News of Mutations in PALB2 Gene Raising Risk of Breast Cancer Offers Opportunity to Explain Limits of Genetic Testing

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Theodora Ross, MD, PhD

Looking at the pace of research on a year-to-year basis can be very frustrating, but if you look back 20 years and then look at where we are now, the difference is unbelievable. Think about how many lives have been saved just based on what we know about Lynch syndrome–associated MMR genes and the hereditary breast and ovarian cancer–associated BRCA genes.

—Theodora Ross, MD, PhD

The response among patients to news reports about mutations in a gene known as PALB2 raising the risk of breast cancer “has been predictable,” Theodora Ross, MD, PhD, wrote in The New York Times.1 As an example, Dr. Ross, Director of the Cancer Genetics Program at The University of Texas Southwestern Medical Center in Dallas, cited one patient who called to make an appointment for a whole-genome scan. In an interview with The ASCO Post, Dr. Ross said that several other patients called to see if their genetic testing had included PALB2 and if not, whether it should have.

While the response from patients may have been expected, Dr. Ross did not expect the response to her New York Times article, explaining the current limitations of genetic testing and the futility of germ-line whole-genome sequencing as a means of assessing breast cancer risk. She received “hundreds of emails from people saying, ‘Thank you. Somebody needed to say this.’”

Having said that, Dr. Ross went on to explain the value of genetic testing for specific known mutations, particularly among patients with family histories of certain cancers. These would include mutations in BRCA1 and BRCA2 and now PALB2, known to increase the risk of breast cancer, and the mismatch repair genes responsible for Lynch syndrome, also known as hereditary nonpolyposis colorectal cancer (HNPCC).

Screening for PALB2 Mutations

“Loss-of-function mutations in PALB2 are an important cause of hereditary breast cancer, with respect both to the frequency of cancer-predisposing mutations and to the risk associated with them. Our data suggest the breast-cancer risk for PALB2 mutation carriers may overlap with that for BRCA2 mutation carriers,” Antoniou et al reported in The New England Journal of Medicine.2 That study involved 362 members of 154 families with loss-of-function mutations PALB2. This included 311 women (229 with breast cancer), as well as 51 men (7 with breast cancer).

“The risk of breast cancer for female PALB2 mutation carriers, as compared with the general population, was eight to nine times as high among those younger than 40 years of age, six to eight times as high among those 40 to 60 years of age, and five times as high among those older than 60 years of age,” the researchers reported. “Because of the widespread availability of multigene panels and whole-exome sequencing, screening for inherited loss-of-function mutations in PALB2 has begun to enter clinical practice,” the authors added.

Such screening has already begun at the Cancer Genetics Program that Dr. Ross directs. “Some argue that the panels are premature, but I would say that the paper in The New England Journal of Medicine helped. What was so beautiful about the paper was the large number of families with this mutation that have early-onset cancers.” As more screening is done, “we are going to collect more and more of this kind of much-needed data,” Dr. Ross said.

Genetic Screening: An Ongoing Process

“Genetic testing is a process for many patients, not a one-time event,” Dr. Ross noted in the Times article. Patients “need to know that, because when their family history changes, they’ve got to let us know,” Dr. Ross stated. In addition, when changes in the clinical research area, such as the PALB2 study, move an aspect of genetic testing from the research into the practical arena, there might be a need to reconnect with a patient.

“That is why we always tell patients to recontact us in a few years,” Dr. Ross emphasized. She realizes, however, that some patients may be lax about calling back. “Physicians can be the worst patients about checking in, indicating that it is not just lack of information that blocks a reconnection. Emotional issues reflected in denial and practial issues such as inconvenience may interfere for many patients,” she said.

“In the coming weeks, in light of the report on PALB2, as well as the emergence of sophisticated tests that can now analyze many cancer genes at one time, we’ll advise some former patients who tested negative for BRCA or other specific genes to return for more genetic counseling and potentially further testing,” Dr. Ross wrote in the Times. The article itself has prompted calls from patients, as have talks Dr. Ross has presented at survivor groups and other meetings.

