Cynthia Osborne

Iniparib plus chemotherapy in metastatic triple-negative breast cancer.

BACKGROUND Triple-negative breast cancers have inherent defects in DNA repair, making this cancer a rational target for therapy based on poly(adenosine diphosphate-ribose) polymerase (PARP) inhibition. METHODS We conducted an open-label, phase 2 study to compare the efficacy and safety of gemcitabine and carboplatin with or without iniparib, a small molecule with PARP-inhibitory activity, in patients with metastatic triple-negative breast cancer. A total of 123 patients were randomly assigned to receive gemcitabine (1000 mg per square meter of body-surface area) and carboplatin (at a dose equivalent to an area under the concentration-time curve of 2) on days 1 and 8--with or without iniparib (at a dose of 5.6 mg per kilogram of body weight) on days 1, 4, 8, and 11--every 21 days. Primary end points were the rate of clinical benefit (i.e., the rate of objective response [complete or partial response] plus the rate of stable disease for ≥6 months) and safety. Additional end points included the rate of objective response, progression-free survival, and overall survival. RESULTS The addition of iniparib to gemcitabine and carboplatin improved the rate of clinical benefit from 34% to 56% (P=0.01) and the rate of overall response from 32% to 52% (P=0.02). The addition of iniparib also prolonged the median progression-free survival from 3.6 months to 5.9 months (hazard ratio for progression, 0.59; P=0.01) and the median overall survival from 7.7 months to 12.3 months (hazard ratio for death, 0.57; P=0.01). The most frequent grade 3 or 4 adverse events in either treatment group included neutropenia, thrombocytopenia, anemia, fatigue or asthenia, leukopenia, and increased alanine aminotransferase level. No significant difference was seen between the two groups in the rate of adverse events. CONCLUSIONS The addition of iniparib to chemotherapy improved the clinical benefit and survival of patients with metastatic triple-negative breast cancer without significantly increased toxic effects. On the basis of these results, a phase 3 trial adequately powered to evaluate overall survival and progression-free survival is being conducted. (Funded by BiPar Sciences [now owned by Sanofi-Aventis]; ClinicalTrials.gov number, NCT00540358.).

uPAR and HER-2 gene status in individual breast cancer cells from blood and tissues

Overexpression of urokinase plasminogen activator system or HER-2 (erbB-2) in breast cancer is associated with a poor prognosis. HER-2 overexpression is caused by HER-2 gene amplification. The anti-HER-2 antibody trastuzumab significantly improves clinical outcome for HER2-positive breast cancer. Drugs that target the uPA system are in early clinical trials. The aims of this study were to determine whether urokinase plasminogen activator receptor (uPAR) gene amplification occurs and whether analysis of individual tumor cells (TCs) in the blood or tissue can add information to conventional pathological analysis that could help in diagnosis and treatment. Analysis of individual TCs indicates that uPAR amplification occurs in a significant portion of primary breast cancers and also circulating tumor cells (CTCs) from patients with advanced disease. There was complete concordance between touch preps (TPs) and conventional pathological examination of HER-2 and uPAR gene status in primary tumors. There was also excellent concordance of HER-2 gene status between primary tumors and CTCs provided that acquisition of HER-2 gene amplification in CTCs was taken into account. Unexpectedly, gene amplification of HER-2 and uPAR occurred most frequently in the same TC and patient, suggesting a biological bias and potential advantage for coamplification. Expression of HER-2 and uPAR in primary tumors predicted gene status in 100 and 92% of patients, respectively.

Genome and Transcriptome Sequencing in Prospective Metastatic Triple-Negative Breast Cancer Uncovers Therapeutic Vulnerabilities

