Abstract
Purpose
Second primary cancer (SPC) risks after breast cancer (BC) in BRCA1/BRCA2 pathogenic variant (PV) carriers are uncertain. We estimated relative and absolute risks using a novel linkage of genetic testing data to population-scale National Disease Registration Service and Hospital Episode Statistics electronic health records.
Methods
We followed 25,811 females and 480 males diagnosed with BC and tested for germline BRCA1/BRCA2 PVs in NHS Clinical Genetics centers in England between 1995 and 2019 until SPC diagnosis, death, migration, contralateral breast/ovarian surgery plus 1 year, or the 31st of December 2020. We estimated standardized incidence ratios (SIRs) using English population incidences, hazard ratios (HRs) comparing carriers to noncarriers using Cox regression, and Kaplan-Meier 10-year cumulative risks.
Results
There were 1,840 BRCA1 and 1,750 BRCA2 female PV carriers. Compared with population incidences, BRCA1 carriers had elevated contralateral BC (CBC; SIR, 15.6 [95% CI, 11.8 to 20.2]), ovarian (SIR, 44.0 [95% CI, 31.4 to 59.9]), combined nonbreast/ovarian (SIR, 2.18 [95% CI, 1.59 to 2.92]), colorectal (SIR, 4.80 [95% CI, 2.62 to 8.05]), and endometrial (SIR, 2.92 [95% CI, 1.07 to 6.35]) SPC risks. BRCA2 carriers had elevated CBC (SIR, 7.70 [95% CI, 5.45 to 10.6]), ovarian (SIR, 16.8 [95% CI, 10.3 to 26.0]), pancreatic (SIR, 5.42 [95% CI, 2.09 to 12.5]), and combined nonbreast/ovarian (SIR, 1.68 [95% CI, 1.24 to 2.23]) SPC risks. Compared with females without BRCA1/BRCA2 PVs on testing, BRCA1 carriers had elevated CBC (HR, 3.60 [95% CI, 2.65 to 4.90]), ovarian (HR, 33.0 [95% CI, 19.1 to 57.1]), combined nonbreast/ovarian (HR, 1.45 [95% CI, 1.05 to 2.01]), and colorectal (HR, 2.93 [95% CI, 1.53 to 5.62]) SPC risks. BRCA2 carriers had elevated CBC (HR, 2.40 [95% CI, 1.70 to 3.40]), ovarian (HR, 12.0 [95% CI, 6.70 to 21.5]), and pancreatic (HR, 3.56 [95% CI, 1.34 to 9.48]) SPC risks. Ten-year cumulative CBC, ovarian, and combined nonbreast/ovarian cancer risks were 16%/6.3%/7.8% (BRCA1 carriers), 12%/3.0%/6.2% (BRCA2 carriers), and 3.6%/0.4%/4.9% (noncarriers). Male BRCA2 carriers had higher CBC (HR, 13.1 [95% CI, 1.19 to 146]) and prostate (HR, 5.61 [95% CI, 1.96 to 16.0]) SPC risks than noncarriers.
Conclusion
Survivors of BC carrying BRCA1 and BRCA2 PVs are at high SPC risk. They may benefit from enhanced surveillance and risk-reduction measures.
Introduction
BRCA1 and BRCA2 pathogenic variant (PV) prevalences in females diagnosed with breast cancer (BC) have been estimated as 1.1% and 1.5%, respectively.1 Survivors of BC found to carry BRCA1 and BRCA2 PVs are likely to increase in number because of the increasing frequency of genetic testing in oncology2 and good survival outcomes, with 15-year BC-specific survival rates estimated as around 81% in BRCA1 and 75% in BRCA2 PV carriers.3 Second primary cancer (SPC) risks for BRCA1 and BRCA2 PV carriers remain uncertain. Studies reporting nonbreast4–6 or contralateral BC (CBC) risks3,6–8 are limited in number and size. Precise estimates could inform cancer surveillance and risk-reduction options for survivors of BC carrying BRCA1/BRCA2 PVs. Although male BC is rare,9 BRCA2 PV prevalence among male BC patients is high (8.1%).10 To our knowledge, no study has estimated SPC risks after BC in male PV carriers.
