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Photodynamic therapy (PDT) is an effective noninvasive therapeutic strategy that can convert oxygen to highly cytotoxic singlet oxygen (1O2) through the co-localization of excitation light and photosensitizers. However, compromised by the hypoxic tumor microenvironment, the therapeutic efficacy of PDT is reduced seriously. Herein, to overcome tumor-associated hypoxia, and further achieve tumor-targeted synergistic chemotherapy/PDT/photothermal therapy (PTT), we have constructed a biodegradable oxygen-producing nanoplatform (named Ini@PM-HP), which was composed of the porous metal-organic framework (PCN-224(Mn)), the poly (ADP-ribose) polymerase (PARP) inhibitor (Iniparib), and the polydopamine-modified hyaluronic acid (HA-PDA). Since HA can specifically bind to the overexpressed HA receptors (cluster determinant 44, CD44) on tumor cell, Ini@PM-HP prefers to accumulate at the tumor site once injected intravenously. Then iniparib can be released in tumor environment (TME), thereby dysfunctioning DNA damage repair and promoting cell apoptosis. At the same time, the chelating of Mn and tetrakis(4-carboxyphenyl) porphyrin (Mn-TCPP) can generate O2 in situ by reacting with endogenous H2O2, relieving the hypoxic TME and achieving enhanced PDT. Moreover, owing to the high photothermal conversion efficiency of PDA, PTT can be driven by the 808 nm laser irradiation. As systematically demonstrated in vitro and in vivo, this nanotherapeutic approach enables the combined therapy with great inhibition on tumor. Overall, the as-prepared nanoplatform provide a promising strategy to overcome tumor-associated hypoxia, and shows great potential for combination tumor therapy. Statement of significance A delicately designed biodegradable oxygen-producing nanoplatform Ini@PM-HP is constructed to achieve combination therapy of solid tumors. Taking advantage of the active-targeting, PTT, enhanced PDT and PARPi, this nanotherapeutic approach successfully enables the combined chemo/photothermal/photodynamic therapy with great inhibition of solid tumors.

Background: Triple-negative breast cancer (TNBC), the most common type of breast cancer, is associated with poor patient prognosis. Platinum-containing chemotherapies are commonly used in the treatment and prevention of advanced TNBC. Objectives and Methods: To systematically evaluate the effectiveness and safety of platinum-containing chemotherapies in patients with advanced TNBC, we searched several databases, including PubMed, Medline, Embase, ClinicalTrials.gov, Cochrane Library, CNKI, CBM, and the Chinese Cochrane Center, to collect published randomized controlled clinical studies of platinum-containing chemotherapies for advanced TNBC before November 2020. The meta-analysis was performed using Review Manager version 5.3. To assess effectiveness and safety, dichotomous and continuous variables were assessed using odds ratio (OR) and mean difference (MD), respectively, with 95% CI. Results: A total of 1,222 patients with advanced TNBC were enrolled in 11 eligible trials, including 489 patients in the treatment group (platinum-containing) and 447 patients in the control group (non-platinum-containing). We also retrieved information whether a PARP inhibitor was combined with platinum-containing chemotherapy for patients with metastatic TNBC and identified 224 patients who received a PARP inhibitor combined with platinum-containing chemotherapy and 62 patients in the platinum-containing group who did not. The platinum-containing chemotherapy group had a significantly better objective response rate (OR 1.43, 95% CI 1.20–1.71, p < 0.001) and longer progression-free survival (PFS; MD 1.15, 95% CI 0.03–2.28, p < 0.05) than the non-platinum-containing chemotherapy group. However, there was no significant difference in overall survival (OS) of patients with advanced TNBC between the two groups (MD 2.04, 95% CI –0.83 to 4.91, p > 0.05). Related adverse effects of platinum-containing chemotherapies involved gastrointestinal reaction, myelosuppression and liver function damage. Platinum-containing chemotherapies were not associated with an increased incidence of adverse side effects compared with non-platinum-containing chemotherapies, with the exception of nausea and vomiting (OR 2.22, 95% CI 1.10–4.46, p < 0.05). Furthermore, the addition of the PARP inhibitor iniparib to gemcitabine and carboplatin treatment improved the rate of clinical benefit, OS and PFS. Conclusions: Platinum-containing chemotherapy remains a highly recommended therapeutic regimen due to greater effectiveness and tolerance for patients with advanced TNBC.