Triple-negative breast cancer (TNBC) is characterized by the absence of expression of estrogen receptor, progesterone receptor, and HER-2. Thirty percent of patients recur after first-line treatment, and metastatic TNBC (mTNBC) has a poor prognosis with median survival of one year. Here, we present initial analyses of whole genome and transcriptome sequencing data from 14 prospective mTNBC. We have cataloged the collection of somatic genomic alterations in these advanced tumors, particularly those that may inform targeted therapies. Genes mutated in multiple tumors included TP53, LRP1B, HERC1, CDH5, RB1, and NF1. Notable genes involved in focal structural events were CTNNA1, PTEN, FBXW7, BRCA2, WT1, FGFR1, KRAS, HRAS, ARAF, BRAF, and PGCP. Homozygous deletion of CTNNA1 was detected in 2 of 6 African Americans. RNA sequencing revealed consistent overexpression of the FOXM1 gene when tumor gene expression was compared with nonmalignant breast samples. Using an outlier analysis of gene expression comparing one cancer with all the others, we detected expression patterns unique to each patients tumor. Integrative DNA/RNA analysis provided evidence for deregulation of mutated genes, including the monoallelic expression of TP53 mutations. Finally, molecular alterations in several cancers supported targeted therapeutic intervention on clinical trials with known inhibitors, particularly for alterations in the RAS/RAF/MEK/ERK and PI3K/AKT/mTOR pathways. In conclusion, whole genome and transcriptome profiling of mTNBC have provided insights into somatic events occurring in this difficult to treat cancer. These genomic data have guided patients to investigational treatment trials and provide hypotheses for future trials in this irremediable cancer. Mol Cancer Ther; 12(1); 104–16. ©2012 AACR.

Effect of a Scalp Cooling Device on Alopecia in Women Undergoing Chemotherapy for Breast Cancer: The SCALP Randomized Clinical Trial

Importance Chemotherapy may induce alopecia. Although scalp cooling devices have been used to prevent this alopecia, efficacy has not been assessed in a randomized clinical trial. Objectives To assess whether a scalp cooling device is effective at reducing chemotherapy-induced alopecia and to assess adverse treatment effects. Design, Setting, and Participants Multicenter randomized clinical trial of women with breast cancer undergoing chemotherapy. Patients were enrolled from December 9, 2013, to September 30, 2016. One interim analysis was planned to allow the study to stop early for efficacy. Data reported are from the interim analysis. This study was conducted at 7 sites in the United States, and 182 women with breast cancer requiring chemotherapy were enrolled and randomized. Interventions Participants were randomized to scalp cooling (n = 119) or control (n = 63). Scalp cooling was done using a scalp cooling device. Main Outcomes and Measures The primary efficacy end points were successful hair preservation assessed using the Common Terminology Criteria for Adverse Events version 4.0 scale (grade 0 [no hair loss] or grade 1 [<50% hair loss not requiring a wig] were considered to have hair preservation) at the end of 4 cycles of chemotherapy by a clinician unaware of treatment assignment, and device safety. Secondary end points included wig use and scores on the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire–Core 30, Hospital Anxiety and Depression Scale, and a summary scale of the Body Image Scale. Results At the time of the interim analysis, 142 participants were evaluable. The mean (SD) age of the patients was 52.6 (10.1) years; 36% (n = 51) received anthracycline-based chemotherapy and 64% (n = 91) received taxane-based chemotherapy. Successful hair preservation was found in 48 of 95 women with cooling (50.5%; 95% CI, 40.7%-60.4%) compared with 0 of 47 women in the control group (0%; 95% CI, 0%-7.6%) (success rate difference, 50.5%; 95% CI, 40.5%-60.6%). Because the 1-tailed P value from the Fisher exact test was <.001, which crossed the superiority boundary (P = .0061), the data and safety monitoring board recommended study termination on September 26, 2016. There were no statistically significant differences in changes in any of the scales of quality of life from baseline to chemotherapy cycle 4 among the scalp cooling and control groups. Only adverse events related to device use were collected; 54 adverse events were reported in the cooling group, all grades 1 and 2. There were no serious adverse device events. Conclusions and Relevance Among women with stage I to II breast cancer receiving chemotherapy with a taxane, anthracycline, or both, those who underwent scalp cooling were significantly more likely to have less than 50% hair loss after the fourth chemotherapy cycle compared with those who received no scalp cooling. Further research is needed to assess longer-term efficacy and adverse effects. Trial Registration clinicaltrials.gov Identifier: NCT01986140

Triple negative breast cancer: a phase 2, multi-center, open-label, randomized trial of gemcitabine/carboplatin (G/C), with or without BSI-201, a PARP inhibitor.

