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Background Gene expression signatures for the prediction of differential survival of patients undergoing anti-cancer therapies are of great interest because they can be used to prospectively stratify patients entering new clinical trials, or to determine optimal treatment for patients in more routine clinical settings. Unlike prognostic signatures however, predictive signatures require training set data from clinical studies with at least two treatment arms. As two-arm studies with gene expression profiling have been rarer than similar one-arm studies, the methodology for constructing and optimizing predictive signatures has been less prominently explored than for prognostic signatures. Results Focusing on two “use cases” of two-arm clinical trials, one for metastatic colorectal cancer (CRC) patients treated with the anti-angiogenic molecule aflibercept, and the other for triple negative breast cancer (TNBC) patients treated with the small molecule iniparib, we present derivation steps and quantitative and graphical tools for the construction and optimization of signatures for the prediction of progression-free survival based on cross-validated multivariate Cox models. This general methodology is organized around two more specific approaches which we have called subtype correlation (subC) and mechanism-of-action (MOA) modeling, each of which leverage a priori knowledge of molecular subtypes of tumors or drug MOA for a given indication. The tools and concepts presented here include the so-called differential log-hazard ratio, the survival scatter plot, the hazard ratio receiver operating characteristic, the area between curves and the patient selection matrix. In the CRC use case for instance, the resulting signature stratifies the patient population into “sensitive” and “relatively-resistant” groups achieving a more than two-fold difference in the aflibercept-to-control hazard ratios across signature-defined patient groups. Through cross-validation and resampling the probability of generalization of the signature to similar CRC data sets is predicted to be high. Conclusions The tools presented here should be of general use for building and using predictive multivariate signatures in oncology and in other therapeutic areas.

Iniparib is a prodrug that converts to highly reactive cytotoxic metabolites intracellularly with activity in preclinical glioma models. We investigated the maximum tolerated dose (MTD) of iniparib with monthly (m) and continuous (c) temozolomide (TMZ) dosing schedules in patients with malignant gliomas (MG). Adults with newly diagnosed MG who had successfully completed ≥80% of radiation (RT) and TMZ without toxicity received mTMZ dosing (150-200 mg/m(2) days 1-5/28 days) or cTMZ dosing (75 mg/m(2)/days × 6 weeks) in conjunction with iniparib (i.v. 2 days/week) in the adjuvant setting. Iniparib was dose escalated using a modified continual reassessment method (mCRM). 43 patients (32 male; 34 GBM, 8 AA, 1 gliosarcoma; median age 54 years; median KPS 90) were enrolled across 4 dose levels. In the mTMZ group, 2/4 patients had dose limiting toxicities (DLT) at 19 mg/kg/week (rash/hypersensitivity). At 17.2 mg/kg/week, 1/9 patients had a DLT (grade 3 fatigue). Additional grade 3 toxicities were neutropenia, lymphopenia, and nausea. In the cTMZ group, one DLT (thromboembolic event) occurred at 10.2 mg/kg/week. Dose escalation stopped at 16 mg/kg/week based on mCRM. The mean maximum plasma concentration of iniparib increased with dose. Concentration of the two major circulating metabolites, 4-iodo-3-aminobenzamide and 4-iodo-3-aminobenzoic acid, was ≤5% of the corresponding iniparib concentration. Iniparib is well tolerated, at doses higher than previously investigated, in combination with TMZ after completion of RT + TMZ in patients with MG. Recommended phase 2 dosing of iniparib based on mCRM is 17.2 mg/kg/week with mTMZ and 16 mg/kg/week with cTMZ. An efficacy study of TMZ/RT + iniparib followed by TMZ + iniparib in newly diagnosed GBM using these doses has completed enrollment. Survival assessment is ongoing.

Poly (ADP-ribose) polymerase (PARP) is a novel therapeutic target in cancer. Preclinical studies demonstrate that PARP inhibitors selectively kill BRCA-deficient cells and potentiate the effects of DNA-damaging agents. There are several PARP inhibitors in clinical development, including olaparib, iniparib, veliparib, PF-01367338, and MK-4827. Phase II studies of single-agent olaparib demonstrate activity in BRCA-associated cancers. A randomized phase II trial showed that the addition of iniparib to gemcitabine and carboplatin in patients with metastatic triple-negative breast cancer (TNBC) improved progression-free survival and overall survival. A phase III trial evaluating this combination in metastatic TNBC has completed accrual. Phase III studies of olaparib in BRCA-associated breast cancer and veliparib in breast cancer are being planned. This article reviews the clinical studies to date that have evaluated PARP inhibitors as a single agent or in combination with chemotherapy in patients with breast cancer, including BRCA-associated breast cancer and TNBC.

