Paul Ellis

Definition of Clinically Distinct Molecular Subtypes in Estrogen Receptor–Positive Breast Carcinomas Through Genomic Grade

PURPOSE A number of microarray studies have reported distinct molecular profiles of breast cancers (BC), such as basal-like, ErbB2-like, and two to three luminal-like subtypes. These were associated with different clinical outcomes. However, although the basal and the ErbB2 subtypes are repeatedly recognized, identification of estrogen receptor (ER) -positive subtypes has been inconsistent. Therefore, refinement of their molecular definition is needed. MATERIALS AND METHODS We have previously reported a gene expression grade index (GGI), which defines histologic grade based on gene expression profiles. Using this algorithm, we assigned ER-positive BC to either high-or low-genomic grade subgroups and compared these with previously reported ER-positive molecular classifications. As further validation, we classified 666 ER-positive samples into subtypes and assessed their clinical outcome. RESULTS Two ER-positive molecular subgroups (high and low genomic grade) could be defined using the GGI. Despite tracking a single biologic pathway, these were highly comparable to the previously described luminal A and B classification and significantly correlated to the risk groups produced using the 21-gene recurrence score. The two subtypes were associated with statistically distinct clinical outcome in both systemically untreated and tamoxifen-treated populations. CONCLUSION The use of genomic grade can identify two clinically distinct ER-positive molecular subtypes in a simple and highly reproducible manner across multiple data sets. This study emphasizes the important role of proliferation-related genes in predicting prognosis in ER-positive BC.

Randomized Phase IIB Trial of BLP25 Liposome Vaccine in Stage IIIB and IV Non–Small-Cell Lung Cancer

PURPOSE To evaluate the effect of BLP25 liposome vaccine (L-BLP25) on survival and toxicity in patients with stage IIIB and IV non-small-cell lung cancer (NSCLC). Secondary objectives included health-related quality of life (QOL) and immune responses elicited by L-BLP25. PATIENTS AND METHODS Patients with an Eastern Cooperative Oncology Group performance status of 0 to 2 and stable or responding stage IIIB or IV NSCLC after any first-line chemotherapy were prestratified by stage and randomly assigned to either L-BLP25 plus best supportive care (BSC) or BSC alone. Patients in the L-BLP25 arm received a single intravenous dose of cyclophosphamide 300 mg/m2 followed by eight weekly subcutaneous immunizations with L-BLP25 (1,000 microg). Subsequent immunizations were administered at 6-week intervals. RESULTS The survival results indicate a median survival time of 4.4 months longer for patients randomly assigned to the L-BLP25 arm (88 patients) compared with patients assigned to the BSC arm (83 patients; adjusted hazard ratio [HR] = 0.739; 95% CI, 0.509 to 1.073; P = .112). The greatest effect was observed in stage IIIB locoregional (LR) patients, for whom the median survival time for the L-BLP25 arm has not yet been reached compared with 13.3 months for the BSC arm (adjusted HR = 0.524; 95% CI, 0.261 to 1.052; P = .069). No significant toxicity was observed. QOL was maintained longer in patients on the L-BLP25 arm. CONCLUSION L-BLP25 maintenance therapy in patients with advanced NSCLC is feasible with minimal toxicity. The survival difference of 4.4 months observed with the vaccine did not reach statistical significance. In the subgroup of patients with stage IIIB LR disease, a strong trend in 2-year survival in favor of L-BLP25 was observed.

Predicting prognosis using molecular profiling in estrogen receptor-positive breast cancer treated with tamoxifen

BackgroundEstrogen receptor positive (ER+) breast cancers (BC) are heterogeneous with regard to their clinical behavior and response to therapies. The ER is currently the best predictor of response to the anti-estrogen agent tamoxifen, yet up to 30–40% of ER+BC will relapse despite tamoxifen treatment. New prognostic biomarkers and further biological understanding of tamoxifen resistance are required. We used gene expression profiling to develop an outcome-based predictor using a training set of 255 ER+ BC samples from women treated with adjuvant tamoxifen monotherapy. We used clusters of highly correlated genes to develop our predictor to facilitate both signature stability and biological interpretation. Independent validation was performed using 362 tamoxifen-treated ER+ BC samples obtained from multiple institutions and treated with tamoxifen only in the adjuvant and metastatic settings.ResultsWe developed a gene classifier consisting of 181 genes belonging to 13 biological clusters. In the independent set of adjuvantly-treated samples, it was able to define two distinct prognostic groups (HR 2.01 95%CI: 1.29–3.13; p = 0.002). Six of the 13 gene clusters represented pathways involved in cell cycle and proliferation. In 112 metastatic breast cancer patients treated with tamoxifen, one of the classifier components suggesting a cellular inflammatory mechanism was significantly predictive of response.ConclusionWe have developed a gene classifier that can predict clinical outcome in tamoxifen-treated ER+ BC patients. Whilst our study emphasizes the important role of proliferation genes in prognosis, our approach proposes other genes and pathways that may elucidate further mechanisms that influence clinical outcome and prediction of response to tamoxifen.