We performed a novel linkage of the National Cancer Registration data set (NCRD),11 Hospital Episode Statistics Admitted Patient Care (HES APC)12 and outpatients (HES OP)13 data sets, and individual-level germline testing information from regional molecular genetics laboratories across England14 (henceforth germline testing data set). We describe these data sets in the Data Supplement (online only). We established a cohort of individuals diagnosed with BC and tested for BRCA1 or BRCA2 PVs through NHS Clinical Genetics centers in England. We estimated relative and absolute SPC risks at combined and specific sites for BRCA1/BRCA2 PV carriers after a BC diagnosis. We investigated how these risks varied by age at diagnosis, and estrogen receptor (ER) status, of the first BC.
Methods
Study Population
We constructed the retrospective cohort using data on all individuals diagnosed with invasive, nonmetastatic BC between January 1, 1995, and December 31, 2019, in England, linked to BRCA1/BRCA2 PV germline testing data submitted by 16 National Health Service (NHS) molecular genetic laboratories in England. Testing eligibility was based on established guidelines for the same period.15 Cohort eligibility was restricted to those with genetic testing information. Surgery data were extracted from the HES APC/OP data sets. Data on death, cancer diagnoses, sex, sociodemographic factors, treatments, and embarkation were drawn from the NCRD. Data on genes tested, pathogenic classes, test dates, coding DNA sequence changes and protein impact of variants, and genetic test free-text records were drawn from the germline testing data set. Pseudonymized patient data were linked using unique tumor and patient identifiers. Consent from patients was not required as these data are collected by NHS England under Section 254 of the Health and Social Care Act 2012. Ethical approval for the data analyses was granted to the CanGene-CanVar research program (REC:18/WS/0192).
Defining BRCA1 and BRCA2 PV Carrier Status
We divided the cohort into BRCA1 PV carriers, BRCA2 PV carriers, BRCA1/BRCA2 PV noncarriers, and those of other BRCA1/BRCA2 PV status (Data Supplement, Table S1). Survivors of BC were predominantly assigned other carrier status because of being untested for PVs in one of the genes or missing test results (Data Supplement). We do not present analyses for this group unless stated otherwise.
Statistical Analyses
Follow-up (FU) began at the latest of the BRCA1 PV test date, BRCA2 PV test date, and 365 days after the BC diagnosis, and continued until the next cancer diagnosis, death, migration, contralateral breast/ovarian surgery plus 1 year (Data Supplement, Table S2), or the 31st of December 2020. We did not consider cancers diagnosed from death certificates, ipsilateral BCs, CBCs diagnosed <93 days after the first BC, and nonmelanoma skin cancers as SPCs, so FU continued after these diagnoses when applicable. We defined cancer sites using the International Classification of Diseases-10 code groups employed by Cancer Research UK16 (Data Supplement, Table S3).
Comparison of SPC Risks for PV Carriers Relative to Population Risks
To compare cancer incidences in BRCA1/BRCA2 PV carriers after BC to population incidences, we estimated ratios of observed to expected SPCs (standardized incidence ratios [SIRs]) separately by BRCA1/BRCA2 PV carrier status for SPCs at the contralateral breast, ovary, all nonbreast/ovarian sites combined, and any other site where at least three cancers were observed in BRCA1 or BRCA2 PV carriers. The expected counts were calculated using age-, calendar year−, sex-, and site-specific incidence rates for the English population,17 who predominantly had no cancer history. We filtered cancers diagnosed from death certificates and nonmelanoma skin cancers from the expected counts. In females, we stratified SIRs by age at BC diagnosis (younger than 45 years/45 years or older) and first BC ER status (positive/negative), as both are associated with BRCA1/BRCA2 PV carrier status8,18 and SPC risks.19
Comparison of SPC Risks for BRCA1 and BRCA2 PV Carriers Relative to Noncarriers