INTRODUCTION Poly (ADP-ribose) polymerase inhibitors (PARPi) are already part of the armamentarium of drugs available against ovarian and breast cancer. There is less data available on the efficacy of these drugs in the treatment of non-small cell lung cancer (NSCLC). AREAS COVERED The authors have analyzed the preclinical studies that justified the use of PARPi in NSCLC. They then evaluate the in vivo efficacy of the combination of these drugs with chemotherapy, radiotherapy, and immunotherapy. EXPERT OPINION Data from clinical trials available to date have discouraged the use of PARPi in association with chemotherapy or radiotherapy in NSCLC. The knowledge available to date opens the door to the use of PARPi in association with immunotherapy. In fact, the activity of these drugs would not be based only on direct cytotoxic action, but also on the modification of the intra-tumor microenvironment, in particular by increasing the expression of PD-L1 on tumor cells. This action might potentially enhance available treatments with a modest increase in toxicity.

Background: Many breast and ovarian cancer patients have germline or somatic mutations in BRCA 1&2 genes. These proteins are important for repairing double-strand DNA breaks by homologous recombinational repair. In patients who have mutations in these genes, PARP is the major alternative for repairing single-strand DNA breaks. PARP inhibitors (PARPi) inhibit PARP, thereby causing cell death by accumulation of damaged DNA in cells. Many PARPi, including Olaparib, have been approved and used in treatment of metastatic ovarian cancer patients with BRCA 1&2 mutation. Recently, Olaparib was also approved by the FDA for treatment of metastatic breast cancer patients with germline BRCA 1&2 mutation, and many other PARPi are in clinical trial. In this study we analyzed breast cancer patients' awareness, use and experience with PARPi s. Many patients share their experiences on online forums which contain millions of freely shared messages. These can be used to analyze patient concerns and experiences. However, this data is unstructured and difficult to analyze. We used our automated system VoCP, that uses techniques from Big Data Science and Artificial Intelligence (deep learning, topic modeling, information retrieval, and natural language processing) to analyze these messages. Methods: We collected 15.13 million unique messages by 987,189 users from 37 unrestricted cancer forums that provide clinically relevant information. We built custom ontologies for breast cancer, various PARPi, chemotherapy and side effects, and then used our automated system VoCP to extract relevant information from these messages. Results: We found 1,536 breast cancer patients discussing PARPi. 459 patients mentioned use of PARPi whereas 706 patients shared the information about PARPi and 196 inquired about them. 176 patients mentioned that they were planning to use PARPi. 76 patients using PARPi mentioned having BRCA 1 or 2 mutation and 1 patient mentioned CHEK 2 mutation. 91 patients mentioned having triple negative cancer. 212 patients mentioned being treated on clinical trial and 10 mentioned being off trial. 162 patients mentioned use of chemotherapy with PARPi and 40 mentioned use of PARPi as single agent. Specific PARPi: 47 mentioned Olaparib, 104 mentioned Valiparib, & Talazoparib, 6 rucaparib and 4 Niraparib. Most patient just mentioned “PARP inhibitor.” Some patients mentioned iniparib on clinical trial. Side effects were reported by 60 patients. These include: · Nausea: 14 · Fatigue: 15 · GI side effect: 7 · Thrombocytopenia: 5 · Anemia: 2 · Neutropenia: 2 · Neuropathy: 5 · Insomnia:2 99 patients mentioned PARPi were “effective,” 21 mentioned they were “somewhat effective” and 36 mentioned they were “ineffective.” 144 patient expressed positive sentiments, 30 patients expressed negative sentiments and 16 patients expressed neutral sentiment for PARPi. Conclusion: · There is increasing awareness and curiosity for PARPi in breast cancer patients as more patients are being tested for BRCA and other mutations. · Among the users, PARPi are generally associated with low toxicity and positive sentiments. · VoCP reliably provides meaningful insights from the patient's point of view; it also gives insight into unmet needs where more resources and research should be focused. Citation Format: Aggarwal S, Sharma R, Singh M, Aggarwal A. Voice of cancer patient: Analysis of breast cancer patients' experience with PARP inhibitors [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-16-02.