PIK3CA mutations associated with gene signature of low mTORC1 signaling and better outcomes in estrogen receptor–positive breast cancer

PIK3CA mutations are reported to be present in approximately 25% of breast cancer (BC), particularly the estrogen receptor–positive (ER+) and HER2-overexpressing (HER2+) subtypes, making them one of the most common genetic aberrations in BC. In experimental models, these mutations have been shown to activate AKT and induce oncogenic transformation, and hence these lesions have been hypothesized to render tumors highly sensitive to therapeutic PI3K/mTOR inhibition. By analyzing gene expression and protein data from nearly 1,800 human BCs, we report that a PIK3CA mutation–associated gene signature (PIK3CA-GS) derived from exon 20 (kinase domain) mutations was able to predict PIK3CA mutation status in two independent datasets, strongly suggesting a characteristic set of gene expression–induced changes. However, in ER+/HER2− BC despite pathway activation, PIK3CA mutations were associated with a phenotype of relatively low mTORC1 signaling and a good prognosis with tamoxifen monotherapy. The relationship between clinical outcome and the PIK3CA-GS was also assessed. Although the PIK3CA-GS was not associated with prognosis in ER− and HER2+ BC, it could identify better clinical outcomes in ER+/HER2− disease. In ER+ BC cell lines, PIK3CA mutations were also associated with sensitivity to tamoxifen. These findings could have important implications for the treatment of PIK3CA-mutant BCs and the development of PI3K/mTOR inhibitors.

Dissecting the Heterogeneity of Triple-Negative Breast Cancer

Triple-negative breast cancer (TNBC) accounts for 15% to 20% of breast cancers. It is a heterogeneous disease, not only on the molecular level, but also on the pathologic and clinical levels. TNBC is associated with a significantly higher probability of relapse and poorer overall survival in the first few years after diagnosis when compared with other breast cancer subtypes. This is observed despite its usual high sensitivity to chemotherapy. In the advanced setting, responses observed with chemotherapy lack durability. Early-stage clinical studies suggested impressive potential when a poly (ADP-ribose) polymerase (PARP) inhibitor is given for the treatment of advanced TNBC with BRCA gene dysfunction. The molecular complexity of TNBC has led to proposed subclassifications, which will be of great value for the development of targeted therapies. In this review, we discuss the biology of TNBC at the pathologic and the molecular levels. We also elaborate on the role of systemic therapies and the results of the first phase III clinical trial evaluating the addition of iniparib, a novel investigational anticancer agent that does not possess characteristics typical of the PARP inhibitor class, in combination with chemotherapy in advanced TNBC.

Chemotherapy for Breast Cancer During Pregnancy: An 18-Year Experience From Five London Teaching Hospitals

PURPOSE The rare association between breast cancer and pregnancy means that few oncologists gain an expertise in this area. In particular, there are few published data concerning the use of chemotherapy for breast cancer during pregnancy. In this retrospective case series, we describe the experiences of five hospitals in London, United Kingdom, and how they manage this condition. PATIENTS AND METHODS Retrospective searches were performed at five London hospitals in order to identify women who received chemotherapy for breast cancer while pregnant. RESULTS Twenty-eight women were identified who had received chemotherapy for breast cancer during pregnancy. Twenty-four women received adjuvant or neoadjuvant chemotherapy for early breast cancer, and four women received palliative chemotherapy for metastatic disease. A total of 116 cycles of chemotherapy were administered during pregnancy. Sixteen women were treated with anthracycline-based chemotherapy and 12 received cyclophosphamide, methotrexate, and fluorouracil. All but one of the women were treated after the first trimester. One spontaneous abortion occurred in the woman treated during her first trimester; otherwise, there were no serious adverse consequences for the mothers or neonates. CONCLUSION These data provide evidence that in terms of peripartum complications and immediate fetal outcome, chemotherapy can be safely administered to women during the second and third trimesters of pregnancy.

Breast carcinoma during pregnancy

Breast carcinoma during pregnancy (BCP) is a difficult clinical situation, as it appears to put the health of the mother in conflict with that of the fetus.

Phase II Study of the Efficacy and Tolerability of Two Dosing Regimens of the Farnesyl Transferase Inhibitor, R115777, in Advanced Breast Cancer

PURPOSE R115777 is an orally active farnesyl transferase inhibitor that specifically blocks farnesylation of proteins involved in growth-factor-dependent cell-signal-transduction pathways. We conducted a phase II study in 76 patients with advanced breast cancer. PATIENTS AND METHODS Two cohorts of patients were recruited sequentially. The first cohort (n = 41) received a continuous dosing [CD] regimen of R115777 400 or 300 mg bid. The second cohort (n = 35) received 300 mg bid in a cyclical regimen of 21 days of treatment followed by 7 days of rest (intermittent dosing [ID]). RESULTS In the CD cohort, four patients (10%) had a partial response (PR) and six patients (15%) had stable disease at > or = 24 weeks (SD). In the ID cohort, five patients (14%) had a PR and three patients (9%) had prolonged SD. The first six patients in the CD cohort treated at 400 mg bid all developed grade 3 to 4 neutropenia, so the subsequent 35 patients were treated at 300 mg bid. The incidence of hematologic toxicity was significantly lower in the ID than in the CD (300-mg bid) cohort: grade 3 to 4 neutropenia (14% v 43%; P =.016) and grade 3 to 4 thrombocytopenia (3% v 26%; P =.013). One patient in the ID cohort developed grade 2 to 3 neurotoxicity compared with 15 patients in the CD cohort (3% v 37%; P =.0004). CONCLUSION The farnesyl transferase inhibitor R115777 has demonstrated clinical activity in patients with metastatic breast cancer, and the ID regimen has a significantly improved therapeutic index compared with the CD regimen.