SIRs estimate SPC risks in survivors of BC carrying BRCA1/BRCA2 PVs relative to the general population. Therefore, they reflect risk alterations conferred by the first BC, BRCA1/BRCA2 PVs, and genetic testing selection criteria such as cancer family history (FH).20 To compare SPC risks in survivors of BC carrying PVs with survivors of BC tested negative for PVs in both genes, we estimated hazard ratios (HRs) for SPCs at all sites with significantly elevated SIR estimates for BRCA1 or BRCA2 carriers, using Cox proportional hazards models. For females, we adjusted these models for age and calendar year at BC diagnosis and ER status of the first BC, where missing ER status data were imputed using multiple imputation by chained equations21 (Data Supplement). As a sensitivity analysis, we further adjusted these models for receipt of chemotherapy, radiotherapy, and hormonal therapy. As a separate sensitivity analysis, we included females untested for a PV in one gene and confirmed not to carry a PV in the other gene after predictive testing in the noncarrier group rather than the other carrier group. We performed these sensitivity analyses when estimating HRs for CBC, ovarian cancer (OC), and nonbreast/ovarian cancer, but not for other SPCs because of low event counts. For males, we included only PV carrier status (BRCA2 PV carrier or BRCA1 and BRCA2 PV noncarrier) in the models because of low sample sizes. To assess whether the effect of a BRCA1 PV on CBC risk was modified by age at first BC diagnosis in females, we fit a Cox model including an interaction term between continuous age at first BC diagnosis and PV carrier status (separately for BRCA1 and BRCA2) and compared this to the corresponding original model by performing likelihood ratio tests in each imputed data set and comparing the pooled test statistic to an F-distribution.21 We tested whether the effect of BRCA1 or BRCA2 PVs on CBC, OC, and combined nonbreast/ovarian cancer risks were modified by age at first BC diagnosis, year at first BC diagnosis, and first BC ER status in females analogously. We assessed the proportional hazards assumption by inspecting transformed survival functions (Data Supplement, Figs S9-S11).
Incidence Rates and Cumulative Risks
In females, we estimated 10-year cumulative CBC, OC, and combined nonbreast/ovarian SPC risks using Kaplan-Meier techniques. We estimated incidences per 10,000 person-years for these cancers between 0-5 years and 5-10 years of FU. We also estimated the corresponding incidences during a 5-year FU period, stratified by year at first BC diagnosis (before 2013/2013 or after). All analyses were stratified by carrier status.
We conducted all analyses in R version 4.3.1 22 (packages in the Data Supplement).
Results
Unless stated otherwise, results refer to females.
Cohort Description
The cohort included 1,840 BRCA1 PV carriers, 1,750 BRCA2 PV carriers, and 21,543 noncarriers (Fig 1). Median age at first BC diagnosis was 39 years (IQR, 14 years) in BRCA1 carriers, 45 years (IQR, 14 years) in BRCA2 PV carriers, and 46 years (IQR, 15 years) in noncarriers. Corresponding median FU lengths were 3.5 years (IQR, 4.4 years), 3.8 years (IQR, 4.3 years), and 3.5 years (IQR, 3.8 years). CBC was the commonest cancer in all groups (BRCA1 PV carriers: 66 events, BRCA2 PV carriers: 43 events, noncarriers: 237 events). The cohort was primarily of White ethnicity (BRCA1 PV carriers: 82%, BRCA2 PV carriers: 90%, noncarriers: 87%). Among those with available ER status data, 71% of BRCA1 PV carriers, 26% of BRCA2 PV carriers, and 38% of noncarriers had ER-negative first BC. The majority of the cohort received chemotherapy (BRCA1 PV carriers: 81%, BRCA2 PV carriers: 68%, noncarriers: 64%) and radiotherapy (BRCA1 PV carriers: 52%, BRCA2 PV carriers: 55%, noncarriers: 66%) and did not receive hormonal therapy (BRCA1 PV carriers: 86%, BRCA2 PV carriers: 70%, noncarriers: 74%) by 1 year after BC diagnosis. By the end of FU, most BRCA1/BRCA2 PV carriers had received contralateral breast surgery (BRCA1 PV carriers: 64%, BRCA2 PV carriers: 61%, noncarriers: 22%) and bilateral ovarian surgery (BRCA1 PV carriers: 55%, BRCA2 PV carriers: 62%, noncarriers: 10%). Further descriptives are in Table 1 and the Data Supplement (Tables S4 and S12 and Figs S1-S4).
FIG 1.
Cohort assembly. aThe other BRCA1/BRCA2 PV carrier status is defined in the Data Supplement (Table S1). BC, breast cancer; FU, follow-up; PV, pathogenic variant. respectively. Further descriptives are in the Data Supplement (Tables S5 and S6 and S13 and Figs S5-S8).