Abstract #2120 Background: PARP is a critical enzyme of cell proliferation and DNA repair and BSI-201 has been shown to be a potent inhibitor of PARP-1 in humans. Triple negative breast cancer (TNBC) shares important features with BRCA1-related breast cancer, a validated target for PARP inhibition. Our studies demonstrate that PARP-1 gene expression is statistically significantly upregulated in TNBC compared with normal breast tissue. The primary objective of this study is to assess the Clinical Benefit Rate (CBR=CR+PR+SD > 6 months) of Gemcitabine/Carboplatin with or without BSI-201 in patients with TNBC.
 Methods: Eligible subjects are ≥ 18 years old who had received ≤ 2 prior chemotherapies for metastatic disease with histologically documented breast cancer that is ER-negative, PR-negative, and HER2-negative. Patients were randomized (1:1 ratio) to one of 2 study arms: a) arm 1: G/C alone; b) arm 2: BSI-201 + G/C. G/C was given on days 1 and 8; G = 1000 mg/m2, C at an AUC=2. In study arm 2, BSI-201 was administered I.V. twice weekly (days 1, 4, 8 and 11) at a dose of 5.6 mg/kg. Cycles were defined as being 21 days in duration. Modified RECIST criteria are used to assess tumor response every 6 weeks (every 2 cycles). Subjects who have progressive disease may crossover to receive BSI-201 and continue G/C. Archived tissue samples were retrieved for the assay of cancer related genes including PARP-1 by multiplex quantitative RT-PCR.
 Results: To date, 50 subjects have been enrolled and treated for up to 8 cycles of therapy. Overall 39 of 50 (78%) subjects experienced at least 1 adverse event. The frequency and nature of the AE9s do not differ between the two treatment groups. Gene expression profiling results from the first 28 patients enrolled confirm that the cancers of patients enrolled have uniformly low hormone receptor expression, variable HER2 receptor expression and significant upregulation of PARP-1 compared with normal breast tissue.
 Conclusions: This is the first randomized study of a PARP inhibitor in cancer patients. BSI-201 is safe and well tolerated when given in combination with G/C and adverse events observed were consistent with the known safety profiles of G / C regimens. An updated evaluation of toxicity profile and PARP-1 expression analysis will be presented. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2120.

Community-based assessment of adjuvant hormone therapy in women with breast cancer, 1991-1997

Abstract:  This study used population‐based tumor registry data to describe the patterns of adjuvant hormone therapy and to examine the correlates of hormone therapy for women with breast cancer. The study population included 5101 women (age 20 years) who were diagnosed with breast cancer in 1991 through 1997 in the entire state of New Mexico. Overall, 32% of women with stage I, II, or IIIA breast cancer received adjuvant hormone therapy. The likelihood of receiving adjuvant hormone therapy increased with tumor stage at diagnosis. Women less than 50 years of age were significantly less likely to receive adjuvant hormone therapy compared to those age 50 to 54 years, but there was no significant difference in the use of adjuvant hormone therapy for women age 55 years and older. The use of adjuvant hormone therapy was influenced by hormone receptor status and lymph node status. Patients who received adjuvant chemotherapy were also more likely to receive adjuvant hormone therapy than those who did not. The use of adjuvant hormone therapy alone was relatively stable over time and the use of adjuvant chemotherapy alone increased, but the receipt of chemotherapy combined with hormone therapy decreased from 1991 to 1997. There was no significant difference with age in the use of adjuvant hormone therapy among 55‐year‐old women compared to those age 50 to 54 years, whereas women less than 50 years of age were significantly less likely to receive this therapy. The use of adjuvant hormone therapy varied significantly by tumor stage, lymph node status, hormone receptor status, and the receipt of adjuvant chemotherapy. 

Aromatase inhibitors in the treatment of breast cancer in post-menopausal female patients: an update.

