A randomized phase III study of iniparib (BSI-201) in combination with gemcitabine/carboplatin (G/C) in metastatic triple-negative breast cancer (TNBC).

O’Shaughnessy, J.; Schwartzberg, Lee S.; Danso, Michael A.; Rugo, HS; Miller, K.; Yardley, Denise A.; Carlson, R. W.; Finn, RS; Charpentier, Eric; Freese, Maria; Gupta, Supriya; Blackwood‐Chirchir, Anne; Winer, Eric P.

doi:10.1200/jco.2011.29.15_suppl.1007

Cited by 201 publications

(146 citation statements)

References 0 publications

Supporting

Mentioning

135

Contrasting

Unclassified

Order By: Relevance

“…260 Adding a second PARP inhibitor, Iniparib, to treatment with gemcitabine and carboplatin improved response rates and time to progression in patients with metastatic triple-negative breast cancer in a phase II study; 261 however, a phase III follow-up study failed to confirm significant improvement. 262 Notably, recent experimental evidence has thrown doubt on the efficacy of Iniparib as a PARP inhibitor. 263 Although PARP may interact with multiple processes involved in DNA damage response 264 and experimental evidence suggested PARP inhibitors may enhance cytotoxic efficacy of different cytotoxic compounds including temozolamide in different models, 265 as for today the jury is still out regarding whether PARP inhibition may have any place in the clinic for tumours wild type for BRCA1/2 except for high-grade ovarian cancers.…”

Section: Homologous Recombination Repairmentioning

confidence: 99%

Mapping genetic alterations causing chemoresistance in cancer: identifying the roads by tracking the drivers

Lønning

Knappskog

2013

Oncogene

View full text Add to dashboard Cite

Although new agents are implemented to cancer therapy, we lack fundamental understandings of the mechanisms of chemoresistance, the main obstacle to cure in cancer. Here we review clinical evidence linking molecular defects to drug resistance across different tumour forms and discuss contemporary experimental evidence exploring these mechanisms. Although evidence, in general, is sparse and fragmentary, merging knowledge links drug resistance, and also sensitivity, to defects in functional pathways having a key role in cell growth arrest or death and DNA repair. As these pathways may act in concert, there is a need to explore multiple mechanisms in parallel. Taking advantage of massive parallel sequencing and other novel high-throughput technologies and base research on biological hypotheses, we now have the possibility to characterize functional defects related to these key pathways and to design a new generation of studies identifying the mechanisms controlling resistance to different treatment regimens in different tumour forms.

show abstract

Section: Homologous Recombination Repairmentioning

confidence: 99%

Mapping genetic alterations causing chemoresistance in cancer: identifying the roads by tracking the drivers

Lønning

Knappskog

2013

Oncogene

View full text Add to dashboard Cite

show abstract

“…The value of this approach has been demonstrated in breast and ovarian cancer patients with BRCA1 and BRCA2 mutations [46] but has not been demonstrated conclusively in the setting of sporadic BRCAness. Results of an initial promising phase II trial of the putative PARP inhibitor iniparib among sporadic metastatic breast cancer patients with TNBC have not been replicated in a larger phase III trial [47,48]. Another phase II trial has failed to demonstrate any objective responses to the single-agent PARP inhibitor olaparib in TNBC patients [49].…”

Section: Parp1 and The Concept Of "Synthetic Lethality"mentioning

confidence: 99%

Differential Chemotherapeutic Sensitivity for Breast Tumors With “BRCAness”: A Review

