Abstract
This genetic association study examines the prevalence of pathogenic/likely pathogenic germline variants among patients with metastatic breast cancer.
There is still considerable debate on the value of multigene panel testing for inherited cancer in patients with breast cancer, based on both the prevalence of pathogenic/likely pathogenic (P/LP) variants and any therapeutic implications from genetic test results. Recent studies demonstrate that the prevalence of P/LP variants is similar in patients with breast cancer whether or not they meet critera for testing by the National Comprehensive Cancer Network (NCCN) guidelines.1,2 However, most participants in these studies were patients with early stage breast cancer and many low-risk variants were identified, raising the question of clinical actionability. The recent US Food and Drug Administration (FDA) approval of polyadenosine diphosphate–ribose polymerase (PARP) inhibitors for patients with metastatic human epidermal growth factor receptor 2 (HER2/ERBB2)-negative breast cancer with germline BRCA1 and BRCA2 (BRCA) pathogenic variants,3,4 suggests germline testing of patients with metastatic breast cancer could have therapeutic implications. Indeed, a recent study found 11.8% of otherwise unselected patients with metastatic prostate cancer harbored a P/LP germline variant,5 leading to a change in NCCN guidelines recommending germline testing for all patients with metastatic prostate cancer. However, to our knowledge, analogous studies to quantify the prevalence of P/LP variants among patients with metastatic breast cancer have not been performed.
Methods
In a Johns Hopkins institutional review board approved study, we prospectively enrolled 100 patients diagnosed with metastatic breast cancer and performed germline testing using a panel of 30 genes (Color Genomics) associated with hereditary cancer without consideration for NCCN guidelines. All patients provided written informed consent. Eligible patients could have either a recurrent or de novo diagnosis of metastatic disease and prior germline testing was allowed if testing contained 10 or fewer genes and results were negative for P/LP variants. Demographics of our cohort are shown in Table 1. The median (SD) age at time of consent for the study was 59 (12.0) years. Of 100 participants, 76 reported their race as white, and 66 patients had hormone receptor positive/HER2/ERBB2-negative disease, including 2 male patients with breast cancer.
Table 1. Demographics of Patient Cohort.
| Characteristic | Patients, No. |
|---|---|
| Age at time of, median (SD), y | |
| Consent | 59 (12.0) |
| Initial diagnosis of breast cancer | 49 (11.6) |
| Diagnosis of metastatic diseasea | 56 (11.9) |
| Race | |
| White | 76 |
| Black | 12 |
| Asian | 6 |
| Hispanic | 3 |
| Other | 3 |
| Receptor status | |
| HR-positive/HER2/ERBB2-negativeb | 66 |
| TNBC | 13 |
| HR-positive/HER2/ERBB2-positive | 13 |
| HR-negative/HER2/ERBB2-positive | 8 |
Abbreviations: HER2/ERBB2, Human Epidermal Growth Factor Receptor 2; HR, hormone receptor; TNBC, triple negative breast cancer.
Unknown for 5 patients.
Includes 2 male patients.
Results
Of the 100 patients, 14 were found to have a P/LP variant, and 21 were found to have a variant of unknown significance (VUS) (Table 2). Among patients with P/LP variants, 6 of 14 (43%) did not meet NCCN guidelines for genetic testing, though none were BRCA gene variants. Of the 6 patients with P/LP BRCA variants, 2 had never received genetic testing prior to our study despite meeting NCCN criteria, underscoring the need for improved implementation of recommended guidelines.
Table 2. Germline Variants in Patients With Metastatic Breast Cancer.
| Gene | P/LP | Nucleotide (Protein or Other Change) | VUS | Nucleotide (Protein or Other Change) |
|---|---|---|---|---|
| APC | 3a | c.3920T>A (p.Ile1307Lys) | ||
| c.3920T>A (p.Ile1307Lys) | ||||
| c.3920T>A (p.Ile1307Lys) | ||||
| ATM | 1a | c.6404_6405insTT (p.Arg2136*) | 5 | c.1163A>G (p.Lys388Arg) |
| c.4471T>G (p.Phe1491Val) | ||||
| c.6482G>A (p.Arg2161His) | ||||
| c.7089 + 3A>G (intron variant) | ||||
| c.8762C>A (p.Thr2921Lys) | ||||
| BAP1 | 1 | c.1217A>T (p.Glu406Val) | ||
| BARD1 | 1 | c.616C>A (p.Gln206Lys) | ||
| BRCA1 | 1 | c.68_69delAG (p.Glu23Valfs*17) | 2 | c.4111G>A (p.Gly1371Arg) |
| c.593 + 4A>G (intron variant) | ||||
| BRCA2 | 5 | c.1929delG (p.Arg645Glufs*15) | 1 | c.388G>A (p.Val130Ile) |
| c.1813dupA (p.Ile605Asnfs*11) | ||||
| c.5576_5579delTTAA (p.Ile1859Lysfs*3) | ||||
| c.6450dup* (p.Val2151Serfs*25) | ||||
| c.7681C>T (p.Gln2561*) | ||||
| BRIP1 | 1a | c.1425_1429del (p.Leu475Phefs*34) | 1 | c.*6C>G (variant after stop codon) |
| CDH1 | 2 | c.1289T>G (p.Val430Gly) | ||
| c.1315G>A (p.Ala439Thr) | ||||
| CHEK2 | 1a | c.470T>C (p.Ile157Thr) | 3 | c.917G>T (p.Gly306Val) |
| c.1357G>C (p.Ala453Pro) | ||||
| c.1427C>T (p.Thr476Met) | ||||
| MITF | 1 | c.952G>A (p.Glu318Lys) | ||
| MLH1 | 1 | c.548A>G (p.Tyr183Cys) | ||
| MSH2 | 1 | c.645 + 3A>G (intron variant) | ||
| MUTYH | 1 | c.934-2A>G (splice acceptor variant) | 1 | c.679G>A (p.Ala227Thr) |
| PMS2 | 1 | c.475G>A (p.Val159Met) | ||
| STK11 | 1 | c.617C>T (p.Ala206Val) | ||
| Total, No. (%) | 14 (14) | 21 (21) |
Abbreviations: P/LP, pathogenic/likely pathogenic variant; VUS, variant of unknown signficance.
Patients who did not meet National Comprehensive Cancer Network guidelines for germline testing.
Discussion
Limitations of our study include the relatively small sample size and the fact that the gene panel (Color Genomics) does not analyze the complete coding sequence of all tested genes. In addition, we excluded patients with prior germline testing unless the results were negative for 10 or fewer genes. Thus, our study may underestimate the true prevalence of germline variants in patients with metastatic breast cancer.
Our results provide additional support for testing patients with metastatic breast cancer based on their relatively high prevalence of P/LP variants, including a 6% frequency of P/LP variants in BRCA. Furthermore, given that many of the genes included on the multigene panel are involved in DNA repair, there is scientific rationale that some of these P/LP variants (ATM, BRIP1, CHEK2) may also be predictive for response to PARP inhibitors, a hypothesis currently being tested in clinical trials (NCT03344965). Consequently, our results provide evidence to support genetic testing for inherited cancer predisposition among all patients with metastatic breast cancer because this group represents a population with a high prevalence of P/LP variants that could have therapeutic implications.
References
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