Estrogen and its metabolites play a significant role in the proliferation of hormone receptor-positive breast cancer. In postmenopausal women, aromatase inhibitors can significantly reduce estrogen levels by blocking enzyme-mediated estrogen synthesis within tissues. Third-generation aromatase inhibitors have now surpassed tamoxifen as first-line therapy for postmenopausal women with metastatic, hormone receptor-positive, breast cancer, showing improved response rates and time to progression. Aromatase inhibitors have shown incremental improvements in disease-free survival, lower local recurrence rates, lower metastatic recurrence rates, and a lower incidence of contralateral breast cancer over tamoxifen when used in the adjuvant setting. Aromatase inhibitors are recommended to be used as adjuvant therapy within the first 5 years of hormonal therapy and may be used either upfront for 5 years or sequenced with tamoxifen. No superiority of one aromatase inhibitor over another has yet been shown. The side effect profiles of aromatase inhibitors have some key differences compared with tamoxifen. These differences may influence treatment choices as well as impact compliance.

Interim safety results of eribulin (E) combined with ramucirumab (RAM) in patients (pts) with advanced metastatic breast cancer (MBC).

110 Background: VEGF-mediated angiogenesis contributes to breast cancer (BC) pathogenesis. RAM (IMC-1121B), a fully human IgG1 monoclonal antibody (MAb), targets VEGFR-2, blocking the interaction of VEGF ligands and VEGFR‑2. DC101 (murine anti-VEGFR-2 MAb) impairs vascular function and increases tumor hypoxia in xenograft BC models and inhibits tumor growth in cytotoxic-resistant models. E is a novel non-taxane microtubule inhibitor indicated in MBC pts who have received ≥2 prior chemotherapy regimens, including an anthracycline and a taxane. It is hypothesized that addition of RAM to E as 3rd-5th line therapy in MBC will result in an improvement of median PFS in this ongoing, multicenter, US study. A planned safety analysis of an initial cohort is reported. METHODS Pts with locally recurrent or MBC (HER2+ or HER2-) and 2-4 prior chemotherapy regimens are randomized 1:1 to receive RAM+E or E (E 1.4 mg/m2 Days 1, 8; RAM 10 mg/kg Day 1; q21 days). Pts are stratified by TNBC and prior antiangiogenic therapy status and must have ECOG PS 0-1 and normal LVEF. Planned accrual: 134 pts. RESULTS Evaluable pts (n=13, 8 RAM+E) received ≥1 dose of RAM+E or E and completed 2 cycles of therapy (or discontinued prior to completing the initial 2 cycles). Median age is 55 yrs. Assessment of adverse events (all cause) revealed nausea, fatigue, headache, and neutropenia were more frequent for RAM+E; anemia was more frequent for E. G1 sensory neuropathy was reported for 1 pt in each arm. One RAM+E pt experienced G3 febrile neutropenia and odynophagia, recovered within a week, and subsequently received reduced dosage (E = 1.1 mg/m2; RAM = 8 mg/kg). No deaths are reported. The safety assessment committee recommended to continue the trial unmodified. CONCLUSIONS Based on preliminary data, the combination of RAM+E demonstrates an acceptable toxicity profile. Accrual continues, with planned updated safety and dose intensity data to be presented at the meeting. [Table: see text].

Ixabepilone and Carboplatin for Hormone Receptor Positive/HER2-neu Negative and Triple Negative Metastatic Breast Cancer

Micro‐Abstract The combination of ixabepilone and carboplatin was investigated in a phase II study of 103 patients with hormone receptor‐positive (HR+) and triple negative (TN) metastatic breast cancer (MBC) previously treated with 0 to 2 chemotherapy regimens for MBC. The objective response rate was 34% and 30.4% in the HR+ and TN cohorts, respectively. Toxicities were manageable without cumulative myelosuppression. Background: Hormonal therapies and single‐agent sequential chemotherapeutic regimens are the standards of care for HER2− metastatic breast cancer (MBC). However, treating patients with hormone‐refractory and triple negative (TN) MBC remains challenging. We report the results of combined ixabepilone and carboplatin in a single‐arm phase II trial. Patients and Methods: In the present prospective analysis of hormone receptor‐positive (HR+)/HER2− and TN MBC cohorts, patients could have received 0 to 2 chemotherapy regimens for MBC before enrollment. All patients received ixabepilone 20 mg/m2 and carboplatin (area under the curve, 2.5) on days 1 and 8 every 21 days. The primary endpoint was the objective response rate (ORR). The secondary objectives included progression‐free survival (PFS), clinical benefit rate (CBR), overall survival (OS), and toxicity. Results: We enrolled 54 HR+ and 49 TN patients (median, 1 previous chemotherapy regimen for metastatic disease; most in addition to adjuvant chemotherapy). The ORR was 34% and 30.4% for the HR+ and TN patients, respectively, with a corresponding CBR of 56.6% and 41.3%. The ORRs were similar in taxane‐pretreated patients (ORR, 31.4% and 28.6% for HR+ and TN patients, respectively). The median OS was 17.9 months for HR+ patients and 12.5 months for TN patients. The median PFS was similar for both groups at 7.6 months. Grade 3/4 nonhematologic toxicities included neuropathy (9%) and fatigue (8%). Nine patients developed grade 3/4 neuropathy, 7 of whom had received previous taxane treatment. Conclusion: Ixabepilone plus carboplatin is active even in later‐line HR+ and TN disease. Toxicities were manageable without cumulative myelosuppression. This combination is a reasonable option for those patients with MBC who require combination chemotherapy.

