ACTIONABILITY KNOWLEDGE REPOSITORY ACTIONABILITY CURATION INTERFACE

Adult Summary Report Secondary Findings in Adult Subjects Non-diagnostic, excludes newborn screening & prenatal testing/screening A Current Version Rule-Out Dashboard Release History Status (Adult): Passed (Consensus scoring is Complete) Curation Status (Adult): Released 1.0.0

GENE/GENE PANEL: PALB2
Condition: PALB2-related cancers
Mode(s) of Inheritance: Autosomal Dominant
Actionability Rationale
This topic was initially scored prior to development of the process for making actionability assertions. The Actionability Working Group decided to defer making an assertion until after the topic could be reviewed through the update process.
Final Consensus Scoresa
Outcome / Intervention Pair
Severity
Likelihood
Effectiveness
Nature of the
Intervention
Total
Score
Breast cancer / Chemoprevention
2
2C
2B
2
8CB
Breast cancer / Mastectomy
2
2C
3B
1
8CB
Breast cancer / Breast cancer surveillance
2
2C
2B
3
9CB

 
Topic
Narrative Description of Evidence
Ref
1. What is the nature of the threat to health for an individual carrying a deleterious allele?
Prevalence of the Genetic Condition
For women, a lifetime risk estimates indicate that 12.3% will develop breast cancer and 2.8% will die from it. It is unclear what percent of breast cancers overall are related to a PALB2 mutation. However, among familial breast cancer families without a BRCA1/2 mutation, PALB2 mutations have been detected in 1-4% of cases. The annual incidence of familial pancreatic carcinoma is estimated at 1-10/1,000,000, representing 5-10% of all pancreatic cancer cases. Germline mutations in PALB2 have been detected in up to 3% of patients with familial pancreatic cancer.
1 2 3 4 5
Clinical Features
(Signs / symptoms)
PALB2 "partner and localizer of BRCA2," interacts with the BRCA2 protein and is involved in DNA repair and tumor suppression. PALB2 mutations are associated with an increased risk of breast and pancreatic cancer. In addition, some data has suggested that PALB2 mutations may also be associated with an increased risk of ovarian cancer.
1 6 7
Natural History
(Important subgroups & survival / recovery)
Breast cancer risk increases with age in women with a PALB2 mutation, with a 14% cumulative risk of cancer by age 50 and 35% by age 70. A prospective cohort analysis among carriers of two founder mutations in Poland identified that women with a PALB2 mutation were diagnosed at a similar age to non-carriers (53.3 vs 53.5); however, PALB2 mutation carriers were found to be at an increased risk of breast cancer (OR=4.39, 95% CI: 2.30-8.37). In addition, patients with PALB2 mutations were more likely have triple negative cancers (34% vs. 14%, p<0.0001) and bilateral cancer (10% vs. 3%, p=0.001). 10-year survival was found to be worse for women with breast cancer and a PALB2 mutation at 48.0% (95% CI: 36.5-63.2), compared with 74.7% (95% CI: 73.5-75.8) for patients with breast cancer without a mutation (adjusted hazard ratio for death 2.27, 95% CI: 1.64-3.15; p<0ยท0001).
1 8 9
2. How effective are interventions for preventing harm?
Information on the effectiveness of the recommendations below was not provided unless otherwise stated.
Patient Management
Women should be familiar with their breasts and promptly report changes to their health care provider. However, there is a lack of evidence for a high risk population that either clinical breast examination or self-examination is useful as the sole surveillance modality. (Tier 2)
2 8 10 11 12
While no chemoprevention recommendations were identified for patients with PALB2 mutations specifically, guidelines based on lifetime risk levels similar to those associated with PALB2 mutations state that healthcare professionals within a specialist genetic clinic should discuss and give written information on the absolute risks and benefits of all options for chemoprevention to women at high risk or moderate risk of breast cancer.
 
