It has been difficult to identify subcategories in ovarian cancer that can be used to tailor treatment. However, a new study has taken a step forward toward better characterization of sporadic ovarian tumors by identifying their DNA repair protein expression profile.
The molecular characterizations of tumor samples from 186 women were analyzed for specific protein expression levels by Tanja Pejovic, a gynecologic oncologist at the Knight Cancer Institute in Portland, Oregon, and colleagues. Their work is published in the Public Library of Science online journal PLoS One.
The study shows that patients with simultaneously high expression levels of the DNA repair proteins PARP, FANCD2, and p53 have a higher risk of early ovarian cancer recurrence and resistance to platinum-based chemotherapy.
Ovarian cancer is the most common cause of death among women with a gynecological cancer, with approximately 14,000 ovarian cancer deaths occurring every year and 21,000 new diagnoses. Many patients are not diagnosed with ovarian cancer until an advanced stage of disease. Standard of care is cytoreductive surgery and platinum-based chemotherapy, which has not significantly improved long-term survival.
The study by Pejovic et al shows that patients with simultaneously high expression levels of the DNA repair proteins PARP, FANCD2 (part of the Fanconi’s anemia [FA] gene group), and p53 have a higher risk of early ovarian cancer recurrence and resistance to platinum-based chemotherapy. Patients who had high levels of all three proteins were twice as likely to have earlier recurrence within 3 years compared with all other patients after adjustment for age, cancer status, and time of diagnosis (P = .03).
The authors suggest that dual inhibition of the FA/BRCA pathway and PARP may be effective in these triple-profile ovarian cancers. Poly(ADP ribose) polymerase (PARP) inhibitors emerged as a promising treatment, showing promising results in patients who have BRCA1- or BRCA2-positive ovarian cancer. Approximately 10% to 15% of ovarian tumors harbor germline mutations in either of these two genes, but sporadic mutations in BRCA1 or BRCA2 and other DNA repair genes are also prevalent. As many as 20% of high-grade serous sporadic ovarian tumors have BRCA1 and BRCA2 mutations. The study by Pejovic et al now shows that PARP inhibitors may work in a broader range of ovarian cancers, ones that have mutations in other DNA repair genes besides BRCA1 and BRCA2.
PARP inhibitors are thought to be effective in ovarian cancer because they prevent DNA repair that might otherwise keep cancerous cells alive. The set of DNA repair genes that are mutated, including PARP, PTEN, RAD51, and the FA genes in the tumor is known as its “BRCAness profile.”
The rationale is that adding a PARP inhibitor on top of platinum-based chemotherapy will specifically kill cancer cells that are already sensitive to a platinum treatment regimen. This is the concept of synthetic lethality, according to which targeting two components of the same pathway should result in cell death rather than adaptation because blocking another repair pathway in cells already deficient in DNA repair (that’s the BRCAness profile) and simultaneously increasing DNA damage via platinum-based chemotherapy results in a lethal phenotype. Or at least that is the hope.
The trouble with ovarian tumors is their characteristic genomic instability, which may contribute to evolving mutations in DNA repair genes. The variation in DNA repair genes can influence whether a tumor responds to treatment.
This may be the reason for the recent setbacks in the development of PARP inhibitors. The class of drugs has just not been studied in the correct subpopulation. The PARP inhibitor olaparib had shown promise in a phase II trial, exhibiting a significantly prolonged progression-free survival in patients with platinum-sensitive relapsed serous ovarian cancer, as reported at ASCO last year. Unfortunately, at the end of 2011, the company developing the drug announced that the progression-free survival seen was not likely to translate to an overall survival benefit. The drug was given in combination with a platinum-based chemotherapy regimen; however, patients were not specifically selected based on a BRCAness profile or reduced DNA repair profile of their tumors.
“The judgment on PARP inhibitors in ovarian cancer is still pending. We still do not have all the data we need. Certainly identifying the right group of patients who are likely to benefit from these drugs has been one of the challenges,” Tanja Pejovic commented.
