PALB2 germline pathogenic variants are associated with a substantially increased risk for breast cancer and a smaller increased risk for pancreatic and ovarian cancers, warranting enhanced surveillance and the option of risk-reducing interventions, according to a global team of cancer genetic specialists who recently published a clinical practice resource in Genetics and Medicine.1
Surveillance for breast cancer in people with PALB2 germline pathogenic or likely pathogenic variants (PALB2 heterozygotes) “should be equivalent to that for BRCA1/2 heterozygotes,” according to the recommendations issued by the American College of Medical Genetics and Genomics (ACMG) in this resource document. Guided by personalized risk assessments, risk-reducing mastectomy can be considered as an option, the team counseled.
<p><strong>“People who harbor a germline pathogenic or likely pathogenic variant in <em>PALB2</em> face challenging questions….”</strong></p>— Douglas R. Stewart, MD
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“Pancreatic cancer surveillance should be considered, but ideally as part of a clinical trial…. Ovarian cancer surveillance should not be offered, and risk-reducing salpingo-oophorectomy should include shared decision-making and should rarely be considered before the age of 50,” the authors wrote.
“Our primary goal in writing the paper was to develop advice on the clinical management of people who have a pathogenic or likely pathogenic PALB2 variant,” said Douglas R. Stewart, MD, one of the authors, in an interview with The ASCO Post. Dr. Stewart is Senior Investigator, Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, at the National Cancer Institute. He is also a past Chair of the ACMG Professional Practice and Guidelines Committee.
No Known Additive Effect
PALB2 (partner and localizer of BRCA2) “is sometimes referred to as ‘BRCA3,’ given its importance in the risk of breast cancer,” Dr. Stewart noted. “People who harbor a germline pathogenic or likely pathogenic variant in PALB2 face challenging questions, especially about their personal risk of developing cancers of the breast, ovaries, and pancreas and how to manage that risk.”
Although rare, an individual can have a PALB2 variant with or without BRCA1 or BRCA2 variants. “There are undoubtedly people in the population with a germline pathogenic variant of BRCA1 or BRCA2, as well as PALB2,” Dr. Stewart said. From the small amount of data available, the increased risk of breast cancer from having a PALB2 variant and BRCA1 and BRCA2 variants “doesn’t appear to be additive,” he stated. “We know that people who have a BRCA1 and a BRCA2 variant aren’t at a dramatically increased risk compared with those who have just one or the other. Presumably, the same is true for PALB2, but we are not 100% sure.”
Dr. Stewart continued: “I would expect that our estimates of risk will get better as more and more testing is done. Historically, genetic testing was done on a patient who showed up in clinic with a tumor. Now, with changes in practice and cost, genetic testing is done much more widely; we are testing people who are completely asymptomatic, and we are finding some of these risk estimates are actually trending down, which is good, but we have to continue to evolve our recommendations based on those revisions. This is a dynamic process that needs to be revisited over time.”
Germline and Tumor Testing
The ACMG recommends that “PALB2 should be included in breast, ovarian, and pancreas germline cancer gene panels.” Testing for PALB2 variants is included on many panels already, Dr. Stewart said.
Overall indications listed in the resource document for genetic testing for inherited breast cancer “are based on personal and/or family cancer history, taking into account age at diagnosis (at or below age 45), triple-negative breast cancer (at or below age 60), or presence of another primary cancer or family history of cancer. A diagnosis of ovarian or pancreatic cancer in an individual is sufficient to meet current National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology for germline testing. In addition, germline testing should be offered when a PALB2 variant is identified through tumor testing,” he said.
“If there is a concerning family history of ovarian, pancreatic, or breast cancer, then PALB2 is certainly a gene to consider testing for in somebody who is asymptomatic.”— Douglas R. Stewart, MD
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“If an individual has a later-stage tumor, it is now routine to remove the tumor and test its genetics. But it is important to remember that mutations may have arisen in the development of that tumor.” Dr. Stewart explained. “Sometimes in sequencing tumors, you can find, or suspect, a variant in the germline. When those results are found, those samples are returned to the physician, who would presumably share them with the patient as well, because it is helpful to understand the risk in both an individual and a family.”
