Iniparib Plus Chemotherapy - More Effective in Treating Triple-Negative Breast Cancer

Triple-negative breast cancer is an aggressive subtype of breast cancer. It is estrogen-receptor (ER)–negative, progesterone-receptor (PR)–negative and does not over express human epidermal growth factor receptor type 2 (HER2).

Triple-negative breast cancer (TNBC) is characterized by higher rates of metastases in the visceral and central nervous system and has a poorer survival rate in comparison to the hormone receptor–positive subtypes.

Although preoperative chemotherapy is more effective in triple-negative breast cancer patients those with the metastatic disease have a very poor prognosis of approximately 1 year.

TNBCs account for 15 to 20% of all cases of breast cancers and shares features, both clinical and pathological, with hereditary, BRCA1 gene -related breast cancers. In the sporadic type of TNBCs, irregularities of the BRCA1, has been attributed to a number of faulty mechanisms.

Iniparib - Poly adenosine diphosphate–ribose polymerase 1 (PARP1),an important enzyme that regulates DNA base-excision–repair pathway, has now been identified as a therapeutic target for triple-negative breast cancer.

Pre-clinical studies have demonstrated that combining PARP1 inhibitors with chemotherapy agents can be very effective.Iniparib (also known as BSI-201) is one such PARP inhibitor.

Phase II Study – Goal - Clinical studies have shown that the combination of chemo-drugs gemcitabine and carboplatin chemotherapy generates a response rate ranging from 26 to 34% in metastatic breast cancer. In in vitro models of triple-negative breast cancer iniparib enhanced the cytotoxic and antiproliferative effects of these drugs.

The present phase II study was designed to evaluate the ability of iniparib in enhancing the anti cancer effects of carboplatin and gemcitabine with acceptable toxicity levels in patients with metastatic triple-negative breast cancer.

It must be noted that earlier studies have revealed that iniparib has shown minimal toxicity.

Methodology - The highlights include:

• This open-labeled, randomized study was carried out at 20 different centers belonging to the US oncology network 

• Subjects were females 18 years or older,who were diagnosed with metastatic breast cancer  Up to two prior chemotherapy regimens were permitted,

• All patients were provided with written informed consent before enrolling in the study.

• Patients were recruited between September 2007 to March 2009

Chemotherapy on subjects - Patients received chemotherapy for a 21-day period. It consisted of

a) Intravenous gemcitabine (1000 mg per square meter of body-surface ) for 30-minute period

b) Intravenous carboplatin (at a dose equivalent to an area under the concentration–time curve of 2) for 60-minute period.

c) These drugs were either administered alone or along with intravenous iniparib (4.0 mg per kilogram) for 60-minute period. The dose was later increased to 5.6 mg per kilogram

d) Safety was measured through standard clinical and laboratory tests

Limitations -This open-label, phase 2 study had its own limitations. They include small sample size, investigator bias in assessments and the slight tilt in prognosis favoring the iniparib group over the chemotherapy-alone group.

Conclusion -Despite all the inherent limitations, this phase 2 study proved that a combination of iniparib along with gemcitabine–carboplatin provided remarkable clinical benefit in patients with metastatic triple-negative breast cancer.

Also, Iniparib–gemcitabine–carboplatin therapy showed no significant increase in toxicity as compared with gemcitabine–carboplatin alone.

The results of this study has prompted a phase 3 trial on the same lines on the overall survival including progression-free survival in metastatic triple-negative breast cancer.

Source-Medindia