Larger cohort studies that molecularly define ovarian tumors and correlate the profiles to treatment response and recurrence are necessary to better classify ovarian cancers and tailor treatments, as has been done for other types of tumors. The current study only analyzed a subset of DNA repair proteins, while others may play a major role in disease development and response to treatment.
“Identifying alterations in DNA repair proteins beyond BRCA proteins may give access to clinical trials—with PARP inhibitors, for example—to many more women with ovarian cancer,” said Dr. Pejovic.
Dr. Pejovic is already thinking about the next step—to perform functional assays and understand what the differences in protein expression and tumor mutations actually mean for the tumor cell’s ability to repair DNA damage. “We need to perform functional studies to confirm that these patients that we identified with high PARP, FANCD2, and p53 protein expression indeed have defective homologous recombination [HR],” she explained. “The testing for defects in HR has not been standardized, so I am working with a colleague here on developing a RAD51 foci formation test as a surrogate for HR status,” she added.
There have not been many new treatments developed for ovarian cancer in the last 20 years. The molecular characterization of these tumors should facilitate a more targeted approach that may identify the patients who will most benefit from the drugs currently in development for ovarian cancer.
1.Wysham WZ, Mhawech-Faucedia P, Li H, et al. BRCAness profile of sporadic ovarian cancer predicts disease recurrence. PLoS One. 2012;7:e30042.
Vismodegib Granted FDA Approval for Treatment of Basal Cell Carcinoma
The US Food and Drug Administration (FDA) announced the approval of vismodegib (Erivedge), for the treatment of advanced basal cell carcinoma, the most common type of skin cancer, for patients who are not eligible for surgery or radiation, and for metastatic disease.
The drug, delivered in a once-a-day oral capsule, is manufactured by Genentech and is the first approved drug for metastatic basal cell carcinoma.
Vismodegib was reviewed under the FDA’s priority review program that provides for an expedited 6-month review of drugs that may offer major advances in treatment.
“Today’s approval provides a new treatment for people with advanced basal cell carcinoma who, until now, had no approved medicines to help shrink disfiguring or potentially life-threatening lesions,” said Hal Barron, MD, chief medical officer and head, Global Product Development at Genentech, in a press release. “We are pleased that in the last six months we have been able to provide two new medicines for different types of advanced skin cancer to people who previously had few or no treatment options.” Genentech also produces vemurafenib (Zelboraf), approved last year for melanoma patients who harbor a BRAF V600E mutation.
In the pivotal study, involving 96 patients, vismodegib shrank tumors or healed lesions in 43% of patients with locally advanced basal cell carcinoma (27 of 63) and in 30% of patients with metastatic basal cell carcinoma (10 of 33). The objective response rates for the two groups were 60% and 46%, respectively, and progression-free survival for both groups was 9.5 months. Study participants received 150 mg of vismodegib orally, once daily, until disease progression or unacceptable toxicity.
Basal cell carcinoma is associated with mutations in components of the hedgehog signaling pathway. These mutations can result in unrestrained proliferation of basal cells of the skin. “Our understanding of molecular pathways involved in cancer, such as the hedgehog pathway, has enabled the development of targeted drugs for specific diseases,” said Richard Pazdur, MD, director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, in a press release announcing the approval. “This approach is becoming more common and will potentially allow cancer drugs to be developed more quickly. This is important for patients, who will have access to more effective therapies with potentially fewer side effects.”
The most common adverse events reported for patients taking vismodegib were muscle spasms, alopecia, dysgeusia, nausea, diarrhea, fatigue, decreased appetite, arthralgias, constipation, vomiting, and ageusia.
Vismodegib is being approved with a boxed warning alerting patients and health care professionals of the potential risk of death or severe birth effects to a fetus. Pregnancy status must be verified prior to the start of vismodegib treatment. Male and female patients should be warned about these risks and the need for birth control.