Abstract
This case series study examines differences in surgical treatment among adult females with invasive breast cancer who have pathogenic or likely pathogenic variants in genes with high vs moderate breast cancer penetrance.
The 5% to 10% of breast cancers due to hereditary breast cancer (HBC) genes include pathogenic or likely pathogenic (P/LP) variants in genes with high (eg, BRCA1, BRCA2, PALB2) or moderate (eg, ATM, CHEK2) penetrance, with lifetime breast cancer risk of more than 40% and 25% to 30%, respectively.1,2 Risk-reducing mastectomy is a consideration in female BRCA1, BRCA2, and PALB2 heterozygotes, in contrast with ATM and CHEK2 heterozygotes, per current national practice guidelines.3 The objective of this study was to evaluate differences in surgical treatment across high- and moderate-penetrance breast cancer genes with differing clinical recommendations.
Methods
This case series study was conducted from June 2021 to April 2022. Through the Inherited Cancer Registry (ICARE),4 a registry of individuals with or at risk for inherited cancer predisposition, we identified adult females with invasive breast cancer who had a P/LP variant in BRCA1, BRCA2, PALB2, ATM, or CHEK2. Participants with stage IV disease at initial diagnosis or with missing surgery data were excluded. Data were collected using surveys and medical records. Type of surgical treatment (lumpectomy, mastectomy, or bilateral mastectomy) and family history of breast cancer were compared across the 5 genes using χ2 tests. Genetic testing was categorized as done before surgery (year of surgery or earlier) or after surgery. Crude and multivariable adjusted logistic regression was used to assess factors associated with receipt of bilateral mastectomy. Models to calculate the adjusted odds ratio (AOR) included age (<50 years, ≥50 years), timing of genetic testing, family history of breast cancer, and gene. Data were analyzed using SAS Studio, version 9.4; 2-sided P < .05 was significant. The study was approved by Vanderbilt University; participants provided written informed consent. We followed the reporting guideline for case series.
Results
We identified 684 adult females with breast cancer and a confirmed P/LP variant in BRCA1 (235 participants), BRCA2 (217), PALB2 (121), ATM (50), or CHEK2 (61) in the ICARE registry who met inclusion criteria. Mean age at diagnosis was 53 years (range, 23-83 years.) Participants were predominantly White (623 [91%]), college educated (396 of 580 with available data [68%]), and privately insured (455 [67%]). Family history of breast cancer was similar across all 5 genes (Table 1), with no association between receipt of bilateral mastectomy and family history of breast cancer (Table 2). Bilateral mastectomy was associated with breast cancer diagnosed before age 50 years (AOR, 2.21; 95% CI, 1.44-3.40) and genetic testing before surgery (AOR, 5.79; 95% CI, 3.83-8.76). There were no significant differences in bilateral mastectomy rates across participants with BRCA1 (42%), BRCA2 (44%), PALB2 (45%), ATM (55%) and CHEK2 (43%) P/LP variants (P = .73; Table 1) or in participants with P/LP variants in high-penetrance (BRCA1, BRCA2, PALB2) vs moderate-penetrance (ATM, CHEK2) genes (191 of 573 participants [33%] vs 40 of 111 [36%]; P = .47). Multivariate logistic regression analysis revealed no association between receipt of bilateral mastectomy and the gene in which the P/LP variant was detected, after adjustment for potential confounders (Table 2).
Table 1. Characteristics of the Study Population.
