David M. Euhus, MD
For many years after the commercialization of multigene panel testing for hereditary breast and ovarian cancer syndrome, BRCA1
remained the most commonly identified pathologic variants. Recent studies have found that variants in genes other than BRCA1
now account for 56% to 71% of pathogenic variants identified among women recently diagnosed with breast cancer. The majority of these variants occur in PALB2
, or ATM
. Clinicians who advise patients with these mutations must be prepared to answer questions about risk-reducing mastectomy, the safety of radiation therapy after breast conservation, the risk of other types of cancers, and whether the variant should be considered in decisions about systemic therapies.
The first task when confronted with a positive genetic test is to quantify cancer risk. In general, contralateral breast cancer risk will parallel the breast cancer risk that has been associated with a given mutation. There is no single risk value that can be assigned to any gene, but point estimates of risk abound in the literature, making them a reasonable starting place to think about risk.
Point estimates of lifetime breast cancer risk for a 40-year-old unaffected woman are about 40% for PALB2
, 35% for ATM
, and 22% for CHEK2 (table). However, penetrance varies widely, based on the variant type and the family history. Frame-shifting nonsense variants (usually insertion or deletion of some number of nucleotides that is not a multiple of 3, often resulting in an early-stop codon) are generally associated with greater risk than missense mutations (nucleotide substitutions that may or may not change the amino acid sequence).
, the breast cancer risk ranges from 20% to 90%. PALB2
is increasingly recognized as a high-risk gene similar to BRCA2
. For ATM
, there is evidence that only variants capable of causing ataxia–telangiectasia in the homozygous state, mostly nonsense mutations, increase breast cancer risk in the heterozygous state. Estimates of breast cancer risk for ATM
range from 18% to 60%, depending on the variant type. CHEK2
appears to be a moderate-risk gene, with breast cancer risks ranging from 15% to 44%, depending on the specific variant and the family history. Risk can exceed 40% for women who have a family history of breast cancer in first- and second-degree relatives. Women with nonsense mutations in PALB2
, or CHEK2
and a strong family history have contralateral breast cancer risk levels that warrant a discussion about bilateral mastectomy. Nearly any woman with a PALB2
, or CHEK2
mutation will reach a risk level warranting discussion about breast magnetic resonance imaging (MRI). An exception is the common CHEK2
variant, which will rarely generate a lifetime breast cancer risk greater than 20%.
-, and ATM
-associated breast cancers are usually estrogen receptor–positive and amenable to the same range of surgical options as sporadic breast cancers. Patients with ataxia–telangiectasia, which is caused by 2 variant copies of the ATM
gene, are hypersensitive to radiation, and there has been concern that patients with breast cancer with 1 variant copy may be as well. One study found that ATM
heterozygotes treated with breast conservation and whole-breast radiation had a small increase in contralateral breast cancer risk (odds ratio, 2.8) compared with women who did not receive radiation. This effect was thought to be due to radiation side scatter. Others have looked at acute and delayed radiation toxicity in relation to heterozygous ATM
variants. These studies have not been convincing. At this time, guidelines are not cautioning against the use of breast conservation and radiation therapy in ATM
In addition to breast cancer, there is some evidence that PALB2
, and ATM
can increase the risk for other cancers. Most notable for PALB2
is pancreatic cancer and male breast cancer. For CHEK2
, it is colorectal and kidney cancer. For ATM
, it is ovarian, kidney, pancreatic, and lung cancer.
Value of Routine Screening Is Questionable
It is important to recognize that there is a difference between a statistically significant increased risk and a clinically significant increased risk. Some have advocated for extra screening tests if the lifetime risk for a cancer exceeds 5%. This is ill advised. Successful cancer screening requires a test with sensitivity and specificity that is tuned to the incidence of occult disease in the screened population in order to avoid excess false positives. In addition, it must be proven that some well-tolerated intervention will interrupt the progression of the disease of interest if it is detected early. Every medical test exposes the patient to some risk of harm. Screening can only be recommended when it is clear that the benefits outweigh the harms. This requires knowledge of the probability of benefit (eg, reduced mortality) balanced against the frequency and severity of harm.