Background: Emerging data suggest that some patients with TNBC could benefit from the addition of immune-based therapy. This observation is in part due to the significant association between distinct tumor-infiltrating lymphocytes (TILs) and prognosis in TNBC. Efforts to comprehensively characterize the immune microenvironment of TNBCs are critically important to gain a better understanding of the immune landscape and how it influences response to both standard chemotherapy and immunotherapy. We previously assessed both stromal TILs (sTILs) and intraepithelial TILs (iTILs) from pre-treatment tumor samples from patients enrolled on a phase II study of neoadjuvant gemcitabine, carboplatin and iniparib (PrECOG 0105; NCT00813956). We found that both iTILS and sTILS significantly associated with pathologic response. Furthermore, we assessed a novel 'in silico flow cytometry' gene expression-based method, CIBERSORT, designed to assess overall immune content and deconvolute the relative levels of distinct leukocyte subsets in tumors. Specific leukocyte subsets significantly associated with pCR included activated memory CD4+ T cells, CD8+ T cells and M1 macrophages (all p Methods: We performed SPARTA - Spatial Perception And Regional Tumor Analysis - a multiplexed immunohistochemistry-based technology with data visualization and analysis modules that is designed to capture clinically relevant information about the tumor microenvironment in 72 pre-treatment FFPE tumor sections from patients enrolled on PrECOG 0105. SPARTA was used to test and analyze the coordinated expression of PD-L1, PD-1, CD45RO, CD4, CD8 and HLA-DRA in the study cohort from whole slide scanned images. Pathologic response at the time of surgery was evaluated using the residual cancer burden index. Germline BRCA1 and BRCA2 status was known for all patients. Results: Of 72 samples, 67 were evaluable for SPARTA analysis. Within a subset of tumors separately profiled by both SPARTA (FFPE/IHC microscopy) and CIBERSORT (Frozen/RNA GEP), we found significant correlation for clinically relevant TIL subpopulations, including for CD8+ T cells (r=0.83, p Conclusions: Spatial mapping of the immune microenvironment in primary TNBC reveals distinct immune cell populations associated with response to neoadjuvant platinum-based therapy. Citation Format: Telli ML, Vinayak S, Khododoust MS, Gruber JJ, Ford JM, Sanchez P, Banayan N, Azimi S, Tumeh PC, Newman AM, Alizadeh AA. Spatial mapping of the immune microenvironment in primary triple-negative breast cancer (TNBC) and association with neoadjuvant therapy response [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr PD5-12.

Currently women that have a hereditary breast cancer predisposition face screening, chemoprevention, and risk-reducing surgery as options for preventing the disease. Bilateral preventive oophorectomy, combined with either MRI screening or a bilateral preventive mastectomy, can contribute considerably to a better life expectancy. Bilateral prophylactic mastectomy can reduce the risk of breast cancer by up to 95% in BRCA1/BRCA2 mutation carriers. There are two important works that must be considered seminal in the treatment of hereditary breast cancer mainly BRCA1/2 carriers. Wesierska-Gądek et al. have shown that using PARP inhibitors could be relevant in carriers of BRCA1\2 mutations based on the knowledge that BRCA1/2-mutant cells are hypersensitive to inactivation of poly(ADP-ribose) polymerase 1 (PARP-1). Another seminal paper published by Arun et al. in 2015 comparing three different PARP inhibitors such as the ABT-888 (Veliparib), BSI-201 (Iniparib), and AZD228 (Olaparib) demonstrated that they have anti-proliferative effects in breast cancer cell lines with BRCA1 or BRCA2 mutations. An interesting observation from this study was that AZD228 (Olaparib) was the most potent PARP inhibitor but only in those cells that have allelic loss.

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.

Purpose: Iniparib is a purported prodrug causing cell death through intracellular conversion to nitro radical ions. We assessed the efficacy and safety of iniparib with standard radiotherapy and temozolomide in patients with newly diagnosed glioblastoma (GBM). Patients and Methods: Adults meeting eligibility criteria were enrolled in this prospective, single-arm, open-label multi- institution phase II trial with median overall survival (mOS) compared with a historical control as the primary objective. A safety run-in component of radiotherapy + temozolomide + iniparib (n = 5) was followed by an efficacy study (n = 76) with the recommended phase II doses of iniparib (8.0 mg/kg i.v. twice/week with radiotherapy + daily temozolomide followed by 8.6 mg/kg i.v. twice/week with 5/28-day temozolomide). Results: The median age of the 81 evaluable participants was 58 years (63% male). Baseline KPS was ≥ 80% in 87% of participants. The mOS was 22 months [95% confidence interval (CI), 17–24] and the HR was 0.44 (95% CI, 0.35–0.55) per-person-year of follow-up. The 2- and 3-year survival rates were 38% and 25%, respectively. Treatment-related grade 3 adverse events (AEs) occurred in 27% of patients; 9 patients had AEs requiring drug discontinuation including infusion-related reaction, rash, gastritis, increased liver enzymes, and thrombocytopenia. Conclusions: Iniparib is well tolerated with radiotherapy and temozolomide in patients with newly diagnosed GBM at up to 17.2 mg/kg weekly. The primary objective of improved mOS compared with a historical control was met, indicating potential antitumor activity of iniparib in this setting. Dosing optimization (frequency and sequence) is needed prior to additional efficacy studies.

