New study finds black women have higher frequency of BRCA mutations than previously reported

The higher BRCA mutation frequency in young black women may contribute to higher rates of aggressive breast cancer

Women who have inherited mutations in the BRCA1 or BRCA2 genes are more likely to develop breast cancer or ovarian cancer, especially at a younger age. Approximately 5 percent of women with breast cancer in the United States have mutations in BRCA1 or BRCA2 based on estimates in non-Hispanic white women. Moffitt Cancer Center researchers recently conducted the largest U.S. based study of BRCA mutation frequency in young black women diagnosed with breast cancer at or below age 50 and discovered they have a much higher BRCA mutation frequency than that previously reported among young white women with breast cancer.

Young black women are more likely to have aggressive types of breast cancer compared to non-Hispanic white women, yet the reason for this disparity remains uncertain. Moffitt researchers wanted to assess if mutations in the BRCA gene could help account for this higher rate of aggressive breast cancers among young black women in the U.S. They analyzed the BRCA mutation frequency and family history of 396 black women in Florida who were diagnosed with invasive breast cancer under the age of 50. They discovered that 12.4 percent of the participants had mutations in either BRCA1 or BRCA2. Furthermore, over 40 percent of those with a mutation had no close relatives with breast or ovarian cancer, which suggests that family history alone, may not identify those at risk for carrying a BRCA mutation.

As personalized medicine becomes more integrated into clinical care, it is becoming increasingly important for physicians to be aware of potential BRCA mutations at the time of diagnosis to be able to recommend the best therapy for their patients. “Our results suggest that it may be appropriate to recommend BRCA testing in all black women with invasive breast cancer diagnosed at or below age 50,” said Tuya Pal, M.D., a clinical geneticist at Moffitt, who led this effort.

However, many minorities do not undergo recommended genetic testing and counseling. According to an earlier report by the same researchers published in the journal Breast Cancer Research and Treatment, only about half of the black women were referred for or received genetic counseling or testing. They discovered that healthcare providers tend to refer patients for genetic counseling more frequently if the patients have a college education, are 45 years of age or younger, or have triple negative breast cancer. Additionally, black patients are more likely to seek genetic services if they receive a physician’s referral, have private health insurance, and higher incomes. “Overall, our results suggest that there is a great need to improve access to genetic services among high-risk black women.” says lead author of this report, Deborah Cragun, Ph.D., researcher and genetic counselor at Moffitt.

Patients who become aware of BRCA mutations can choose to have more breast cancer screening, or preventative mastectomies or oophorectomies. Additionally, this knowledge can be shared with family members so they can also be more proactive about cancer prevention. “Women who are identified with a mutation have an opportunity to be proactive about their health through cancer preventive options,” explained Susan Vadaparampil, Ph.D., M.P.H., behavioral scientist at Moffitt, who co-led this effort.

Pal et al. A high frequency of BRCA mutations in young black women with breast cancer residing in Florida. Cancer. 2015; DOI: 10.1002/cncr.29645 [Abstract]


Longer colonoscopies linked to lower cancer rate

If a colonoscopy seems like the type of thing you’d like to get done with quickly, think again.

Research by a Veterans Affairs team has confirmed that longer-lasting colonoscopies are associated with lower cancer rates.The findings appear online in the journal Gastroenterology. They were based on nearly 77,000 screening colonoscopies.

Experts already know about the link between colonoscopy withdrawal time and patient outcomes, but the new study provides some of the strongest evidence yet to back clinical guidelines covering this aspect of the procedure.

Our results support the use of withdrawal time as a quality indicator, as recommended by current guidelines,” said lead author Dr. Aasma Shaukat, with the Minneapolis VA Health Care System and the University of Minnesota.

In a colonoscopy, a doctor inserts a long, thin tube with a tiny camera fitted to the end into the patient’s colon. After the tube is fully inserted, it is then slowly withdrawn. It is during this “withdrawal time” that the doctor carefully examines the lining of the colon, looking at a view of the colon on a monitor in the exam room. Any small growths, or polyps, are removed with the scope’s snipping tool and sent for biopsy. These growths may grow into cancer within a few years.

