Research Highlights from ASCO 2013
by Tracy Diaz and Sue Friedman
On May 31st, more than 25,000 oncology professionals trekked to Chicago for the annual American Society of Clinical Oncology (ASCO) meeting. Thousands of abstracts on groundbreaking cancer research were published or presented; the following were presentations relevant for the hereditary breast and ovarian cancer (HBOC) community.
- PARP inhibitors continue to show promise for cancer treatment.
- Inherited mutations are common in African American women with breast cancer and family history is not the only criteria on which genetic evaluation should be based.
- National guidelines for BRCA testing women with triple-negative breast cancer are appropriate but access to testing in women who meet these guidelines is still a barrier.
- Not all women with a BRCA mutation are being followed using recommended screening guidelines while many women without mutations are being followed using unproven ovarian screening.
- Twice yearly breast MRI in high-risk women improved early detection of breast cancer.
- The diabetes medication metformin may lower the risk for developing and dying from certain cancers in people with diabetes.
- Metformin is associated with improved survival in diabetic women with ovarian cancer
Read below for further details about these presentations.
How Well Do PARP Inhibitors Work?
PARP inhibitors (PARPis) are experimental medications that were found in early studies to be specifically effective against BRCA-related cancers. These drugs block an enzyme used by cells to mend breaks in DNA. Cancer cells in people with BRCA mutations have problems repairing DNA already, and PARPis make that worse. Theoretically, these drugs should spare healthy cells that have at least one working copy of the BRCA gene, with limited side effects or toxicity. Because they are not yet FDA-approved, PARPis are not available outside clinical trials, but several such trials are currently recruiting participants.
Olaparib for ovarian cancer maintenance therapy
“Maintenance therapy” refers to medication that is continued for a set period of time after a response to initial treatment. Dr. Jonathan Ledermann from University College London presented results from an olaparib (AstraZeneca) maintenance study in BRCA mutation carriers and non-mutation carriers with platinum-sensitive ovarian cancer. A previous study showed improvement in progression-free survival (PFS)—the length of time a patient lives without their cancer getting worse—in women receiving olaparib compared to women who did not receive the therapy. However, the study did not show an increase in overall survival (OS) for patients on the drug. This updated efficacy analysis presented at ASCO followed 265 women with ovarian cancer, including 136 who had confirmed mutations. The study showed:
- PFS improvement of 6.9 months in women with BRCA mutations who received olaparib versus those who received placebo
- PFS improvement of 12.5 months in women with BRCA mutations who received olaparib compared to women without mutations who received olaparib or placebo. No advantage was observed for women who did not have a BRCA mutation and used olaparib over placebo
- OS improvement of 3 months in women with mutations who received olaparib compared to women with mutations who did not receive olaparib
This study concluded that olaparib maintenance therapy in ovarian cancer has the greatest benefit for women with BRCA mutations, improving both PFS and OS. As a result, a phase III trial in women with ovarian cancer who have a BRCA mutation is scheduled to start later this year.
Another small study looked at PARP inhibitors in ovarian, breast, and other BRCA-associated cancers. Dr. Michie from the Institute of Cancer Research in the UK presented results from a phase I trial of the PARP inhibitor niraparib (Tesaro) in BRCA1/2 mutation carriers. Researchers concluded that this drug is well tolerated, and 3 of 4 patients with platinum-sensitive ovarian cancer responded. A 40% response was observed in BRCA1/2-associated ovarian cancer, and a 50% response in BRCA1/2-associated breast cancer. Extended stable disease (no worsening of disease) was seen in men with BRCA-associated advanced prostate cancer. These data support further development of niraparib in cancer patients carrying BRCA1/2 mutations.
Results from two separate phase 1 studies of rucaparib (Clovis), another PARP inhibitor, were also presented. Dr. Molife from the Institute of Cancer Research in the UK discussed a study of oral rucaparib in combination with carboplatin for 28 people with advanced solid tumors, including ovarian, breast, pancreatic, and other tumors. The study was open to people with and without BRCA mutations. Surprisingly, in ovarian cancer patients, the highest disease control was seen in women without mutations. Researchers concluded that this drug can be safely combined with carboplatin, and that responses and durable stable disease was seen in ovarian and breast cancer patients. In the second rucaparib study, Dr. Kristeleit from the University College of London Cancer Institute also presented results from a study of patients with advanced solid tumors. Of the 37 participants, 21 had breast cancer, 10 had ovarian cancer, and 6 had another type of cancer. Disease control in ovarian cancer patients was seen in women with BRCA mutations and those with unknown mutation status. For breast cancer, disease control was seen both in patients with and without BRCA mutations. The study concluded that rucaparib was well tolerated and has clinical activity. Further studies are needed to determine which patients will respond more favorably to this drug.
Triple-Negative Breast Cancer and Genetic Testing
Genetic testing in African American women with breast cancer
Breast cancer survival rates are lower for African American women than for white women, with the gap in mortality rate increasing over the last 20 years. African American women face a worse overall survival (OS) when getting the same treatment as white women. One reason for this disparity may be due to differences in tumor biology. African American women are more likely to develop breast cancer at a younger age, and their cancers tend to be higher grade and are more likely to be triple negative. Inherited breast cancer genes are thought to contribute to these unfavorable trends. One study by Dr. Jane E. Churpek from the University of Chicago provided gene testing for African American breast cancer patients to estimate the prevalence of inherited mutations. A total of 249 breast cancer patients were tested using the BROCA assay, which looks at 42 genes, including 18 that are known to increase breast cancer risk. The results showed that:
- the median age at diagnosis was 43 years; younger than in white patients
- 22% (56 of 249) of women were identified as having a deleterious mutation
- 79% of those with mutations had BRCA1 or BRCA2 mutations
- others had mutations in the ATM, CHEK2, PALB2, and PTEN genes
- women with multiple breast cancer diagnoses, triple negative cancer, or grade III breast cancer were more likely to have an inherited mutation
- more than half of patients had a family history of breast or ovarian cancer
- while 30-40% of patients with a family history of breast or ovarian cancer were found to have a mutation, 12% of patients without a family history also carried mutations, so family history alone is not a predictor of likelihood to carry mutation
- patients with a family history of pancreatic cancer were almost as likely to carry mutations as those with family history of breast or ovarian cancer
Dr. Churpek stressed the need to provide wider access to genetic counseling and genetic testing, especially in underserved populations.