Sequential docetaxel as adjuvant chemotherapy for early breast cancer (TACT): an open-label, phase III, randomised controlled trial

Summary Background Incorporation of a taxane as adjuvant treatment for early breast cancer offers potential for further improvement of anthracycline-based treatment. The UK TACT study (CRUK01/001) investigated whether sequential docetaxel after anthracycline chemotherapy would improve patient outcome compared with standard chemotherapy of similar duration. Methods In this multicentre, open-label, phase III, randomised controlled trial, 4162 women (aged >18 years) with node-positive or high-risk node-negative operable early breast cancer were randomly assigned by computer-generated permuted block randomisation to receive FEC (fluorouracil 600 mg/m2, epirubicin 60 mg/m2, cyclophosphamide 600 mg/m2 at 3-weekly intervals) for four cycles followed by docetaxel (100 mg/m2 at 3-weekly intervals) for four cycles (n=2073) or control (n=2089). For the control regimen, centres chose either FEC for eight cycles (n=1265) or epirubicin (100 mg/m2 at 3-weekly intervals) for four cycles followed by CMF (cyclophosphamide 600 mg/m2, methotrexate 40 mg/m2, and fluorouracil 600 mg/m2 at 4-weekly intervals) for four cycles (n=824). The primary endpoint was disease-free survival. Analysis was by intention to treat (ITT). This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN79718493. Findings All randomised patients were included in the ITT population. With a median follow-up of 62 months, disease-free survival events were seen in 517 of 2073 patients in the experimental group compared with 539 of 2089 controls (hazard ratio [HR] 0·95, 95% CI 0·85–1·08; p=0·44). 75·6% (95% CI 73·7–77·5) of patients in the experimental group and 74·3% (72·3–76·2) of controls were alive and disease-free at 5 years. The proportion of patients who reported any acute grade 3 or 4 adverse event was significantly greater in the experimental group than in the control group (p<0·0001); the most frequent events were neutropenia (937 events vs 797 events), leucopenia (507 vs 362), and lethargy (456 vs 272). Interpretation This study did not show any overall gain from the addition of docetaxel to standard anthracycline chemotherapy. Exploration of predictive biomarker-defined subgroups might have the potential to better target the use of taxane-based therapy. Funding Cancer Research UK (CRUK 01/001), Sanofi-Aventis, Pfizer, and Roche.

Iniparib Nonselectively Modifies Cysteine-Containing Proteins in Tumor Cells and Is Not a Bona Fide PARP Inhibitor

Purpose: PARP inhibitors are being developed as therapeutic agents for cancer. More than six compounds have entered clinical trials. The majority of these compounds are β-nicotinamide adenine dinucleotide (NAD+)-competitive inhibitors. One exception is iniparib, which has been proposed to be a noncompetitive PARP inhibitor. In this study, we compare the biologic activities of two different structural classes of NAD+-competitive compounds with iniparib and its C-nitroso metabolite. Experimental Design: Two chemical series of NAD+-competitive PARP inhibitors, iniparib and its C-nitroso metabolite, were analyzed in enzymatic and cellular assays. Viability assays were carried out in MDA-MB-436 (BRCA1-deficient) and DLD1−/− (BRCA2-deficient) cells together with BRCA-proficient MDA-MB-231 and DLD1+/+ cells. Capan-1 and B16F10 xenograft models were used to compare iniparib and veliparib in vivo. Mass spectrometry and the 3H-labeling method were used to monitor the covalent modification of proteins. Results: All NAD+-competitive inhibitors show robust activity in a PARP cellular assay, strongly potentiate the activity of temozolomide, and elicit robust cell killing in BRCA-deficient tumor cells in vitro and in vivo. Cell killing was associated with an induction of DNA damage. In contrast, neither iniparib nor its C-nitroso metabolite inhibited PARP enzymatic or cellular activity, potentiated temozolomide, or showed activity in a BRCA-deficient setting. We find that the nitroso metabolite of iniparib forms adducts with many cysteine-containing proteins. Furthermore, both iniparib and its nitroso metabolite form protein adducts nonspecifically in tumor cells. Conclusions: Iniparib nonselectively modifies cysteine-containing proteins in tumor cells, and the primary mechanism of action for iniparib is likely not via inhibition of PARP activity. Clin Cancer Res; 18(2); 510–23. ©2011 AACR.