib for 2 weeks, then letrozole+palbociclib to 14 weeks; or letrozole+palbociclib for 14 weeks. Biopsies were taken at baseline, 2 and 14 weeks and surgery at varying times after stopping palbociclib.

Efficacy and safety of first-line veliparib and carboplatin-paclitaxel in patients with HER2- advanced germline BRCA+ breast cancer: Subgroup analysis of a randomised clinical trial.

Background: Addition of veliparib to carboplatin-paclitaxel, with continuation of veliparib monotherapy if carboplatin-paclitaxel was discontinued, improved progression-free survival (PFS) in patients with germline BRCA-associated locally advanced/metastatic HER2- breast cancer and ≤2 lines of previous cytotoxic therapy for metastatic disease in BROCADE3. A pre-planned subgroup analysis evaluated efficacy and safety in patients without previous cytotoxic therapy for metastatic disease.

Methods: Patients were randomised 2:1 to receive veliparib (120 mg orally BID) or placebo on days -2 to 5.

Phase 1 study of safety, pharmacokinetics, and pharmacodynamics of tivantinib in combination with bevacizumab in adult patients with advanced solid tumors.

Purpose: We investigated the combination of tivantinib, a c-MET tyrosine kinase inhibitor (TKI), and bevacizumab, an anti-VEGF-A antibody.

Methods: Patients with advanced solid tumors received bevacizumab (10 mg/kg intravenously every 2 weeks) and escalating doses of tivantinib (120-360 mg orally twice daily). In addition to safety and preliminary efficacy, we evaluated pharmacokinetics of tivantinib and its metabolites, as well as pharmacodynamic biomarkers in peripheral blood and skin.

Relevance of Platinum-free Interval and Reversion Mutations for Veliparib Monotherapy after Progression on Carboplatin/Paclitaxel for g Advanced Breast Cancer (BROCADE3 Crossover).

Purpose: Safety, efficacy, and exploratory biomarker analyses were evaluated in patients with advanced HER2-negative germline breast cancer susceptibility gene (g)-associated breast cancer enrolled in the BROCADE3 trial who received crossover veliparib monotherapy after disease progression on placebo plus carboplatin/paclitaxel.

Patients And Methods: Eligible patients ( = 513) were randomized 2:1 to veliparib plus carboplatin/paclitaxel or placebo plus carboplatin/paclitaxel; patients had variable platinum-free intervals (PFI) at progression. In the placebo arm, patients were eligible to receive crossover veliparib monotherapy (300-400 mg twice daily continuous).

Prognostic factors and survival of patients undergoing surgical intervention for breast cancer bone metastases.

Introduction: Bone is the most common distant site of breast cancer metastasis. Skeletal lesions can cause significant morbidity due to pain, pathologic fracture, and electrolyte abnormalities. Current treatment for patients with bone metastases (BoM) from breast cancer is highly personalized and often involves a multidisciplinary approach with chemotherapy, hormone therapy, bone-targeted antiresorptive agents, radiation therapy, and surgery.

Veliparib with carboplatin and paclitaxel in BRCA-mutated advanced breast cancer (BROCADE3): a randomised, double-blind, placebo-controlled, phase 3 trial.

Background: BRCA1 or BRCA2-mutated breast cancers are sensitive to poly(ADP-ribose) polymerase (PARP) inhibitors and platinum agents owing to deficiency in homologous recombination repair of DNA damage. In this trial, we compared veliparib versus placebo in combination with carboplatin and paclitaxel, and continued as monotherapy if carboplatin and paclitaxel were discontinued before progression, in patients with HER2-negative advanced breast cancer and a germline BRCA1 or BRCA2 mutation.

Methods: BROCADE3 was a randomised, double-blind, placebo-controlled, phase 3 trial done at 147 hospitals in 36 countries.

TBCRC 002: a phase II, randomized, open-label trial of preoperative letrozole with or without bevacizumab in postmenopausal women with newly diagnosed stage 2/3 hormone receptor-positive and HER2-negative breast cancer.

Background: In preclinical studies, the expression of vascular endothelial growth factor (VEGF) in hormone receptor-positive breast cancer is associated with estrogen-independent tumor growth and resistance to endocrine therapies. This study investigated whether the addition of bevacizumab, a monoclonal antibody against VEGF, to letrozole enhanced the antitumor activity of the letrozole in the preoperative setting.

Methods: Postmenopausal women with newly diagnosed stage 2 or 3 estrogen and/or progesterone receptor-positive, HER2-negative breast cancer were randomly assigned (2:1) between letrozole 2.

ANG1005, a Brain-Penetrating Peptide-Drug Conjugate, Shows Activity in Patients with Breast Cancer with Leptomeningeal Carcinomatosis and Recurrent Brain Metastases.

Purpose: ANG1005, a novel taxane derivative, consists of three paclitaxel molecules covalently linked to Angiopep-2, designed to cross the blood-brain and blood-cerebrospinal barriers and to penetrate malignant cells via LRP1 transport system. Preclinical and clinical evidence of efficacy with ANG1005 has been previously shown.

Patients And Methods: A multicenter, open-label phase II study in adult patients with measurable recurrent brain metastases from breast cancer (BCBM), with or without leptomeningeal carcinomatosis was conducted ( = 72 BCBM; = 28 leptomeningeal carcinomatosis subset).

Pre- and Postoperative Neratinib for HER2-Positive Breast Cancer Brain Metastases: Translational Breast Cancer Research Consortium 022.

Purpose: This pilot study was performed to test our ability to administer neratinib monotherapy before clinically recommended craniotomy in patients with HER2-positive metastatic breast cancer to the central nervous system, to examine neratinib's central nervous system penetration at craniotomy, and to examine postoperative neratinib maintenance.

Patients And Methods: Patients with HER2-positive brain metastases undergoing clinically indicated cranial resection of a parenchymal tumor received neratinib 240 mg orally once a day for 7 to 21 days preoperatively, and resumed therapy postoperatively in 28-day cycles. Exploratory evaluations of time to disease progression, survival, and correlative tissue, cerebrospinal fluid (CSF), and blood-based analyses examining neratinib concentrations were planned.

Phase 1 study of veliparib (ABT-888), a poly (ADP-ribose) polymerase inhibitor, with carboplatin and paclitaxel in advanced solid malignancies.

Purpose: Veliparib is an oral inhibitor of poly (ADP-ribose) polymerase (PARP)-1 and -2. PARP-1 expression may be increased in cancer, and this increase confers resistance to cytotoxic agents. We aimed to determine the recommended phase 2 dose (RP2D), maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and pharmacokinetics (PK) of veliparib combined with paclitaxel and carboplatin.

Health-related quality of life in patients receiving first-line eribulin mesylate with or without trastuzumab for locally recurrent or metastatic breast cancer.

Background: Eribulin mesylate is a nontaxane microtubule dynamics inhibitor approved for second-line (European Union) or third-line (United States) treatment of metastatic breast cancer. Two phase 2 single trials, evaluating first-line eribulin as monotherapy (Study 206; NCT01268150) or in combination with trastuzumab (Study 208; NCT01269346) in locally recurrent or metastatic breast cancer, demonstrated objective response rates of 28.6 and 71.

TBCRC 022: A Phase II Trial of Neratinib and Capecitabine for Patients With Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer and Brain Metastases.

Purpose: Evidence-based treatments for metastatic, human epidermal growth factor receptor 2 (HER2)-positive breast cancer to the CNS are limited. We previously reported modest activity of neratinib monotherapy for HER2-positive breast cancer brain metastases. Here we report the results from additional study cohorts.