Genetic testing is recommended for those diagnosed with ovarian and pancreatic cancers. “Following a standard scenario in clinical genetics, if there is a concerning family history of ovarian, pancreatic, or breast cancer, then PALB2 is certainly a gene to consider testing for in somebody who is asymptomatic,” Dr. Stewart noted.
Variants in PALB2 were first associated with an increased cancer risk in 2007, and clinical testing has been available since then. “Testing for PALB2 increased with its inclusion on multigene cancer panels, starting around 2012 to 2013. It has come to be considered as the third most important breast cancer gene after BRCA1 and BRCA2, following the 2014 publication of robust breast cancer risk estimates that overlap with BRCA2,” the authors noted.2
An article in TheNew York Times, “This Breast Cancer Gene Is Less Well Known, but Nearly as Dangerous,” reported: “Now, doctors are increasingly recommending that anyone who was tested before 2014 go through genetic testing again” to check for PALB2 mutations.3
Asked about retesting, Dr. Stewart remarked: “It is a routine recommendation in clinical genetics in general—not just cancer genetics—to revisit older genetic testing results, because we are constantly learning more.” Individuals concerned about breast cancer who previously had BRCA1 or BRCA2 testing alone and tested negative may consider additional testing through an expanded panel that would include PALB2.
“If you have a finding in a germline variant—a risk variant—that is not going to go away. But if it is a negative test, as research continues, we identify additional genes, and testing again in the future may be beneficial,” Dr. Stewart said. Many test reports, he noted, include advice for patients to discuss the findings again with their physicians in a year’s time and see whether any new developments in genetics or testing indicate additional action.
Increasing awareness of PALB2 may be spurring testing. “In the genetics community, we’ve known about PALB2 for over a decade, but sometimes it takes a while for the information to ripple out beyond the research community to other practicing oncologists and the general public,” Dr. Stewart stated. He credited the article in TheNew York Times and other press coverage with helping to transmit important information about PALB2 and the risks associated with variants.
Surveillance and Interventions
The ACMG document calls for “BRCA1/2-equivalent breast surveillance” for those with PALB2 variants. Surveillance for pancreatic cancer “may be considered in the context of family history, ideally as part of a clinical trial. Participation in a clinical trial is recommended, as the effectiveness of different approaches to pancreatic screening is not known.”
There are several ongoing pancreatic cancer trials in Europe and the United States, including the Cancer of the Pancreas Screening Study (CAPS) at Johns Hopkins. Among those advised in the CAPS information material to consider pancreatic cancer screening in a research setting are “individuals who have the BRCA1, BRCA2, or PALB2 mutation and have at least one relative affected by pancreatic cancer.” More information on that trial is available at https://pathology.jhu.edu/pancreas/participating-research/caps.
“Among PALB2 heterozygotes,” the resource document notes, “the NCCN recommends discussion of risk-reducing bilateral mastectomy, with nipple-sparing mastectomy as an option.” Risk-reducing mastectomy for women with BRCA1/BRCA2 mutations is not without some controversy. Might controversy also be expected surrounding bilateral mastectomy for women with PALB2 variants?
“Yes,” Dr. Stewart said. “That’s why, in the document we wrote about PALB2, we have a lot of very careful language and caveats; it is controversial, and there are inherent uncertainties. And one of the things we emphasize is the importance of shared decision-making by patients and their clinical team.”
The ACMG recommends: “Ovarian cancer surveillance should not be offered [based on PALB2 heterozygotes]. There is insufficient evidence based on PALB2 variant status alone to recommend risk-reducing salpingo-oophorectomy. Shared decision-making should take into account other risk and protective factors, and the procedure should rarely be considered before the age of 50.”