Purpose: In germline BRCA1 or BRCA2 (BRCA1/2) mutation carriers, restoration of tumor BRCA1/2 function by a secondary mutation is recognized as a mechanism of resistance to platinum and PARP inhibitors, primarily in ovarian cancer. We evaluated this mechanism of resistance in newly diagnosed patients with BRCA1/2-mutant breast cancer with poor response to neoadjuvant platinum-based therapy. Experimental Design: PrECOG 0105 was a phase II neoadjuvant study of gemcitabine, carboplatin, and iniparib in patients with stage I–IIIA triple-negative or BRCA1/2 mutation–associated breast cancer (n = 80). All patients underwent comprehensive BRCA1/2 genotyping. For mutation carriers with moderate or extensive residual disease after neoadjuvant therapy, BRCA1/2 status was resequenced in the residual surgical breast tumor tissue. Results: Nineteen patients had a deleterious germline BRCA1/2 mutation, and four had moderate residual disease at surgery. BRCA1/2 sequencing of residual tissue was performed on three patients. These patients had BRCA1 1479delAG, 3374insGA, and W1712X mutations, respectively, with LOH at these loci in the pretreatment tumors. In the first case, a new BRCA1 mutation was detected in the residual disease. This resulted in a 14–amino acid deletion and restoration of the BRCA1 reading frame. A local relapse biopsy 4 months later revealed the identical reversion mutation, and the patient subsequently died from metastatic breast cancer. Conclusions: We report a BRCA1 reversion mutation in a patient newly diagnosed with triple-negative breast cancer that developed over 18 weeks of platinum-based neoadjuvant therapy. This was associated with poor therapy response, early relapse, and death. Clin Cancer Res; 23(13); 3365–70. ©2017 AACR.