Table 1. Cohort Description—Age at BC Diagnosis, Years of FU, First BC Diagnosis Dates, Genetic Test Dates, Sociodemographic Factors, and SPC Counts in Females.
| BRCA1 PV Carriers | BRCA2 PV Carriers | BRCA1/BRCA2 PV Noncarriers | ||||
|---|---|---|---|---|---|---|
| Median age at BC dx: 39 years (IQR, 14 years) | Median age at BC dx: 45 years (IQR, 14 years) | Median age at BC dx: 46 years (IQR, 15 years) | ||||
| Median FU contributed: 3.5 years (IQR, 4.4 years) | Median FU contributed: 3.8 years (IQR, 4.3 years) | Median FU contributed: 3.5 years (IQR, 3.8 years) | ||||
| Variable | Entire Cohort, No. (%) | With SPC, No. (%) | Entire Cohort, No. (%) | With SPC, No. (%) | Entire Cohort, No. (%) | With SPC, No. (%) |
| Age at first BC dx | ||||||
| Under 45 years | 1,237 (67.2) | 84 (53.2) | 859 (49.1) | 30 (26.5) | 9,616 (44.6) | 245 (33.1) |
| 45 years or over | 603 (32.8) | 74 (46.8) | 891 (50.9) | 83 (73.5) | 11,927 (55.4) | 496 (66.9) |
| FU contributed | ||||||
| Under 5 years | 1,188 (64.6) | 118 (74.7) | 1,101 (62.9) | 84 (74.3) | 14,750 (68.5) | 551 (74.4) |
| 5 years or over | 652 (35.4) | 40 (25.3) | 649 (37.1) | 29 (25.7) | 6,793 (31.5) | 190 (25.6) |
| Year of first BC dx | ||||||
| 1995-1999 | 99 (5.4) | 18 (11.4) | 116 (6.6) | 21 (18.6) | 1,142 (5.3) | 104 (14.0) |
| 2000-2004 | 141 (7.7) | 33 (20.9) | 154 (8.8) | 22 (19.5) | 1,324 (6.1) | 111 (15.0) |
| 2005-2009 | 152 (8.3) | 26 (16.5) | 166 (9.5) | 17 (15.0) | 1,680 (7.8) | 106 (14.3) |
| 2010-2014 | 590 (32.1) | 51 (32.3) | 536 (30.6) | 34 (30.1) | 6,308 (29.3) | 246 (33.2) |
| 2015-2019 | 858 (46.6) | 30 (19.0) | 778 (44.5) | 19 (16.8) | 11,089 (51.5) | 174 (23.5) |
| Year of BRCA1 PV test | ||||||
| 1995-1999 | 11 (0.6) | 1 (0.6) | 2(0.1) | 0 | 4 (<0.1) | 0 |
| 2000-2004 | 50 (2.7) | 9 (5.7) | 13 (0.7) | 6 (5.3) | 113 (0.5) | 27 (3.6) |
| 2005-2009 | 142 (7.7) | 25 (15.8) | 79 (4.5) | 7 (6.2) | 956 (4.4) | 113 (15.2) |
| 2010-2014 | 561 (30.5) | 54 (34.2) | 349 (19.9) | 31 (27.4) | 5,219 (24.2) | 286 (38.6) |
| 2015-2019 | 1,076 (58.5) | 69 (43.7) | 740 (42.3) | 24 (21.2) | 15,251 (70.8) | 315 (42.5) |
| Untested | 0 | 0 | 567 (32.4) | 45 (39.8) | 0 | 0 |
| Year of BRCA2 PV test | ||||||
| 1995-1999 | 0 | 0 | 10 (0.6) | 3 (2.7) | 5 (<0.1) | 0 |
| 2000-2004 | 17 (0.9) | 1 (0.6) | 48 (2.7) | 9 (8.0) | 113 (0.5) | 27 (3.6) |
| 2005-2009 | 63 (3.4) | 11 (7.0) | 152 (8.7) | 16 (14.2) | 958 (4.4) | 113 (15.2) |
| 2010-2014 | 384 (20.9) | 38 (24.1) | 532 (30.4) | 46 (40.7) | 5,209 (24.2) | 286 (38.6) |