For now, patients are not being individually contacted, but “there are some of those mystery patients that we think we should probably call,” Dr. Ross said. By mystery patients, she means women who have a strong family history of breast and ovarian cancer or have had these cancers themselves but haven’t been found to carry any predicted mutations. “We would have expected that they had a BRCA1 or BRCA2 mutation. They don’t have it, but they clearly have this high risk. There is something genetic, but what is it? We need to discover what it is.”

Who Gets Tested?

Genetic testing “is becoming more mainstream,” Dr. Ross said, but “demographics make a big difference,” with underrepresentation of African American and Hispanic populations. Women seeking genetic testing for breast cancer gene mutations may be prompted by something they have read, a realization or reminder of a family history of breast cancer, or a referral by their primary care physician. About half of the patients already have cancer and are referred by their oncologist.

The University of Texas Southwestern Medical Center has initiated a family history of cancer questionnaire that is embedded into mammogram screening. “The technicians essentially can flag somebody who has a family history, and we are able to pick up some BRCA mutations,” Dr. Ross explained.

Patients who are found by genetic testing to have a BRCA and/or, for example, PALB2 or RAD51C mutation are referred to a breast surgeon and to a gynecologic surgeon for consultation concerning removal of the breasts and ovaries, respectively, Dr. Ross explained.

“Among people with BRCA mutations, if they elect to do breast screening, then they embark on frequent clinical exams as well as alternating breast magnetic resonance imaging and mammograms every 6 months,” she added. “So it really depends on their personal choice.”

There are also some patients who seek genetic testing for breast cancer genetic mutations but do not have cancer or a family history of breast cancer. Those patients might still be candidates for testing based on their age or other factors. This would include ovarian cancer, no matter what their family history, Dr. Ross said.

Several organizations, including the National Comprehensive Cancer Network (NCCN), have issued guidelines for genetic testing to determine cancer risk. “We follow the NCCN guidelines, and other relevant guidelines, as do insurance companies,” Dr. Ross noted.

Using Genetic Information for Prevention

“We can now use genetic information to prevent breast, ovarian, and colon cancer in many patients,” Dr. Ross wrote in the Times article. She expanded on this in the interview with The ASCO Post. “In the case of Lynch syndrome, if patients have yearly colonoscopies where suspicious polyps are removed, the estimated lifetime for these patients is normal, because most deadly colon cancers [in these patients] have been prevented with polypectomies,” Dr. Ross stated.

For patients with a high genetic risk of breast cancer, “if you take out the ovaries and remove the breasts, they will have normal risk,” Dr. Ross noted. “Some people choose not to do that, understandably, and that is where the issue of family history is so important. Because if you have a 30% cancer risk, it may be less urgent to take the preventive action of prophylactic surgeries,” she continued.

Patience With the Pace of Research

“We need to have patience with the pace of research,” Dr. Ross advised. She understands why people get impatient with the pace of clinical translation, for example, when a gene that increases cancer risk has been identified, but it is unclear what to do with that knowledge. “We know that there is some risk, but we are not exactly sure how high a risk,” she said. “PALB2 was called a low-penetrant gene for a long time, and it frequently is not, based on the data reported in The New England Journal of Medicine.”

“Looking at the pace of research on a year-to-year basis can be very frustrating,” she acknowledged, “but if you look back 20 years and then look at where we are now, the difference is unbelievable. Think about how many lives have been saved just based on what we know about Lynch syndrome–associated MMR genes and the hereditary breast and ovarian cancer–associated BRCA genes.” ■

Disclosure: Dr. Ross reported no potential conflicts of interest.


1. Ross T: Cancer and the secret of your genes. New York Times, August 16, 2014.

2. Antoniou AC, Casadei S, Heikkinen D, et al: Breast-cancer risk in families with mutations in PALB2. N Engl J Med 371:497-506, 2014.

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