Five-year results of a phase II trial of preoperative 5-fluorouracil, epirubicin, cyclophosphamide followed by docetaxel with capecitabine (wTX) (with trastuzumab in HER2-positive patients) for patients with stage II or III breast cancer

We aimed to increase pathologic complete response (pCR) in patients with invasive breast cancer by adding preoperative capecitabine to docetaxel following 5‐fluorouracil, epirubicin, cyclophosphamide (FEC) (with trastuzumab for patients with HER2‐positive disease) and to evaluate 5‐year disease‐free survival (DFS) associated with this preoperative regimen. Chemotherapy included four cycles of FEC100 (5‐fluorouracil 500 mg/m2, epirubicin 100 mg/m2, cyclophosphamide 500 mg/m2 IV on Day 1 every 21 days) followed by 4 21‐day cycles of docetaxel (35 mg/m2 days 1 and 8) concurrently with capecitabine (825 mg/m2 orally twice daily for 14 days followed by 7 days off) (wTX). For HER2‐positive patients, treatment was modified by decreasing epirubicin to 75 mg/m2 and adding trastuzumab (H) in standard doses (FEC75‐H →wTX‐H). The study objective was to achieve a pCR rate in the breast and axillary lymph nodes of 37% in patients with HER2‐negative breast cancer and of 67% in patients with HER2‐positive breast cancer treated with preoperative trastuzumab. A total of 186 patients were enrolled on study. In an intent‐to‐treat analysis, the pCR rate was 31% (37/118, 95% CI: 24–40%) in the HER2‐negative patients, 24% (15/62, 95% CI: 14–37%) in ER‐positive/HER2‐negative patients, 39% (22/56, 95% CI: 27–53%) in the ER‐negative/HER2‐negative patients, and 46% (29/63, 95% CI: 34–48%) in the HER2‐positive patients. The pCR rate in the 40 trastuzumab‐treated patients was 53% (21/40, 95% CI: 38–67%). Grade 3 and 4 adverse events included neutropenia, leukopenia, diarrhea, and hand‐foot skin reactions. One trastuzumab‐treated patient developed grade 3 cardiotoxicity, and 4 others experienced grade 1–2 decrements in left ventricular function; all five patients’ cardiac function returned to their baseline upon completion of trastuzumab. At 5 years, disease‐free survival was 70% in the HER2‐negative population (78% in ER‐positive/HER2‐negative and 62% in the ER‐negative/HER2‐negative patients) and 80% in the HER2‐positive patients (87% in the trastuzumab‐treated HER2‐positive patients). At 5 years, overall survival was 80% in the HER2‐negative population (88% in ER‐positive/HER2‐negative and 71% in the ER‐negative/HER2‐negative patients) and 86% in the HER2‐positive patients (94.5% in the trastuzumab‐treated HER2‐positive patients). FEC100 (FEC75 with trastuzumab) followed by weekly docetaxel plus capecitabine, with or without trastuzumab is a safe, effective preoperative cytotoxic regimen. However, the addition of capecitabine to docetaxel following FEC, with or without trastuzumab, did not increase pCR rates nor 5‐year DFS over the rates that have been reported with standard preoperative doxorubicin/cyclophosphamide (AC) followed by paclitaxel, with or without trastuzumab. Therefore, the use of capecitabine as part of preoperative chemotherapy is not recommended.