According to current guidelines, a “normal” colonoscopy – one in which there is no finding of cancer or pre-cancerous growths, and the doctor does not remove any snippets of tissue to be biopsied–should have a withdrawal time of at least six minutes.

Shaukat’s team looked at data on colonoscopies performed over six years by 51 gastroenterologists in a large community practice in Minnesota. The team calculated average withdrawal times for each doctor. The average for the practice on the whole was 8.6 minutes–well within guidelines. But about 10 percent of the doctors had individual averages of under six minutes.

The researchers then checked the state’s cancer registry to look for cases of colorectal cancer among patients who had been screened at the same practice during the study period.

Patients who had been examined by doctors with shorter withdrawal times, on average, were more likely to have cancer. The rate was more than twice as high for patients whose doctors had average withdrawal times of under six minutes, compared with those whose physicians’ average times were over six minutes.

Withdrawal times of longer than eight minutes didn’t seem to afford any extra reduction of risk. As such, the researchers say focusing quality-improvement efforts on withdrawal times of under six minutes would likely have the most impact.

The study included cancers that occurred within about five years of the patient’s last colonoscopy. The assumption is that such “interval cancers” might have grown from polyps that were present during the colonoscopy but not detected, or not fully removed.

Shaukat says the reasons for sub-standard withdrawal times may vary, but “generally, every physician aims to do a complete inspection of the colon lining, regardless of their withdrawal time.”

Even the American College of Gastroenterology acknowledges that not every colonoscopy withdrawal must take at least six minutes, as some colons can be examined effectively in under six minutes.

Just the same, Shaukat says that withdrawal time appears to be a “robust indicator” of interval cancer risk. She urges more research on the topic, and on related quality measures for colonoscopies.

We need to understand the quality indicators better, define thresholds, and be able to adjust them to the particular patient population and underlying risk. Until there are uniform methods for data collection, adjustment, and collection, the numbers don’t mean much. We might be comparing apples to oranges.”

Shaukat says it’s appropriate for patients to ask their gastroenterologists if they collect and review quality metrics for their colonoscopies. At the same time, though, she points out that most patients won’t be in a position to properly make sense of the actual data.

The exact metrics and their cut-offs are debatable, but a commitment to quality needs to be there for every practice.”

Shaukat et al. Longer Withdrawal Time Is Associated With a Reduced Incidence of Interval Cancer After Screening Colonoscopy. Gastroenterology. 2015; S0016-5085(15)00934-8. doi: 10.1053/j.gastro.2015.06.044. [Abstract]

Pancreas cancer spreads from multiple types of wayward cells

Penn animal study has implications for better drug design, ‘unprecedented window’ into tumor evolution.
Tumor cells associated with pancreatic cancer often behave like communities by working with each other to increase tumor spread and growth to different organs. Groups of these cancer cells are better than single cancer cells in driving tumor spread, according to new research from the Perelman School of Medicine at the University of Pennsylvania published in Cancer Discovery online in advance of the print issue.

This is a multi-colored metastasis in the peritoneal lining of the abdomen comprised of red and yellow fluorescent cells demonstrating that pancreatic cancer spreads through interactions between different groups of cells. CREDIT Ravi Maddipati , MD, Perelman School of Medicine, University of Pennsylvania

Ben Stanger, MD, PhD, a professor in the division of Gastroenterology, and first author Ravi Maddipati , MD, an instructor in the division of Gastroenterology, say that these results may prove useful in designing better targeted therapies to stop tumor progression and provide an improved non-invasive method for detecting early disease states in this highly lethal cancer. Stanger is also a professor in the department of Cell and Developmental Biology and the Abramson Family Cancer Research Institute.
From other earlier studies, the Penn team also knew that cells from a primary tumor do better replicating and surviving in a group rather than if they are grown on their own. From this, the researchers asked if the spread of cancer is primarily derived from one cell or a cell cluster derived from the interactions between different cancer cell types. Stanger and Maddipati tested the hunch that clusters of cells of different genetic makeup were better at establishing secondary tumors and found that a significant fraction of metastases involve seeding by more than one type of tumor cell during the natural course of pancreatic tumor progression.