Background: TNBC patients with homologous recombination (HR) deficient tumors have significantly higher pathologic complete response (pCR, ypT0/is ypN0) rates when treated with platinum-based chemotherapy. TILs are prognostic and predictive of chemotherapy benefit in TNBC. Interestingly, recent data suggests that HR deficient TNBCs and BRCA1/2 mutant ovarian cancers may be enriched for immune cell infiltration. Thus, we performed a pooled analysis of 5 phase II studies that included patients with TNBC treated with neoadjuvant platinum-based chemotherapy to evaluate the association of TILs with HR deficiency status and tumor BRCA1/2 mutation status. Methods: 166 patients with TNBC and known HR deficiency status from the following clinical trials were available for analysis: PrECOG 0105 (N=72), NCT00580333 (N=32), NCT01372579 (N=26), TBCRC 008 (N=18) and NCT00148694 (N=18). Neoadjuvant chemotherapy regimens included 1) carboplatin, gemcitabine, iniparib, 2) cisplatin with or without bevacizumab 3) carboplatin, eribulin, 4) carboplatin, nab-paclitaxel, with or without vorinostat. HR deficiency status was defined as a high HRD score (42 or higher) and/or presence of a BRCA1/2 tumor mutation (tBRCA). Digitized pre-treatment core biopsy H&E sections were reviewed and scored by two blinded expert breast cancer pathologists using the international TIL working group guidelines. The density (%) of both intratumoral TILs (iTILs) and stromal TILs (sTILs) was recorded by deciles (n=122 thus far, additional cases to be included in final analysis). Results: Among 122 patients, pCR was achieved in 36 patients (29.5%) and 71 tumors (58.2%) were HR deficient. In total, 24 patients (19.7%) patients had a deleterious BRCA1/2 mutation. Among all tumors, iTIL and sTIL median densities were 0% (range 0-20) and 10% (range 0-80), respectively, and were not statistically different in HR deficient versus non-deficient tumors (iTIL p=0.746; sTIL p=0.159). The same absent association was observed for tBRCA mutation status (iTIL p=0.607; sTIL p=0.315) and binary HRD score (iTIL p=0.879; sTIL p=0.364). Updated results with additional cases scored for TILs will be reported at time of presentation. Additional analyses assessing the relationship between TILs and pCR/residual cancer burden adjusting for HRD status and other clinical variables will also be included at the time of presentation. Conclusion: Several previous studies have reported that TILs are significantly associated with response to standard chemotherapy regimens when given in the neoadjuvant setting. Measures of genomic instability and DNA repair deficiency, including HRD, have been shown to be robust predictors of response to chemotherapy, including platinum containing regimens. It is unclear if TILs will be predictive in a similarly robust way for response to platinum-containing regimens. Results of this study suggest TIL density and HR deficiency status may be independent and non-overlapping. Final analysis including additional cases will be included in the final presentation.Background: TNBC patients with homologous recombination (HR) deficient tumors have significantly higher pathologic complete response (pCR, ypT0/is ypN0) rates when treated with platinum-based chemotherapy. TILs are prognostic and predictive of chemotherapy benefit in TNBC. Interestingly, recent data suggests that HR deficient TNBCs and BRCA1/2 mutant ovarian cancers may be enriched for immune cell infiltration. Thus, we performed a pooled analysis of 5 phase II studies that included patients with TNBC treated with neoadjuvant platinum-based chemotherapy to evaluate the association of TILs with HR deficiency status and tumor BRCA1/2 mutation status. Methods: 166 patients with TNBC and known HR deficiency status from the following clinical trials were available for analysis: PrECOG 0105 (N=72), NCT00580333 (N=32), NCT01372579 (N=26), TBCRC 008 (N=18) and NCT00148694 (N=18). Neoadjuvant chemotherapy regimens included 1) carboplatin, gemcitabine, iniparib, 2) cisplatin with or without bevacizumab 3) carboplatin, eribulin, 4) carboplatin, nab-paclitaxel, with or without vorinostat. HR deficiency status was defined as a high HRD score (42 or higher) and/or presence of a BRCA1/2 tumor mutation (tBRCA). Digitized pre-treatment core biopsy H&E sections were reviewed and scored by two blinded expert breast cancer pathologists using the international TIL working group guidelines. The density (%) of both intratumoral TILs (iTILs) and stromal TILs (sTILs) was recorded by deciles (n=122 thus far, additional cases to be included in final analysis). Results: Among 122 patients, pCR was achieved in 36 patients (29.5%) and 71 tumors (58.2%) were HR deficient. In total, 24 patients (19.7%) patients had a deleterious BRCA1/2 mutation. Among all tumors, iTIL and sTIL median densities were 0% (range 0-20) and 10% (range 0-80), respectively, and were not statistically different in HR deficient versus non-deficient tumors (iTIL p=0.746; sTIL p=0.159). The same absent association was observed for tBRCA mutation status (iTIL p=0.607; sTIL p=0.315) and binary HRD score (iTIL p=0.879; sTIL p=0.364). Updated results with additional cases scored for TILs will be reported at time of presentation. Additional analyses assessing the relationship between TILs and pCR/residual cancer burden adjusting for HRD status and other clinical variables will also be included at the time of presentation. Conclusion: Several previous studies have reported that TILs are significantly associated with response to standard chemotherapy regimens when given in the neoadjuvant setting. Measures of genomic instability and DNA repair deficiency, including HRD, have been shown to be robust predictors of response to chemotherapy, including platinum containing regimens. It is unclear if TILs will be predictive in a similarly robust way for response to platinum-containing regimens. Results of this study suggest TIL density and HR deficiency status may be independent and non-overlapping. Final analysis including additional cases will be included in the final presentation. Citation Format: Telli ML, Badve S, Vinayak S, Silver DP, Isakoff SJ, Kaklamani VG, Gradishar WJ, Stearns V, Connolly RM, Ford JM, Adams S, Garber JE, Evans B, Timms K, Wenstrup R, Richardson AL. Evaluation of tumor infiltrating lymphocytes (TILs) and their association with homologous recombination deficiency and BRCA1/2 mutation status in triple-negative breast cancer (TNBC): A pooled analysis [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-09-09.

Dogs develop cancer spontaneously with age, with breed-specific risk underlying differences in genetics. Mammary tumors are reported as the most frequent neoplasia in intact female dogs. Their high prevalence in certain breeds suggests a genetic component, as it is the case in human familial breast cancer, distinctly in BRCA2-associated cancers. However, the molecular genetics of BRCA2 in the pathogenesis of canine cancer are still under investigation.Genetic variations of canine BRCA2 comprised single nucleotide polymorphisms, insertions and deletions. The BRCA2 level has been shown to be reduced in tumor gland samples, suggesting that low expression of BRCA2 is contributing to mammary tumor development in dogs. Additionally, specific variations of the BRCA2 gene affect RAD51 binding strength, critically damage the BRCA2-RAD51 binding and further provoke a defective repair. In humans, preclinical and clinical data revealed a synthetic lethality interaction between BRCA2 mutations and PARP inhibition. PARP inhibitors are successfully used to increase chemo- and radiotherapy sensitivity, although they are also associated with numerous side effects and acquired resistance. Cancer treatment of canine patients could benefit from increased chemo- and radiosensitivity, as their cancer therapy protocols usually include only low doses of drugs or radiation. Early investigations show tolerability of iniparib in dogs. PARP inhibitors also imply higher therapy costs and consequently are less likely to be accepted by pet owners.We summarized the current evidence of canine BRCA2 gene alterations and their association with mammary tumors. Mutations in the canine BRCA2 gene have the potential to be exploited in clinical therapy through the usage of PARP inhibitors. However, further investigations are needed before introducing PARP inhibitors in veterinary clinical practice.