Prevalence of BRCA mutations in triple-negative breast cancer
In a poster presentation, Dr. Sharma from the University of Kansas Medical Center examined the prevalence of BRCA mutations in a large triple-negative breast cancer (TNBC) registry. Previous studies suggest that 10-40% of patients with TNBC have a BRCA mutation. Current guidelines recommend genetic testing for all TNBC patients who are younger than age 60, regardless of family history. Dr. Sharma’s study enrolled 186 patients with stage I to III TNBC and found that:
- 9.9% had a deleterious BRCA1, 4.4% had a deleterious BRCA2, and 5.5% had either variants of uncertain significance or polymorphisms
- only one BRCA mutation carrier had a TNBC diagnosis after age 61 (she had prior ER-positive breast cancer before age 50)
- medical insurers denied BRACAnalysis for 26% of participants:
- 8.5% of denied patients tested positive for a deleterious BRCA mutation
- 19% of deleterious BRCA mutations would have been missed if patients without insurance coverage were not tested
All of the patients who tested positive for deleterious mutations met the national cancer guidelines for genetic testing. Although national guidelines are appropriate, there are gaps in medical coverage for genetic testing, even in people who meet these guidelines.
Cancer Screening and Surveillance
Compliance with recommended screening guidelines
A study by Dr. Julie Zenger Hain from the Oakwood Healthcare System looked at cancer screening practices after BRCA1/2 testing in Michigan. This study evaluated the uptake and screening practices of women who had undergone BRCA1/2 testing and received genetic counseling in Michigan. A telephone survey of 138 randomly selected patients seen at 8 genetics clinics found that 44% had a personal history of breast or ovarian cancer, and 69.6% tested positive for a BRCA mutation. Among the 21 BRCA mutation carriers over age 25 who had no prior prophylactic mastectomy:
• 52% adhered to breast MRI screening guidelines
• 33% had no breast MRI screening in the preceding year
• 86% reported having a screening mammogram
• 38% had two clinical breast exams; 29% had only one clinical breast exam
• 50% reported having CA-125 testing and transvaginal ultrasound
Among women who were BRCA1/2 true negatives with no cancer history and under the age of 40:
• 42% (5 of 12) had one or more screening mammogram; none had a breast MRI
• CA-125 or transvaginal ultrasound was performed in 20% of all participants of all ages
Study authors concluded that sub-optimal compliance exists with screening guidelines in women who were identified as carriers of deleterious BRCA1/2 mutations. The authors also concluded that an overutilization of unproven ovarian screening for women without mutations also exists; they recommend additional interventions to improve adherence to evidence-based screening guidelines aimed at promoting early detection.
Twice yearly breast MRI in high-risk women
Another study by Dr. Olopade and colleagues looked at the benefits of twice-yearly breast MRI for high-risk women. Almost half of the women in their study (48%) had a BRCA or other genetic mutation that predisposed them to breast cancer. The women in the study received annual mammogram and semi-annual MRI for the first five years of the study, followed by five years of annual mammogram and MRI. The study results showed:
- 11 of 226 (5%) of participants were diagnosed with breast cancer detected by MRI or mammogram during the study.
- Six cancers (55%) were detected only by MRI and missed by mammogram.
- One cancer (9%) was detected only by mammogram and missed by MRI.
- Four cancers (36%) were found on the first round of screening.
- Three cancers (27%) were detected due to the additional MRI during semi-annual screening.
- All cancers were found at an early stage; 27% were diagnosed at stage 0 and 73% were diagnosed at stage 1.
The researchers concluded that high-risk screening using twice-yearly MRI and yearly mammogram was effective in finding cancers at a very early stage in high-risk women. The researchers are continuing to look at whether the additional MRI surveillance annually will improve overall survival in high-risk women, as well as its impact on quality-of-life.
Metformin and cancer incidence
Previous studies showed that the anti-diabetic agent metformin is associated with reduced cancer incidence and mortality. Dr. Sara Gandini presented results of a meta-analysis that reviewed 47 articles published between 1966 and August 2012 that were related to metformin and cancer incidence. (A meta-analysis is a statistical method that combines results from different studies to identify interesting patterns or relationships.) The analysis included 32,647 cancer events, and showed that cancer incidence was reduced by 43% in subjects taking metformin compared with other anti-diabetic medications; cancer mortality was reduced by 49%. Notably, reduction of liver and lung incidence was significant, and breast cancer was reduced by 24% in adjusted studies. Metformin holds promise for cancer prevention, although it may not benefit all populations equally.
Metformin and survival in women with ovarian cancer
Another small study looked at the effect of metformin on recurrence-free survival and overall survival in diabetic patients with advanced ovarian cancer. Researcher Dr. Simonell presented data showing improved recurrence-free survival and overall survival in diabetics who took metformin compared to diabetic patients not receiving the medication. When all diabetic patients were compared to non-diabetic patients no benefit in survival was seen. It should be noted that while the trial had 888 patients, only 27 patients with diabetes were treated with metformin. Results demonstrate a favorable impact of metformin treatment in patients affected by advanced ovarian cancer.
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