No direct evidence on the effectiveness of chemoprevention in patients with PABL2 mutations was detected. Evidence cited in guidelines was based on patients defined as high-risk based on a family history of breast, ovarian or related (prostate/pancreatic cancer) or with a BRCA1, BRCA2, and/or TP53 mutation. Among these patients:
 
-High quality evidence from two randomized trials suggests the incidence of breast cancer is lower in patients given tamoxifen than in those given a placebo (RR 0.65; 95% CI, 0.56-0.74)
 
-Low quality evidence from a single randomized trial suggests the incidence of breast cancer is lower in patients given exemestane compared with those given a placebo (HR 0.35; 95% CI, 0.18-0.70) (Tier 1)
10
One guideline states that there is insufficient evidence to recommend the use of risk-reducing surgery for patients with PALB2 mutations. (Tier 2)
8
However, while not specific to PALB2 mutation carriers, guidelines based on lifetime risk levels similar to those associated with PALB2 mutations state that bilateral mastectomy should be raised as a risk-reducing strategy option with all women at high risk of breast cancer (>30% lifetime risk). Surgery is only appropriate for a small proportion of women who are from high-risk families and should be managed by a multidisciplinary team. No direct evidence on the effectiveness of risk-reducing surgery in patients with PALB2 mutations was identified. Findings from 2 observational studies and 3 decision analysis studies suggest that risk reducing subcutaneous/total mastectomy has a beneficial effect in terms of significantly reducing the risk of breast cancer in women with a family history of breast cancer, or with BRCA1 and BRCA2 mutations. One of the observational studies found that risk reducing mastectomy was also associated with a reduction in breast cancer mortality in women with a family history of breast cancer. Among the two observational studies, one found no cases of invasive breast cancer among women who had undergone bilateral total mastectomy over 3 years (compared to 8/63 patients undergoing surveillance only). The second study showed a reduction in the risk of breast cancer of 89.5% in moderate-risk women who had undergone mastectomy and a reduction of 90-94% among high-risk women. The risk reduction of death among women undergoing mastectomy was 100% among moderate-risk women, and 81-94% among high-risk women. (Tier 1)
10
Surveillance
While no breast cancer screening recommendations were identified for PALB2 mutation carriers, breast cancer screening guidelines agree that women at an increased risk level corresponding to the lifetime risk of a PALB2 mutation carrier should receive earlier breast cancer screening than the general population. However, recommendations for age to start, frequency, and the use of mammography versus MRI vary between guidelines. (Tier 1 and Tier 2)
2 10 11 12
No direct evidence on the effectiveness of breast cancer surveillance in patients with PALB2 mutations was identified. Evidence cited in guidelines was based on patients with a BRCA1/2 mutation or a family history of breast cancer. One guideline summarizes that a low quality evidence suggests a disease specific survival benefit with mammographic surveillance in women aged less than 50 years with a family history of breast cancer. First, an observational study death from breast cancer was less likely in women aged less than 50 years with family history whose breast cancer was diagnosed during mammographic surveillance than in a control group of unscreened women of similar age who developed breast cancer (lead time adjusted HR 0.24 [95% CI 0.09 to 0.66]). Second, a study modelled death from breast cancer in a mammographic surveillance study in women with a family history aged less than 50 years and a control group from another study, using prognostic features at diagnosis and underlying risk. Projected ten year death from breast cancer was lower in the mammographic surveillance group than in the control group of unscreened women of similar age, RR 0.80 (95% CI 0.66 to 0.96). Third, a retrospective study death from any cause was less likely in BRCA1/2 carriers aged between 28 and 77 years diagnosed with breast cancer during an intensive mammographic surveillance program than in those diagnosed outside this program (HR 0.44 [95% CI 0.25 to 0.77]). (Tier 1)
10
Circumstances to Avoid
No circumstances-to-avoid recommendations have been provided for the Adult context.
 
3. What is the chance that this threat will materialize?
Mode of Inheritance
Autosomal Dominant
 
Prevalence of Genetic Variants
Information on PALB2 mutations in the general population was not identified.
 
 
Penetrance
(Include any high risk racial or ethnic subgroups)
Information on the penetrance of PALB2 for pancreatic cancer was not identified.
 