| Characteristic | Gene with variant, No. (%) of participants | P value | |||||
|---|---|---|---|---|---|---|---|
| All (N = 684) | BRCA1 (n = 235) | BRCA2 (n = 217) | PALB2 (n = 121) | ATM (n = 50) | CHEK2 (n = 61) | ||
| Age at first breast cancer diagnosis, mean (range), y | 53 (23-83) | 50 (23-74) | 54 (27-82) | 54 (23-83) | 58 (36-76) | 57 (28-77) | NA |
| Race and ethnicitya | |||||||
| Asian | 4 (1) | 1 (0) | 1 (1) | 2 (2) | 0 | 0 | .47 |
| Black | 32 (5) | 16 (7) | 9 (4) | 6 (5) | 1 (2) | 0 | |
| White | 623 (91) | 210 (89) | 203 (94) | 106 (88) | 46 (92) | 58 (95) | |
| Other | 3 (0) | 1 (0) | 1 (1) | 1 (1) | 0 | 0 | |
| Unknown | 22 (3) | 7 (3) | 3 (1) | 6 (5) | 3 (6) | 3 (5) | |
| First breast cancer surgery | |||||||
| Lumpectomy | 203/524 (39) | 72/182 (40) | 60/167 (36) | 37/91 (41) | 10/31 (32) | 24/53 (45) | .73 |
| Mastectomy | 90/524 (17) | 33/182 (18) | 34/167 (20) | 13/91 (14) | 4/31 (13) | 6/53 (11) | |
| Bilateral mastectomy | 231/524 (44) | 77/182 (42) | 73/167 (44) | 41/91 (45) | 17/31 (55) | 23/53 (43) | |
| Data missing | 160/684 (23) | 53/235 (23) | 50/217 (23) | 30/121 (25) | 19/50 (38) | 8/61 (13) | |
| Received radiotherapy | 260 (38) | 95 (40) | 79 (36) | 48 (40) | 14 (28) | 24 (39) | .60 |
| Relatives with breast cancerb | |||||||
| No family history | 122 (18) | 39 (17) | 32 (15) | 27 (22) | 9 (18) | 15 (25) | .46 |
| First degree | 321 (47) | 105 (45) | 114 (53) | 52 (43) | 26 (52) | 24 (39) | |
| Second degree | 189 (28) | 69 (29) | 58 (27) | 35 (29) | 12 (24) | 15 (25) | |
| Third degree | 52 (8) | 22 (9) | 13 (6) | 7 (6) | 3 (6) | 7 (11) | |
Self-reported on the survey. The Inherited Cancer Registry is open to individuals of all races and ethnicities; these data were included to show the demographic characteristics of the study population. The 3 participants who selected “Other” were prompted to write their race in a text box and indicated Eastern Indian, Mestizo, and Pakistani.
Categorized into 4 mutually exclusive categories based on the closest relative with a history of breast cancer: (1) at least 1 first-degree relative, (2) at least 1 second-degree relative, (3) at least 1 third-degree relative, and (4) no first-, second-, or third-degree relatives (ie, no family history).
Table 2. Multivariate Logistic Regression for Bilateral Mastectomy.
| Variable | OR (95% CI) | |
|---|---|---|
| Unadjusted | Adjusted | |
| Age at first breast cancer diagnosis, y | ||
| <50 | 2.97 (2.03-4.35) | 2.21 (1.44-3.40) |
| ≥50 | 1 [Reference] | 1 [Reference] |
| Timing of genetic testing | ||
| Before surgery | 6.65 (4.45-9.92) | 5.79 (3.83-8.76) |
| After surgery | 1 [Reference] | 1 [Reference] |
| Family history of breast cancer | ||
| No family history | 1 [Reference] | 1 [Reference] |
| First-degree relative | 0.89 (0.53-1.48) | 1.03 (0.57-1.87) |
| Second-degree relative | 1.05 (0.59-1.84) | 0.99 (0.52-1.88) |
| Third-degree relative | 0.58 (0.26-1.28) | 0.63 (0.25-1.56) |
| Gene with variant | ||
| BRCA1 or BRCA2 | 1 [Reference] | 1 [Reference] |
| ATM | 1.45 (0.66-3.18) | 1.62 (0.66-3.95) |
| CHEK2 | 0.97 (0.53-1.78) | 1.23 (0.63-2.42) |
| PALB2 | 1.03 (0.63-1.67) | 1.32 (0.76-2.29) |
Abbreviation: OR, odds ratio.
Discussion
Our findings indicated similar rates of bilateral mastectomy across high- and moderate-penetrance genes. These results are consistent with findings from single-institution and state cancer registry studies that reported identification of P/LP variants in both high- and moderate-penetrance genes was associated with risk-reducing mastectomy.5,6 Although we included a large sample of participants with HBC P/LP variants and robust survey and medical records data, a limitation of our study is that the results may underestimate true deviation of care from practice guidelines, given that our study sample chose to participate in a registry study. It remains important to evaluate this information across diverse populations and health care settings. Similar rates of bilateral mastectomy across all 5 genes of varied penetrance are concerning, given that prophylactic contralateral mastectomy for risk reduction is considered only for high-penetrance genes, per national practice guidelines. These findings warrant further evaluation to explore possible overtreatment among patients with breast cancer who have ATM and CHEK2 P/LP variants.
References
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