Gene markers may predict treatment sensitivity in triple-negative breast cancer
Leif Ellisen (left) and Steven Isakoff (right)
An old medicine may have a new life for some women with an aggressive form of breast cancer. Steven Isakoff, MD, PhD (MGH) is leading a trial to identify a group of breast cancer patients with triple-negative disease who express two genes, p63 and p73, which appear to be linked to increased sensitivity to platinum chemotherapy. Platinum therapy, including cisplatin and carboplatin, has a long track record in other cancers but historically limited success in breast cancer.
The trial stems largely from the work of Leif Ellisen, MD, PhD (MGH) with the p53 family of genes which includes p63 and p73. Preclinical data from Ellisen’s lab suggests that these markers are present in about 30-40% of triple-negative breast cancer so named due to the lack of the three common breast cancer markers: estrogen receptor, progesterone receptor, and HER-2.
Objectives and importance of this trial
This phase II trial, which has been open for almost two years, will enroll about 82 patients—all with metastatic triple-negative breast cancer. Fifteen percent of breast cancer patients have triple-negative disease. These patients suffer from a more aggressive form of disease with generally worse prognosis and higher rates of recurrence. This subtype is generally associated with the kind of breast cancers noted in BRCA1 mutation carriers, partially explaining why it is more commonly seen in younger patients and tends to be more aggressive. Because the tumors are negative for all three of the traditional markers, this subpopulation of patients has no targeted therapy options.
Ellisen’s work shows that cell lines expressing the p63 and p73 markers seem to be particularly sensitive to platinum chemotherapy. Further investigation has shown that those cells lines expressing these markers are the triple negative subtype. “That was a pretty exciting observation because if we can find a subgroup within a subgroup that might get the most benefit, it might potentially lead to a diagnostic test where we could predict who will benefit from this therapy and who will not,” explains Isakoff.
Quantitation of p63 mRNA levels by RT-PCR in a series of triple-negative breast cancer specimens. A high ratio of p63/p73 mRNA may predict which tumors will respond to cisplatin chemotherapy.
Patients will receive single-agent platinum therapy – either cisplatin or carboplatin—as an intravenous infusion. At the conclusion of the trial, investigators will perform reverse transcriptase-polymerase chain reaction (RT-PCR) testing from RNA of archived paraffin-embedded samples from the original tumors of these patients to investigate p63/p73 expression. The primary endpoint of the trial will be to determine if p63/p73 expression in triple-negative breast cancer predicts sensitivity to platinum chemotherapy.
A second primary endpoint will be to assess response rates. Investigators powered the study with the overall goal of seeing at least a 22% response rate shown by radiology scans. Isakoff hopes the response rate will be over 40% in people who express the p63/p73 marker (a third of study participants). “The idea going forward is to identify and treat only the one-third of patients who are likely to get substantial benefit,” says Isakoff. This approach will spare treatment toxicity for the women who are unlikely to respond and delays in receiving another, potentially more successful, therapy.
Though the team will not perform an interim analysis, the early suggestion is that they are on track. “It has not been formally evaluated,” says Isakoff, “but the impression is that we are seeing responses without surprises.
Consortium joins the trial
Isakoff’s trial was adopted and endorsed by the Translational Breast Cancer Research Consortium (TBCRC), a consortium of 14 centers, including DF/HCC, that focus on translational studies. As a result of additional funding from the TBCRC, the trial will be open at six more sites aacross the nation.
The study was initiated with philanthropic funding from Golfers Against Cancer to the MGH Cancer Center and is being funded in part by a $500,000 NCI grant from an Avon Progress for Patient grant to DF/HCC.
A Phase II Study of Cisplatin or Carboplatin for Triple-Negative Metastatic Breast Cancer and Evaluation of p63/p73 as a Biomarker of Response
Steven Isakoff, MD, PhD (MGH)
For eligibility criteria, contact information, and sites, go to NCT00483223 on ClinicalTrials.gov or TBCRC009 at pub.emmes.com/study/bcrc/index.html