CMPACT OF PATHOGENIC VARIANTS OF PALB2, CHEK2, OR ATM10
aPopular point estimate for lifetime risk (observed range).
bMost consistently observed
GENES ACTIVE IN THE BRCA-ASSOCIATED DNA REPAIR PATHWAY10
For example, mammography is associated with a high frequency of low-intensity harm (eg, callbacks, biopsies, and overdiagnosis) but has been convincingly shown to reduce breast cancer mortality for women over age 50. Conversely, screening pancreatic MRI or screening endoscopic ultrasound can be associated with high-intensity harm in the form of pancreatic biopsies or unnecessary pancreaticoduodenectomies. If screening is undertaken in a population with an insufficient disease incidence or if subsequent interventions do not reliably interrupt disease progression, harms will greatly outweigh the benefit. More testing is not necessarily better. No special cancer screening, apart from breast MRI, can be recommended for carriers of PALB2
, or ATM
Pathway Suggests Therapeutic Implications
, and ATM
are all part of the DNA repair pathway orchestrated by BRCA1
(figure). It has been known for some time that BRCA1
- and BRCA2
-associated breast cancers are deficient in DNA double-strand break repair, making them more sensitive to platinum-based chemotherapy and PARP inhibition. There are several clinical trials currently accruing that exploit these deficiencies in DNA repair. Based on success with BRCA1
carriers, some of these trials are also evaluating PALB2
, and ATM
Tumors with DNA repair deficiencies that are similar to the deficiencies recognized in BRCA1
- or BRCA2
-associated tumors are said to express “BRCAness,” and this is thought to be predictive of response to platinum drugs and PARP inhibitors. It has recently been recognized that BRCA1
- and BRCA2
-associated breast cancers harbor a distinct pattern of base-substitution mutations, termed “Signature 3.” PALB2
-associated breast cancers are Signature 3 positive, but CHEK2
- and ATM
- associated breasts cancers are not. This makes it likely that a PALB2
mutation, but not a CHECK2
mutation, will predict special sensitivity to platinum-based chemotherapy.
PARP inhibitors interfere with DNA single-strand break repair. Two new classes of drugs that also target single-strand break repair are the ATR-checkpoint kinase 1 inhibitors and the CHK1 inhibitors. It is not yet known whether ATM
mutations will predict responsiveness to these agents.
- van Os NJ, Roeleveld N, Weemaes CM, et al. Health risks for ataxia-telangiectasia mutated heterozygotes: a systematic review, meta-analysis and evidence-based guideline. Clin Genet. 2016;90(2):105-117. doi: 10.1111/cge.12710.
- Easton DF, Pharoah PD, Antoniou AC, et al. Gene-panel sequencing and the pre- diction of breast-cancer risk. N Engl J Med. 2015;372(23):2243-2257. doi: 10.1056/ NEJMsr1501341.
- Choi M, Kipps T, Kurzrock, R. ATM mutations in cancer: therapeutic implications. Mol Cancer Thera. 2016;15(6): 1781-1791. doi: 10.1158/1535-7163.MCT-15-0945.
- Southe MC, Goldgar DE, Winqvist R, et al. PALB2, CHEK2 and ATM rare variants and cancer risk: data from COGS. J Med Genet. 2016;53(12): 800-811. doi: 10.1136/ jmedgenet-2016-103839.
- Antoniou AC, Casadei S, Heikkinen T, et al. Breast-cancer risk in families with mutations in PALB2. N Engl J Med. 2014;371(6): 497-506. doi: 10.1056/NEJ- Moa1400382.
- Polak P, Kim J, Braunstein LZ, et al. A mutational signature reveals alterations underlying deficient homologous recombination repair in breast cancer. Nat Genet. 2017;49(10): 1476-1486. doi: 10.1038/ng.3934.