| 2015-2019 | 851 (46.2) | 58 (36.7) | 1,008 (57.6) | 39 (34.5) | 15,258 (70.8) | 315 (42.5) |
| Untested | 525 (28.5) | 50 (31.6) | 0 | 0 | 0 | 0 |
| IMD quintilea | ||||||
| 1 (most deprived) | 353 (19.2) | 23 (14.6) | 268 (15.3) | 24 (21.2) | 2,900 (13.5) | 126 (17.0) |
| 2 | 338 (18.4) | 30 (19.0) | 329 (18.8) | 20 (17.7) | 3,735 (17.3) | 120 (16.2) |
| 3 | 349 (19.0) | 30 (19.0) | 342 (19.5) | 20 (17.7) | 4,437 (20.6) | 163 (22.0) |
| 4 | 397 (21.6) | 38 (24.1) | 393 (22.5) | 22 (19.5) | 5,030 (23.3) | 171 (23.1) |
| 5 (least deprived) | 403 (21.9) | 37 (23.4) | 418 (23.9) | 27 (23.9) | 5,441 (25.3) | 161 (21.7) |
| Ethnicity | ||||||
| White | 1,504 (81.7) | 138 (87.3) | 1,571 (89.8) | 109 (96.5) | 18,712 (86.9) | 690 (93.1) |
| Black | 62 (3.4) | 3(1.9) | 28 (1.6) | 1 (0.9) | 546 (2.5) | 15 (2.0) |
| Chinese | 7 (0.4) | 1 (0.6) | 8 (0.5) | 0 | 73 (0.3) | 0 |
| Asian | 117 (6.4) | 9 (5.7) | 42 (2.4) | 2(1.8) | 763 (3.5) | 17 (2.3) |
| Mixed | 24 (1.3) | 3 (1.9) | 6 (0.3) | 0 | 222 (1.0) | 6 (0.8) |
| Other | 53 (2.9) | 3 (1.9) | 35 (2.0) | 0 | 387 (1.8) | 9(1.2) |
| Data missing | 73 (4.0) | 1 (0.6) | 60 (3.4) | 1 (0.9) | 840 (3.9) | 4 (0.5) |
| With SPCsb | ||||||
| Contralateral breast | 66 (3.6) | 43 (2.5) | 287 (1.3) | |||
| Ovary | 47 (2.6) | 22 (1.3) | 30 (0.1) | |||
| Colorectum | 14 (0.8) | 6 (0.3) | 63 (0.3) | |||
| Lung | 6 (0.3) | 8 (0.5) | 85 (0.4) | |||
| Endometrium | 6 (0.3) | 4 (0.2) | 49 (0.2) | |||
| Pancreas | 2(0.1) | 6 (0.3) | 19 (<0.1) | |||
| Skin (melanoma) | 2(0.1) | 5 (0.3) | 44 (0.2) | |||
| Head and neck | 1 (<0.1) | 3 (0.2) | 14 (<0.1) | |||
| Totals | 1,840 (100.0) | 158 (100.0) | 1,750 (100.0) | 113 (100.0) | 21,543 (100.0) | 741 (100.0) |
Abbreviations: BC, breast cancer; dx, diagnosis; FU, follow-up; IMD, indices of multiple deprivation; PV, pathogenic variant; SPC, second primary cancer.
Quintile refers to the entire UK population, not to the study cohort.
We also observed two liver, esophagus, and non-Hodgkin lymphoma cancers, one kidney, leukemia, and thyroid cancer, and five other cancers in BRCA1 carriers. In addition, we observed two esophagus cancers and myelomas, one non-Hodgkin lymphoma and kidney, liver, and thyroid cancer, and eight other cancers in BRCA2 carriers.
Among males, there were seven BRCA1 PV carriers, 74 BRCA2 PV carriers, and 394 noncarriers. They had 0, 15, and 23 SPCs, respectively. Further descriptives are in the Data Supplement (Tables S5 and S6 and S13 and Figs S5-S8).