Chalasani

Livingston

2013

The Oncologist

View full text Add to dashboard Cite

BRCA1 or BRCA2 mutations predispose to cancer development, primarily through their loss of role in the repair of DNA double-strand breaks. They play a key role in homologous recombination repair, which is a conservative, error-free DNA repair mechanism. When mutated, other alternative, errorprone mechanisms for DNA repair take over, leading to genomic instability. Somatic mutations are rare in sporadic breast tumors, but expression of BRCA1 and BRCA2 genes can be downregulated in other mechanistic ways. These tumors have similar features in terms of their phenotypic and genotypic profiles, which are normally regulated by these genes, and mutations lead to defective DNA repair capacity, called "BRCAness." Attempts have been made to exploit this differentially expressed feature between tumors and normal tissues by treatment with DNA-damaging chemotherapy agents. Cells with this functional BRCA deficiency should be selectively susceptible to DNA-damaging drugs. Preclinical and early clinical (primarily retrospective) evidence supports this approach. In contrast, there is emerging evidence of relative resistance of tumors containing BRCA1 or BRCA2 mutations (or BRCAness) to taxanes. In this review, we summarize the data supporting differentialchemotherapeuticsensitivityonthebasisofdefectiveDNA repair. If confirmed with available, clinically applicable techniques, this differential chemosensitivity could lead to treatment choices in breast cancer that have a more individualized biologic basis. The Oncologist 2013;18:909 -916 Implications for Practice: Women with germline BRCA mutations are more prone to develop breast, ovarian, and other cancers because of the inability to repair DNA damage effectively. These mutations cause a small minority of breast cancers, but studies have shown that such tumors respond better when treated with DNA-damaging chemotherapy agents. Evidence shows that nonmutated tumors also have defective DNA repair or "BRCAness" caused by other mechanisms and behave similarly to BRCAmutated tumors. Some clinical data support that tumors with BRCAness respond better to DNA-damaging chemotherapy. Preliminary data suggest that tumors with intact BRCA1 respond better to treatment with antitubulin agents. In this review, we discuss BRCAness and the clinical data supporting preferential responses to different chemotherapy agents. No standardized test to detect BRCAness exists yet, and various techniques are being developed because this test could affect chemotherapy choice.

show abstract

“…Furthermore, analysis of cPARP expression in breast cancer patients treated with neoadjuvant chemotherapy in the GEPARTRIO trial indicated that cPARP was a strong predictive marker for pCR in triple negative tumors, while the same time was prognostic for more aggressive tumors resulting in worst OS and DFS for patients that did not achieve pCR [65] . Despite these promising indications and the positive results from a randomized phase II trial [66] , iniparib a third generation PARP inhibitor failed to improve the outcome in the metastatic setting when added to cytotoxic chemotherapy [67] . Analogously, the interim analysis of the SOLTINeoPARP trial, a randomized phase II study that examined the efficacy of iniparib addition to weekly paclitaxel in the neoadjuvant setting of TNBC, failed to meet its primary endpoint that was pCR improvement [68] .…”

Section: Novel Agents In the Neoadjuvant Treatment Of Tnbcmentioning

confidence: 99%

The recent progress of neoadjuvant chemotherapy in triple negative breast cancer: A short review

Liontos

Karageorgopoulou²,

Michalaki³

et al. 2015

JST

View full text Add to dashboard Cite

Triple negative breast cancer (TNBC) encompasses tumors that do not express either the estrogen receptor (ER) or the progesterone receptor (PR) and also do not overexpress the Human Epidermal growth factor Receptor 2 (HER2). This is a heterogenous group of tumors that significantly overlaps with both basal-like tumors and BRCA1/BRCA2 mutationassociated tumors. TNBC is highly aggressive in nature and exhibits worse prognosis than the other subtypes of breast cancer, despite its increased chemosensitivity. Neoadjuvant chemotherapy (NACT) is a treatment option regularly incorporated in clinical practice to improve subsequent surgical management. In parallel, allows rating of the pathological compete response (pCR) which is associated with the prognosis of these patients and evaluates the efficacy of the applied treatment as well. Platinum-based regimens and novel targeted therapies have shown some benefit in TNBC, though an unmet need for improved therapeutic strategies in this patient population still remains. In this review, the latest progresses in NACT in TNBC are discussed, along with the improved understanding of molecular targets and useful biomarkers in this group of patients.

show abstract

A randomized phase III study of iniparib (BSI-201) in combination with gemcitabine/carboplatin (G/C) in metastatic triple-negative breast cancer (TNBC).

Cited by 201 publications

References 0 publications

Mapping genetic alterations causing chemoresistance in cancer: identifying the roads by tracking the drivers

Mapping genetic alterations causing chemoresistance in cancer: identifying the roads by tracking the drivers

Differential Chemotherapeutic Sensitivity for Breast Tumors With “BRCAness”: A Review

The recent progress of neoadjuvant chemotherapy in triple negative breast cancer: A short review

Contact Info

Product

Resources

About