To understand this spread, the Penn researchers developed a mouse model that uses multiple fluorescent proteins to tag and track different pancreatic cancer cells as they enter the bloodstream and spread to distant organs. In this mouse model, mutations in Kras and p53 genes resulted in the formation of individual tumor cell populations that were labeled with different colors. Similar to humans, the mice developed tumors at secondary sites including the liver, lung, peritoneum, and diaphragm. They observed that these metastases were often made of cells from at least two different colors of tumor cell populations. To understand how these multi-colored lesions originated they examined blood from these mice and found that tumor cells in circulation frequently occurred as clusters comprised of different colored cancer cells.

What’s more, they also found that once these multi-colored clusters arrived at the secondary sites, the exact characteristics of subsequent growth was heavily dependent on the organ in which they now resided. During cell expansion in the peritoneum and diaphragm the lesions remained multi-colored, whereas in the lung and liver only a single color population was able to grow out. This suggested that specific factors in each organ may also influence the evolution of metastases.

These results provide an unprecedented window into the cellular dynamics of tumor evolution and suggest that interactions between subpopulations of tumor cell types contribute to metastatic progression from initial tumors,” Stanger said. “The finding that metastases are frequently polyclonal and that subsequent cellular behavior is site-dependent also gives us insight into the origins and evolution of clonal diversity in metastatic disease.

If cells do cooperate during metastasis, what is the molecular basis for their communication, and can we hit that?,” Stanger asked. The work also reinforces the importance of finding tumor cell clusters in the blood as a mechanism of detecting cancer metastasis earlier.

Maddipati R and Stanger BZ. Pancreatic cancer metastases harbor evidence of polyclonality. Cancer Discovery. 2015; doi: 10.1158/2159-8290.CD-15-0120 [Abstract]

Combining chemotherapy with an immune-blocking drug could stop cancer growing back

Giving patients a drug that blocks part of the immune system from going into overdrive might help prevent cancer coming back in some people, according to research published today in Cancer Research.

Cancer Research UK-funded scientists from the University of Sheffield found that the cancer-killing action of chemotherapy can trigger a swarm of wound-healing, white blood cells to cluster around blood vessels in a treatment-hit tumour. These cells – called M2 macrophages – repair tissue damage and build new blood vessels, a process that sometimes helps the tumour to grow again after treatment.

But by treating mice with cancer with a drug that stops these repair cells from working, the researchers markedly reduced the speed at which tumours grew back after chemotherapy.

The lead scientist on the study, Professor Claire Lewis at the University of Sheffield’s Department of Oncology, said: “Scientists already knew that the body’s drive to heal itself can sometimes backfire when the immune system reacts to tissue damage. Our research shows that treating tumours with chemotherapy can activate this part of the immune system, and this then helps tumours re-grow afterwards.

But combining chemotherapy with a drug that switches off this part of the body’s repair system, slowed the growth of tumours after chemotherapy. This could be particularly important for patients who can’t have surgery and, therefore, need chemotherapy to help them live for as long as possible.

Clinical trials of patients are needed to confirm these early findings to see if the drug – already used in patients for other reasons, such as bone marrow transplants – could help cancer patients after chemotherapy.

Dr Áine McCarthy, science communications officer at Cancer Research UK, said: “Chemotherapy is a cornerstone cancer treatment that saves thousands of lives, but sometimes tumours come back, reducing patients’ chances of survival. We don’t understand all the reasons why tumours do come back, but this study sheds new light on the role of the immune system in causing tumours to grow again and, importantly, identifies a drug that could block this happening if given at the same time as chemotherapy.

But this is early research carried out in mice and more work is needed to see if blocking M2 macrophages can also slow down tumour re-growth in patients.

Hughes et al. Perivascular M2 macrophages stimulate tumour relapse after chemotherapy. Cancer Res., 2015; DOI: 10.1158/0008-5472.CAN-14-3587 [Abstract]