Comparison of SPC Risks for PV Carriers Relative to Population Risks
Compared with population-level incidences, PV carriers were at elevated CBC (BRCA1: SIR, 15.6 [95% CI, 11.8 to 20.2]; BRCA2: SIR, 7.70 [95% CI, 5.45 to 10.6]) and OC (BRCA1: SIR, 44.0 [95% CI, 31.4 to 59.9]; BRCA2: SIR, 16.8 [95% CI, 10.3 to 26.0]) risks. The magnitudes of both increases were higher in BRCA1 than BRCA2 PV carriers (Table 2). BRCA1/BRCA2 PV carriers had elevated combined nonbreast/ovarian cancer SIRs (BRCA1: SIR, 2.18 [95% CI, 1.59 to 2.92]; BRCA2: SIR, 1.68 [95% CI, 1.24 to 2.23]). Colorectal (SIR, 4.80 [95% CI, 2.62 to 8.05]) and endometrial (SIR, 2.92 [95% CI, 1.07 to 6.35]) cancer SIRs were increased in BRCA1 PV carriers. The pancreatic cancer SIR was elevated in BRCA2 PV carriers (SIR, 5.72 [95% CI, 2.09 to 12.5]).
Table 2. SIRs for Second Primary Risks in Females.
| SPC Site | BRCA1 PV Carriers | BRCA2 PV Carriers | BRCA1/BRCA2 PV Noncarriers | |||||
|---|---|---|---|---|---|---|---|---|
| SIR (95% CI) | Observed SPCs, No. |
SIR (95% CI) | Observed SPCs, No. |
SIR (95% CI) | Observed SPCs, No. |
|||
| Entire cohort | ||||||||
| Contralateralbreast | 15.6 (11.8 to 20.2) | 57 | 7.70 (5.45 to 10.6) | 38 | 3.03 (2.67 to 3.43) | 257 | ||
| Ovary | 44.0 (31.4 to 59.9) | 40 | 16.8 (10.3 to 26.0) | 20 | 1.22 (0.82 to 1.74) | 30 | ||
| Nonbreast/ovarian | 2.18 (1.59 to 2.92) | 45 | 1.68 (1.24 to 2.23) | 48 | 1.26 (1.14 to 1.38) | 424 | ||
| Colorectum | 4.80 (2.62 to 8.05) | 14 | 1.40 (0.51 to 3.05) | 6 | 1.23 (0.95 to 1.58) | 63 | ||
| Lung | 1.98 (0.72 to 4.30) | 6 | 1.62 (0.70 to 3.20) | 8 | 1.42 (1.13 to 1.75) | 85 | ||
| Endometrium | 2.92 (1.07 to 6.35) | 6 | 1.36 (0.37 to 3.48) | 4 | 1.43 (1.06 to 1.89) | 49 | ||
| Pancreas | 3.03 (0.34 to 10.9) | 2 | 5.72 (2.09 to 12.5) | 6 | 1.48 (0.89 to 2.31) | 19 | ||
| Skin (melanoma) | 0.92 (0.10 to 3.31) | 2 | 1.97 (0.63 to 4.59) | 5 | 1.52 (1.11 to 2.04) | 44 | ||
| Head and neck | 1.15 (0.02 to 6.38) | 1 | 2.57 (0.52 to 7.52) | 3 | 0.96 (0.51 to 1.65) | 13 | ||
| Younger than 45 years at first BC diagnosis | ||||||||
| Contralateral breast | 23.5 (16.6 to 32.3) | 38 | 9.58 (5.10 to 16.4) | 13 | 4.50 (3.70 to 5.41) | 111 | ||
| Ovary | 37.4 (20.9 to 61.7) | 15 | . | 0 | 1.15 (0.46 to 2.36) | 7 | ||
| Nonbreast/ovarian | 2.46 (1.52 to 3.76) | 21 | 1.75 (0.93 to 2.99) | 13 | 1.68 (1.39 to 2.01) | 117 | ||
| Colorectum | 6.63 (2.66 to 13.7) | 7 | 0 | 2.13 (1.28 to 3.33) | 19 | |||
| Lung | 2.62 (0.29 to 9.46) | 2 | 0 | 2.47 (1.44 to 3.95) | 17 | |||
| Endometrium | 5.59 (1.50 to 14.3) | 4 | 4.35 (0.88 to 12.7) | 3 | 2.39 (1.34 to 3.95) | 15 | ||
| Pancreas | 0 | 11.0 (1.23 to 39.7) | 2 | . | 0 | |||
| Skin (melanoma) | 0 | 1.96 (0.22 to 7.08) | 2 | 1.45 (0.79 to 2.44) | 14 | |||