Background: TNBC patients with homologous recombination (HR) deficient tumors have significantly higher pathologic complete response (pCR, ypT0/is ypN0) rates when treated with platinum-based chemotherapy regimens than TNBC patients whose tumors are HR non-deficient. We performed a pooled analysis of 5 phase II studies that included patients with TNBC treated with neoadjuvant platinum-based chemotherapy to better estimate the pCR rates amongst HR deficient and HR non-deficient tumors. Methods: Patients with TNBC and known HR deficiency status from the following clinical trials were available for analysis: PrECOG 0105 (N=72), NCT00148694/NCT00580333 (N=50), NCT01372579 (N=26), TBCRC 008 (N=18). Neoadjuvant chemotherapy regimens included 1) carboplatin, gemcitabine, iniparib, 2) cisplatin with or without bevacizumab 3) carboplatin, eribulin, 4) carboplatin, nab-paclitaxel, with or without vorinostat. HR deficiency status was defined as a high HRD score (42 or higher) and/or presence of a BRCA1/2 tumor mutation (tBRCA). Logistic regression models were used to adjust for study effects. The addition of data from the TNBC platinum-treated arm of GeparSixto (n=101) to this pooled analysis will be available at the time of presentation bringing the total sample size to 267. Results: pCR was achieved in 51 patients (31%) and 104 patients (63%) were HR deficient (31 with high HRD score and tBRCA mutation, 67 with high HRD score only, and 6 with tBRCA mutation only). Patients with HR deficient tumors were more likely to achieve a pCR than those with HR non-deficient tumors: 44% vs. 8% (p Likelihood of pCR adjusting for studyModel #Predictor VariablePopulation (n)Adjusted Odds RatioLower 95% CIUpper 95% CIP Value1HR DeficiancyAll (166)12.54.237.3 Conclusion: HR deficiency status is a robust predictor of pCR across different neoadjuvant platinum-based regimens. This pooled analysis suggests that HRD can be used to identify TNBC patients with a high probability of obtaining pCR with a platinum-based neoadjuvant chemotherapy regimen. Citation Format: Telli ML, McMillan A, Ford JM, Richardson AL, Silver DP, Isakoff SJ, Kaklamani VG, Gradishar W, Stearns V, Connolly RM, Loibl S, Elkin EP, Timms K, Hartman A-R, von Minckwitz G. Homologous recombination deficiency (HRD) as a predictive biomarker of response to neoadjuvant platinum-based therapy in patients with triple negative breast cancer (TNBC): A pooled analysis. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-07-12.

Metastatic triple-negative breast cancer (TNBC) is a phenotypic breast cancer subgroup with a very poor prognosis, despite standard treatments. Combined twice-weekly iniparib and gemcitabine/carboplatin (GC+tw-iniparib) showed benefit over gemcitabine/carboplatin in a randomized phase II trial, and a phase III was initiated comparing these regimens. The present phase II study was initiated to compare GC+tw-iniparib with a more practical once-weekly schedule (GC+w-iniparib) in TNBC. Metastatic TNBC patients were randomized to receive iniparib weekly (11.2 mg/kg on days 1 and 8) or twice-weekly (5.6 mg/kg on days 1, 4, 8, and 11) with gemcitabine (1000 mg/m2) and carboplatin (area under the curve 2 on days 1 and 8), every 3 weeks. The primary endpoint was the overall response rate (ORR). Pharmacokinetics of iniparib and its two metabolites were analyzed. A total of 163 patients were randomized, 82 GC+w-iniparib and 81 GC+tw-iniparib. Demographic and baseline characteristics were well balanced. ORR was 34.1% (95% CI 23.9–44.4%) vs. 29.6% (95% CI 19.7–39.6%) and median progression-free survival was 5.5 months (95% CI 4.2–5.7) vs. 4.3 months (95% CI 3.0–5.8) for GC+w-iniparib and GC+tw-iniparib, respectively. Safety was similar across treatment arms in terms of event severity and type. Iniparib plasma concentrations and exposure were two-fold higher with w-iniparib compared to tw-iniparib. Iniparib and its metabolites were cleared rapidly with a terminal half-life of