Survival benefits with platinum-based chemotherapy in patients with pancreatic ductal carcinoma and BRCA1/2 or PALB2 variants as well as promising results with PARP inhibitors were cited for the recommendation that “PALB2 heterozygotes should be considered for the same therapeutic regimens and trials as those for BRCA1/2.”
Personalized risk estimates were recommended to guide clinical management. “CanRisk is an online tool to stratify risk,” Dr. Stewart explained. It was developed by a team including the senior author of the ACMG paper, Marc Tischkowitz, MD, PhD, Professor of Medical Genetics and Attending Physician in the Department of Medical Genetics at the University of Cambridge, England.
Marc Tischkowitz, MD, PhD
“The CanRisk cancer assessment tool is designed to assist clinicians during a consultation with the collection of risk information from patients. This information is used to calculate a cancer risk estimate, which will be linked to management recommendations,” according to the CanRisk website. The authors noted that CanRisk-BOADICEA (Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm) is the only risk estimation tool that currently incorporates PALB2.
“There is emerging evidence to suggest that additional genetic variants, such as those found in polygenic risk scores, may modify risk for several cancers, including those of the breast, ovaries, and pancreas,” Dr. Stewart said. “Polygenic risk scores are constructed from variants that are usually identified through genome-wide association studies. Individually, the variants have small effect sizes, but collectively—meaning dozens of them—they may have a large effect.”
Using these risk scores “in clinical management and risk assessment is promising, and an area of active research, but at the moment, we don’t have a lot of data on them,” Dr. Stewart said. “In principle, in the future, an individual with a PALB2 mutation, or BRCA1 or BRCA2 mutation, or another tumor predisposition gene, could have on top of that a [polygenic risk score] that could help stratify risk. The ACMG is actively reviewing evidence for the use of polygenic risk scores in clinical practice and will be publishing resources later this year.”
The authors argue for “the need to move away from compartmentalizing PALB2 and consider risk to be a continuous variable from high to moderate, influenced by family history, polygenic risk score, and other factors.” They also advocate developing personalized risk estimates and strategies to translate this information to enhance medical management.
“PALB2-related breast cancer risks are generally lower than those associated with BRCA1 and overlap with those associated with BRCA2. However, cancer risks are influenced by other factors—family history and maybe other genetic variants like those included in the polygenic risk score,” Dr. Stewart elaborated. “If an individual has these other factors, that can adjust the spectrum of risk for an individual with a PALB2 variant, from a high-risk type gene to one that is lower risk. It is going to depend on a particular individual and a particular family.”
Establishing Clear Metrics
The ACMG also recommendsthat “prospective collection of clinical data from PALB2 patients should be used to establish clear metrics on treatment outcome and survival.”
That effort is being led by two of the resource document authors. “The primary mover and shaker in this field,” Dr. Stewart said, “is Dr. Tischkowitz, who has the largest collection of PALB2 pedigrees in the world,” with data on more than 1,300 families.
Tuya Pal, MD
“Probably the largest collection in the United States at a single institution, with data on more than 300 people, is at Vanderbilt University, Nashville,” he continued. Tuya Pal, MD, a clinical geneticist and Associate Director of Cancer Health Disparities at the Vanderbilt-Ingram Cancer Center, and the senior author on the PALB2 guidance document, is conducting a study to determine optimal treatment for women with a PALB2 mutation and breast cancer.
DISCLOSURE: Dr. Stewart performs contract clinical telehealth services for Genome Medical, Inc, in accordance with relevant NCI ethics policies.
1. Tischkowitz M, Balmaña J, Foulkes WD, et al: Management of individuals with germline variants in PALB2. Genet Med 23:1416-1423, 2021.
2. Antoniou AC, Casadei S, Heikkinen T, et al: Breast cancer risk in families with mutations in PALB2. N Engl J Med 371:497-506, 2014.
“It is important to note that a paper on managing individuals with germline variants in PALB2 was published in the same issue of Genetics in Medicine as an article on reporting secondary findings in clinical exome and genome sequencing,”1,2 Douglas R. Stewart, MD, told The ASCO Post. “PALB2 is a...