| Head and neck | 0 | 5.89 (0.66 to 21.3) | 2 | 1.28 (0.34 to 3.28) | 4 | |||
| Age 45 years or older at first BC diagnosis | ||||||||
| Contralateralbreast | 9.31 (5.60 to 14.5) | 19 | 6.99 (4.52 to 10.3) | 25 | 2.43 (2.05 to 2.86) | 146 | ||
| Ovary | 49.1 (31.8 to 72.5) | 25 | 23.7 (14.5 to 36.6) | 20 | 1.24 (0.79 to 1.86) | 23 | ||
| Nonbreast/ovarian | 1.99 (1.27 to 2.96) | 24 | 1.66 (1.15 to 2.30) | 35 | 1.15 (1.02 to 1.28) | 307 | ||
| Colorectum | 3.76 (1.51 to 7.75) | 7 | 1.80 (0.66 to 3.93) | 6 | 1.04 (0.76 to 1.40) | 44 | ||
| Lung | 1.76 (0.47 to 4.51) | 4 | 1.92 (0.83 to 3.78) | 8 | 1.28 (0.99 to 1.62) | 68 | ||
| Endometrium | 1.49 (0.17 to 5.39) | 2 | 0.44 (0.01 to 2.47) | 1 | 1.22 (0.84 to 1.70) | 34 | ||
| Pancreas | 4.25 (0.48 to 15.3) | 2 | 4.61 (1.24 to 11.8) | 4 | 1.71 (1.03 to 2.66) | 19 | ||
| Skin (melanoma) | 2.14 (0.24 to 7.72) | 2 | 1.97 (0.40 to 5.75) | 3 | 1.56 (1.05 to 2.22) | 30 | ||
| Head and neck | 2.00 (0.03 to 11.1) | 1 | 1.21 (0.02 to 6.73) | 1 | 0.87 (0.40 to 1.65) | 9 | ||
| ER-positive first BC | ||||||||
| Contralateral breast | 9.24 (2.98 to 21.6) | 5 | 4.76 (2.05 to 9.38) | 8 | 2.75 (2.19 to 3.40) | 84 | ||
| Ovary | 100 (51.7 to 175) | 12 | 20.1 (8.67 to 39.7) | 8 | 1.19 (0.60 to 2.14) | 11 | ||
| Nonbreast/ovarian | 1.28 (0.35 to 3.29) | 4 | 1.63 (0.95 to 2.61) | 17 | 1.26 (1.07 to 1.48) | 158 | ||
| Colorectum | 4.60 (0.52 to 16.6) | 2 | 1.96 (0.39 to 5.72) | 3 | 1.07 (0.65 to 1.65) | 20 | ||
| Lung | 0 | 1.78 (0.36 to 5.20) | 3 | 1.24 (0.82 to 1.81) | 27 | |||
| Endometrium | 0 | . | 0 | 1.34 (0.78 to 2.14) | 17 | |||
| Pancreas | 0 | 8.16 (1.64 to 23.9) | 3 | 2.15 (1.03 to 2.95) | 10 | |||
| Skin (melanoma) | 0 | 4.02 (1.08 to 10.3) | 4 | 2.07 (1.31 to 3.11) | 23 | |||
| Head and neck | 7.54 (0.10 to 42.0) | 1 | 2.30 (0.03 to 12.8) | 1 | 1.18 (0.43 to 2.57) | 6 | ||
| ER-negative first BC | ||||||||
| Contralateralbreast | 21.3 (13.6 to 31.7) | 24 | 5.93 (1.19 to 17.3) | 3 | 3.66 (2.74 to 4.79) | 53 | ||
| Ovary | 37.2 (18.5 to 66.5) | 11 | 15.0 (1.69 to 54.3) | 2 | 1.30 (0.42 to 3.04) | 5 | ||
| Nonbreast/ovarian | 1.76 (0.88 to 3.16) | 11 | 1.47 (0.40 to 3.77) | 4 | 1.21 (0.91 to 1.57) | 56 | ||
| Colorectum | 5.89 (1.90 to 13.7) | 5 | 2.55 (0.03 to 14.2) | 1 | 1.34 (0.61 to 2.55) | 9 | ||
| Lung | 3.81 (0.77 to 11.1) | 3 | 0 | 2.40 (1.40 to 3.85) | 17 | |||
| Endometrium | 0 | 0 | 0.43 (0.05 to 1.54) | 2 | ||||
| Pancreas | 0 | 0 | 1.28 (0.14 to 4.62) | 2 | ||||
| Skin (melanoma) | 2.70 (0.30 to 9.73) | 2 | 3.62 (0.05 to 20.1) | 1 | 0.84 (0.23 to 2.15) | 4 | ||
| Head and neck | 0 | 8.19 (0.11 to 45.5) | 1 | 1.00 (0.11 to 3.62) | 2 | |||
Abbreviations: BC, breast cancer; ER, estrogen receptor; PV, pathogenic variant; SIR, standardized incidence ratio; SPC, second primary cancer.
