Adult Summary Report

Secondary Findings in Adult Subjects

Non-diagnostic, excludes newborn screening & prenatal testing/screening

• Status (Adult): Passed (Consensus scoring is Complete)
• Curation Status (Adult): Released 2.2.1
• Status (Pediatric): Incomplete (Consensus scoring is Incomplete)
• GENE/GENE PANEL: PALB2
• Condition: PALB2-related cancers
• Mode(s) of Inheritance: Autosomal Dominant

Actionability Assertion

• PALB2 ⇔ 0016419 (breast cancer): Assertion Pending

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 Scores

Gene Condition Pairs: PALB2 ⇔ 0016419 (OMIM:114480)

Outcome / Intervention Pair	Severity	Likelihood	Effectiveness	Nature of the Intervention	Total Score
Breast cancer / Chemoprevention	2	2C	2B 1	2	8CB
Breast cancer / Mastectomy	2	2C	3B 2	1	8CB
Breast cancer / Breast cancer surveillance	2	2C	2B 3	3	9CB

1. Level of evidence downgraded due to extrapolation from a related condition.

2. Level of evidence downgraded due to extrapolation from a related condition.

3. Level of evidence downgraded due to extrapolation from a related condition.

1. What is the nature of the threat to health for an individual carrying a deleterious allele?

Prevalence of the Genetic Condition

For women, lifetime risk estimates indicate that 12.3% will develop breast cancer and 2.8% will die from it. PALB2 pathogenic variants have been detected in 1-3% of breast cancer cases. [1, 2, 3]

Clinical Features

PALB2 interacts with the BRCA2 protein and is involved in DNA repair and tumor suppression. PALB2 pathogenic variants are associated with an increased risk of breast cancer. [3]

Natural History

For PALB2 heterozygotes, breast cancer risk increases with age in women with a pathogenic variant, with a 14% cumulative risk of cancer by age 50 and 35% by age 70. A prospective cohort analysis among heterozygotes of two founder mutations in Poland reported that women with a PALB2 pathogenic variant 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 pathogenic variants were more likely have triple-negative cancers (34% vs. 14%, p<0.0001) and bilateral cancer (10% vs. 3%, p=0.001). The 10-year survival was found to be worse for women with breast cancer and a PALB2 pathogenic variant 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 pathogenic variant (adjusted hazard ratio for death 2.27, 95% CI: 1.64–3.15; p<0.0001).The risk of breast cancer also increases with family history, with 33% breast cancer risk by age 70 for those with no affected first degree relatives compared to 58% in those with two affected first-degree relatives. [4, 2, 3]

2. How effective are interventions for preventing harm?

Patient Management

While no chemoprevention recommendations were identified for patients with PALB2 pathogenic variants specifically, guidelines based on lifetime risk levels similar to those associated with PALB2 pathogenic variants state that healthcare professionals within a specialist genetics 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 PALB2 pathogenic variants 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 pathogenic variant. 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). Longer term follow-up from one of these trials has subsequently been published; this study found that over a median of 16 years, there was a significant reduction in the occurrence of all breast cancers in the tamoxifen group (HR=0.71; 95% CI: 0.60 to 0.83; p<0.0001). However, no significant difference was found in breast-cancer specific mortality (OR=1.19; 95% CI: 0.68-2.10; p=0.8).
- 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) [5]

Women with a PALB2 pathogenic variant could consider risk-reducing mastectomy based on their family history. (Tier 2) [2]

No direct evidence on the effectiveness of risk-reducing surgery in patients with PALB2 pathogenic variants 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 pathogenic variants. 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 for death among women undergoing mastectomy was 100% among moderate-risk women, and 81-94% among high-risk women. (Tier 1) [5]

Surveillance

Heterozygous female carriers of a PALB2 pathogenic variant are advised to undergo screening with annual mammography starting at age 30, the age when the average 5-year risk for breast cancer exceeds 1%, and may consider screening with breast MRI. (Tier 2) [2]

No direct evidence on the effectiveness of breast cancer surveillance in patients with PALB2 pathogenic variants was identified. Evidence cited in guidelines was based on patients with a BRCA1/2 pathogenic variant or a family history of breast cancer. One guideline summarizes that 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 found that 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 compared to a control group of unscreened women of similar age who developed breast cancer (lead time adjusted HR=0.24; 95% CI: 0.09-0.66]). Second, a study modeled 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: 0.66-0.96). Third, a retrospective study found that death from any cause was less likely in BRCA1/2 mutation 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: 0.25-0.77]). (Tier 1) [5]

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

Breast cancer risk increases with age in women with PALB2 pathogenic variants, with a 14% cumulative risk by age 50 and a 35% cumulative risk by age 70. (Tier 3) [2, 3]

Relative Risk

The 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, with a pooled risk estimate of 5.3 (90% CI: 3.0-9.4). 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) [2, 3]

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. [5]

5. Would the underlying risk or condition escape detection prior to harm in the setting of recommended care?

Chance to Escape Clinical Detection

Given that women with PALB2 pathogenic variants have an increased risk of breast cancer at younger ages than the general population it is possible that cases could be missed by current screening programs.

Date of Search: 12.21.2015 (updated 09.19.2017)

Reference List

1. 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)

2. National Comprehensive Cancer Network. Genetic/Familial High-Risk Assessment: Breast and Ovarian (version 2.2017). Publisher: National Comprehensive Cancer Network. (2016) Website: http://www.nccn.org/professionals/physician_gls/pdf/genetics_screening.pdf

3. 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.

4. 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.

5. 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)