Triple‐negative breast cancer (TNBC) is a heterogeneous disease with poorer prognosis than other subtypes, yet effective therapies are still not available. We aimed to compare the efficacy of various targeted therapies with chemotherapy (CT) in TNBC patients using a network meta‐analysis. A systematic literature search was performed in PubMed, EMBASE, and the Cochrane Library. A total of 27 randomized controlled trials (RCTs), involving 6924 TNBC patients, were included. Olaparib significantly improved PFS (0.43, 0.29‐0.64) and ORR (2.57, 1.31‐5.09) in comparison with CT. As for bevacizumab + CT, it showed a significant improvement of PFS (0.66, 0.55‐0.80) and ORR (2.15, 1.16‐4.05) compared with CT + placebo. It was also superior to CT alone in PFS (0.48, 0.35‐0.65) and pCR (1.30, 1.13‐1.49 for breast and axillary nodes and 1.26, 1.11‐1.44 for breast). Other targeted agents like iniparib, sorafenib, cetuximab, and ipatasertib combined with CT showed significant superiority in PFS compared with CT alone, and the HRs were 0.75 (0.62‐0.90), 0.44 (0.21‐0.91), 0.67 (0.47‐0.96), and 0.44 (0.24‐0.81), respectively, while some other agents such as sunitinib and cetuximab had the lowest SUCRA in OS, PFS, or ORR without any benefits. In conclusion, our results indicated that the addition of bevacizumab to CT was beneficial for TNBC patients, and olaparib had a great effect in PFS and ORR, especially for those with BRCA mutations. When combined with CT, targeted agents including iniparib, sorafenib, cetuximab, and ipatasertib may have better efficacies for treating TNBC.

BRCA1/2-mutant cells are hypersensitive to inactivation of poly(ADP-ribose) polymerase 1 (PARP-1). We recently showed that inhibition of PARP-1 by NU1025 is strongly cytotoxic for BRCA1-positive BT-20 cells, but not BRCA1-deficient SKBr-3 cells. These results raised the possibility that other PARP-1 inhibitors, particularly those tested in clinical trials, may be more efficacious against BRCA1-deficient SKBr-3 breast cancer cells than NU1025. Thus, in the presented study the cytotoxicity of four PARP inhibitors under clinical evaluation (olaparib, rucaparib, iniparib and AZD2461) was examined and compared to that of NU1025. The sensitivity of breast cancer cells to the PARP-1 inhibition strongly varied. Remarkably, BRCA-1-deficient SKBr-3 cells were almost completely insensitive to NU1025, olaparib and rucaparib, whereas BRCA1-expressing BT-20 cells were strongly affected by NU1025 even at low doses. In contrast, iniparib and AZD2461 were cytotoxic for both BT-20 and SKBr-3 cells. Of the four tested PARP-1 inhibitors only AZD2461 strongly affected cell cycle progression. Interestingly, the anti-proliferative and pro-apoptotic potential of the tested PARP-1 inhibitors clearly correlated with their capacity to damage DNA. Further analyses revealed that proteomic signatures of the two studied breast cancer cell lines strongly differ, and a set of 197 proteins was differentially expressed in NU1025-treated BT-20 cancer cells. These results indicate that BT-20 cells may harbor an unknown defect in DNA repair pathway(s) rendering them sensitive to PARP-1 inhibition. They also imply that therapeutic applicability of PARP-1 inhibitors is not limited to BRCA mutation carriers but can be extended to patients harboring deficiencies in other components of the pathway(s).

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.

Purpose This study was designed to assess efficacy, safety, and predictors of response to iniparib in combination with gemcitabine and carboplatin in early-stage triple-negative and BRCA1/2 mutation–associated breast cancer. Patients and Methods This single-arm phase II study enrolled patients with stage I to IIIA (T ≥ 1 cm) estrogen receptor–negative (≤ 5%), progesterone receptor–negative (≤ 5%), and human epidermal growth factor receptor 2–negative or BRCA1/2 mutation–associated breast cancer. Neoadjuvant gemcitabine (1,000 mg/m2 intravenously [IV] on days 1 and 8), carboplatin (area under curve of 2 IV on days 1 and 8), and iniparib (5.6 mg/kg IV on days 1, 4, 8, and 11) were administered every 21 days for four cycles, until the protocol was amended to six cycles. The primary end point was pathologic complete response (no invasive carcinoma in breast or axilla). All patients underwent comprehensive BRCA1/2 genotyping, and homologous recombination deficiency was assessed by loss of heterozygosity (HRD-LOH) in pretreatment core breast biopsies. Results Among 80 patients, median age was 48 years; 19 patients (24%) had germline BRCA1 or BRCA2 mutations; clinical stage was I (13%), IIA (36%), IIB (36%), and IIIA (15%). Overall pathologic complete response rate in the intent-to-treat population (n = 80) was 36% (90% CI, 27 to 46). Mean HRD-LOH scores were higher in responders compared with nonresponders (P = .02) and remained significant when BRCA1/2 germline mutations carriers were excluded (P = .021). Conclusion Preoperative combination of gemcitabine, carboplatin, and iniparib is active in the treatment of early-stage triple-negative and BRCA1/2 mutation–associated breast cancer. The HRD-LOH assay was able to identify patients with sporadic triple-negative breast cancer lacking a BRCA1/2 mutation, but with an elevated HRD-LOH score, who achieved a favorable pathologic response. Confirmatory controlled trials are warranted.