Breast cancer risk increases with age in women with PALB2 mutations, with a 14% cumulative risk by age 50 and a 35% cumulative risk by age 70. (Tier 3)
1 8
Relative Risk
(Include any high risk racial or ethnic subgroups)
The cumulative breast cancer risk among females who have a germline pathogenic variant in PALB2 is estimated to increase by 2.3 to as high as 9 fold depending on the population. Relative risk increases when restricted to those at younger ages with a relative risk 8-9 times higher in those younger than 40, 6-8 times higher in those 40-60, 5 times higher among those older than 60. (Tier 3)
1 6
Expressivity
Information on variable expressivity was not available for the Adult context.
 
4. What is the Nature of the Intervention?
Nature of Intervention
The interventions identified in this report include screening tests, prophylactic surgery to remove target organs, and medications with potential side effects.
10
5. Would the underlying risk or condition escape detection prior to harm in the settting of recommended care?
Chance to Escape Clinical Detection
Given that women with PALB2 mutations have a 14% cumulative risk of breast cancer by age 50, it is possible that cases could be missed by current screening programs.
 
 
Description of sources of evidence:
Tier 1: Evidence from a systematic review, or a meta-analysis or clinical practice guideline clearly based on a systematic review.
Tier 2: Evidence from clinical practice guidelines or broad-based expert consensus with non-systematic evidence review.
Tier 3: Evidence from another source with non-systematic review of evidence with primary literature cited.
Tier 4: Evidence from another source with non-systematic review of evidence with no citations to primary data sources.
Tier 5: Evidence from a non-systematically identified source.

 
Reference List
1. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. PARTNER AND LOCALIZER OF BRCA2; PALB2. MIM: 610355: 2016 Feb 04. World Wide Web URL: http://omim.org.
2. Breast Cancer Screening and Diagnosis (Version 1.2015). Publisher: National Comprehensive Cancer Network. (2015) Website: https://www.nccn.org/professionals/physician_gls/pdf/breast-screening.pdf
3. Risk Assessment, Genetic Counseling, and Genetic Testing for BRCA-Related Cancer: Systematic Review to Update the U.S. Preventive Services Task Force Recommendation (2013 Dec)
4. Canto MI, Harinck F, Hruban RH, Offerhaus GJ, Poley JW, Kamel I, Nio Y, Schulick RS, Bassi C, Kluijt I, Levy MJ, Chak A, Fockens P, Goggins M, Bruno M. International Cancer of the Pancreas Screening (CAPS) Consortium summit on the management of patients with increased risk for familial pancreatic cancer. Gut. (2013) 62(3):339-47.
5. Familial pancreatic carcinoma. Orphanet encyclopedia, http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=1333
6. N Petrucelli, MB Daly, T Pal. BRCA1- and BRCA2-Associated Hereditary Breast and Ovarian Cancer. 1998 Sep 04 [Updated 2016 Dec 15]. In: RA Pagon, MP Adam, HH Ardinger, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1247
7. Toss A, Tomasello C, Razzaboni E, Contu G, Grandi G, Cagnacci A, Schilder RJ, Cortesi L. Hereditary ovarian cancer: not only BRCA 1 and 2 genes. Biomed Res Int. (2015) 2015:341723.
8. National Comprehensive Cancer Network. Genetic/Familial High-Risk Assessment Breast and Ovarian (version 2.2015). Publisher: National Comprehensive Cancer Network. (2015) Website: http://www.nccn.org/professionals/physician_gls/pdf/genetics_screening.pdf
9. Cybulski C, Kluzniak W, Huzarski T, Wokolorczyk D, Kashyap A, Jakubowska A, Szwiec M, Byrski T, Debniak T, Gorski B, Sopik V, Akbari MR, Sun P, Gronwald J, Narod SA, Lubinski J. Clinical outcomes in women with breast cancer and a PALB2 mutation: a prospective cohort analysis. Lancet Oncol. (2015) 16(6):638-44.
10. National Collaborating Centre for Cancer (UK). Familial Breast Cancer: Classification and Care of People at Risk of Familial Breast Cancer and Management of Breast Cancer and Related Risks in People with a Family History of Breast Cancer (2013 Jun)
11. Practice bulletin no. 122: Breast cancer screening. Obstet Gynecol. (2011) 118(2 Pt 1):372-82.
12. Guidelines for preventive activities in general practice, 8th edition. (2012) Website: http://www.racgp.org.au/your-practice/guidelines/redbook/
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