Triple negative breast cancer (TNBC) is an aggressive clinical phenotype characterized by lack of expression (or minimal expression) of estrogen receptor (ER) and progesterone receptor (PR) as well as an absence of human epidermal growth factor receptor–2 (HER2) overexpression. It shows substantial overlap with basal-type and BRCA1-related breast cancers, both of which also have aggressive clinical courses. However, this overlap is not complete, and the expression of ER, PR, and HER2 has been noted in basal-like tumors. TNBC also includes the normal-like subtype, and not all patients with TNBC harbor BRCA1 mutations. Because of its expression profile, TNBC is not amenable to treatment with hormone therapy or the anti-HER2 monoclonal antibody trastuzumab, and systemic treatment options are currently limited to cytotoxic chemotherapy. Overall survival, whether in early-stage or advanced disease, is poor compared with that in patients who have other phenotypes. A number of targeted approaches to TNBC are undergoing clinical evaluation, including the use of agents with poly(ADP-ribose) polymerase inhibitory properties such as iniparib (the United States Adopted Name for the investigational agent BSI-201), olaparib (AZD2281), and veliparib (ABT-888), antiangiogenic agents such as bevacizumab and sunitinib, and epidermal growth factor receptor blockers such as cetuximab and erlotinib. Encouraging results with some of these agents have been reported, thereby offering the promise for improved outcomes in patients with TNBC. The clinical characteristics of TNBC and clinical experience to date with novel targeted agents under development for this aggressive phenotype is reviewed.

Ovarian carcinomas with mutations in the tumour suppressor BRCA2 are particularly sensitive to platinum compounds. However, such carcinomas ultimately develop cisplatin resistance. The mechanism of that resistance is largely unknown. Here we show that acquired resistance to cisplatin can be mediated by secondary intragenic mutations in BRCA2 that restore the wild-type BRCA2 reading frame. First, in a cisplatin-resistant BRCA2-mutated breast-cancer cell line, HCC1428, a secondary genetic change in BRCA2 rescued BRCA2 function. Second, cisplatin selection of a BRCA2-mutated pancreatic cancer cell line, Capan-1 (refs 3, 4), led to five different secondary mutations that restored the wild-type BRCA2 reading frame. All clones with secondary mutations were resistant both to cisplatin and to a poly(ADP-ribose) polymerase (PARP) inhibitor (AG14361). Finally, we evaluated recurrent cancers from patients whose primary BRCA2-mutated ovarian carcinomas were treated with cisplatin. The recurrent tumour that acquired cisplatin resistance had undergone reversion of its BRCA2 mutation. Our results suggest that secondary mutations that restore the wild-type BRCA2 reading frame may be a major clinical mediator of acquired resistance to platinum-based chemotherapy.

Germline mutations in the BRCA1, BRCA2 and Fanconi anaemia genes confer cancer susceptibility, and the proteins encoded by these genes have distinct functions in related DNA-repair processes. Emerging evidence indicates that these processes are disrupted by numerous mechanisms in sporadic cancers. Collectively, there are properties that define 'BRCAness' — that is, traits that some sporadic cancers share with those occurring in either BRCA1- or BRCA2-mutation carriers. These common properties might have important implications for the clinical management of these cancers.

Poly(ADP-ribose) polymerase-1 (PARP-1) is a nuclear DNA-binding enzyme activated by DNA strand breaks and has a key role in the signalling of DNA single-strand breaks as part of the repair process. In anti-cancer therapy, many agents cause DNA damage as their mechanism of cytotoxicity, and repair of damage is a cause of tumour resistance. Additionally in tumours where double-strand break repair is defective (for example in BRCA-related cancers) PARP inhibitors have potential single-agent activity. Thus, PARP-1 was identified as a potential therapeutic target for cancer treatment and PARP inhibitors have entered the clinic both in combination with cytotoxic chemotherapy, as single agents in DNA repair deficient tumours, and more recently in combination with radiotherapy. The first PARP inhibitor to be given to cancer patients in 2003 was {"type":"entrez-nucleotide","attrs":{"text":"AG014699","term_id":"3649917","term_text":"AG014699"}}AG014699 (rucaparib), a tricyclic indole, which is a potent intravenous inhibitor of PARP. This phase I study had a pharmacodynamic endpoint of PARP inhibition in PBMCs, demonstrating for the first time proof of mechanism of the class. Subsequently AZD2281 (olaparib) entered clinical trials as a single agent (2005), and demonstrated the proof of concept of synthetic lethality in BRCA defective tumours in two small phase II studies. Over the last 5 years seven further inhibitors have entered cancer clinical trials either as a single agent (MK4827) or in combination with various cytotoxic regiments (ABT888, veliparib; BSI-201, iniparib; CEP-9722; INO-1001; E7016, BMN 673) in late preclinical development. Initial exciting data suggesting that iniparib improved outcome in patients with triple-negative breast cancer in combination with chemotherapy have not been confirmed in phase III studies, although there are clearly patients who benefit from this agent. In terms of mechanism of action, iniparib differs from all the other compounds in the class that are competitive inhibitors at the NAD+ binding site of PARP. Iniparib is postulated to have a different mechanism of action and may not be a bona fide PARP inhibitor. It has been a period of rapid clinical development of a new class of agents with exciting evidence of improved response rates in some tumour areas. This class of agents also presents some interesting challenges in clinical trial design, and mechanistic understanding. This presentation will overview the current clinical status of PARP inhibitors and will discuss these challenges and potential biomarker strategies.