PARP inhibitors are considered promising anti-cancer agents and currently being tested in clinical trials in hereditary breast cancer patients harboring mutations in BRCA1 and BRCA2 genes. In this study, we investigated the antiproliferative effects and mechanism of PARP inhibitors ABT-888 (Veliparib), BSI-201 (Iniparib) and AZD228 (Olaparib) in breast cancer cell lines with BRCA1 or BRCA2 mutations and 9 different BRCA wild-type cell lines with BRCA1 allelic loss. We found that AZD2281 was the most potent in the PARP inhibitors and induces significant growth inhibition (~95%) in BRCA1 mutant (HCC-1937, MDA-MB-436, and SUM-149PT) and BRCA2 mutant (HCC-1428) cell lines. AZD2281 treatment also resulted in growth inhibition ranging from 20 to 50% in cells with BRCA1 allelic loss, including ER(+), HER2/Neu(+) and triple-negative breast cancer (TNBC) cells, but showed no effect in cells without with type BRCA without allelic loss. Knocking down of BRCA1 or BRCA2 in TNBC cells with BRCA1 allelic loss by RNA interference significantly enhanced AZD2281-induced growth inhibition and induced significant autophagy that was associated with mitophagy in cells with BRCA mutations. Inhibition of autophagy by gene knockdown significantly diminished AZD2281-induced mitophagy and apoptosis, indicating that autophagic process mediates some of the downstream effects of PARP inhibitors. In conclusion, our data provide the first evidence of PARP inhibitor AZD2281 autophagy and mitophagy in breast cancer cell lines with BRCA mutations or BRCA-allelic loss. In addition, our results indicate that the patients with BRCA1 allelic loss may also benefit from PARP inhibitor therapy if BRCA is further inhibited.

Background Iniparib is a novel anticancer agent initially considered a poly (ADP-ribose) polymerase (PARP) inhibitor, but subsequently shown to act via non-selective protein modification through cysteine adducts. This randomized phase II study investigated the addition of iniparib to gemcitabine–cisplatin in metastatic non-small-cell lung cancer (NSCLC) patients. Patients and methods Patients with histologically confirmed stage IV NSCLC were randomized 2 : 1 to receive gemcitabine (1250 mg/m2, days 1/8) and cisplatin (75 mg/m2, day 1) with [gemcitabine/cisplatin/iniparib (GCI)] or without [gemcitabine/cisplatin (GC)] iniparib (5.6 mg/kg, days 1/4/8/11) every 3 weeks for six cycles. The primary end point was the overall response rate (ORR). Secondary objectives included progression-free survival (PFS), overall survival (OS), and safety. The study was not designed for formal efficacy comparison, the control arm being to benchmark results against the literature. Results One hundred and nineteen patients were randomized (39 GC and 80 GCI). More GCI patients were male (80% GCI and 67% GC) and had PS 0 (61% GCI and 49% GC). The ORR was 25.6% [95% confidence interval (CI) 13.0%–42.1%] with GC versus 20.0% (95% CI 11.9%–30.4%) with GCI, which did not allow rejection of the null hypothesis (ORR with GCI ≤20%; P = 0.545). Median PFS was 4.3 (95% CI 2.8–5.6) months with GC and 5.7 (95% CI 4.6–6.6) months with GCI (hazard ratio 0.89, 95% CI 0.56–1.40). Median OS was 8.5 (95% CI 5.5 to not reached) months with GC, and 12.0 (95% CI 8.9–17.1) months with GCI (hazard ratio 0.78, 95% CI 0.48–1.27). More GCI patients received second-line treatment (51% GC and 68% GCI). Toxicity was similar in the two arms. Grade 3–4 toxicities included asthenia (28% GC and 8% GCI), nausea (3% GC and 14% GCI), and decreased appetite (10% in each). Conclusions Addition of iniparib to GC did not improve ORR over GC alone. The GCI safety profile was comparable to GC alone. Imbalances in PS and gender distribution may have impacted study results regarding PFS and OS. Trial Registration ClinicalTrial.gov Identifier NCT01086254.