The CBC SIR was higher in BRCA1 PV carriers first diagnosed with BC at under age 45 years than at 45 years or over (under age 45 years: SIR, 23.5 [95% CI, 16.6 to 32.3]; 45 years or over: SIR, 9.31 [95% CI, 5.60 to 14.5]). There was no clear difference in CBC SIRs by age at first BC diagnosis in BRCA2 PV carriers, although SIRs were elevated in both groups (under age 45 years: SIR, 9.58 [95% CI, 5.10 to 16.4]; 45 years or over: SIR, 6.99 [95% CI, 4.52 to 10.3]). There were no clear differences by age at first BC diagnosis in SPC SIRs at other sites in BRCA1/BRCA2 PV carriers.
Noncarriers had elevated CBC and nonbreast/ovarian cancer SIRs, which were lower than the corresponding BRCA1-or BRCA2-specific SIRs (CBC: SIR, 3.03 [95% CI, 2.67 to 3.43]; nonbreast/ovarian: SIR, 1.26 [95% CI, 1.14 to 1.38]). The CBC SIR was more elevated in those diagnosed with BC at under age 45 years (under age 45 years: SIR, 4.50 [95% CI, 3.70 to 5.41]; 45 years or over: SIR, 2.43 [95% CI, 2.05 to 2.86]).
There was a modest increased endometrial cancer SIR in noncarriers (SIR, 1.43 [95% CI, 1.06 to 1.89]), and no significant evidence for increased ovarian, colorectal, or pancreatic cancer SIRs. There was some evidence for a nonbreast/ovarian cancer risk difference by age at first BC diagnosis in noncarriers (under 45 years: SIR, 1.68 [95% CI, 1.39 to 2.01]; 45 years or over: SIR, 1.15 [95% CI, 1.02 to 1.28]), which we did not observe for BRCA1/BRCA2 PV carriers.
We observed no clear SPC SIR differences by first BC ER status at any site, in any carrier group.
Male BRCA2 PV carriers had elevated CBC (SIR, 431 [95% CI, 48.5 to 1,559]), pancreatic (SIR, 20.2 [95% CI, 4.07 to 59.1]), and prostate (SIR, 4.46 [95% CI, 1.79 to 9.19]) cancer SIRs. No SIRs were significantly elevated in noncarriers (Data Supplement, Table S7).
Comparison of SPC Risks Between PV Carriers and Noncarriers
BRCA1 PV carriers were at increased CBC (HR, 3.60 [95% CI, 2.65 to 4.90]), OC (HR, 33.0 [95% CI, 19.1 to 57.1]), colorectal (HR, 2.93 [95% CI, 1.53 to 5.62]), and nonbreast/ovarian (HR, 1.45 [95% CI, 1.05 to 2.01]) cancer risks compared with noncarriers (Table 3). BRCA2 PV carriers were at increased CBC (HR, 2.40 [95% CI, 1.70 to 3.40]), ovarian (HR, 12.0 [95% CI, 6.70 to 21.5]), and pancreatic (HR, 3.56 [95% CI, 1.34 to 9.48]) cancer risks. There was no significant evidence for interactions between age at diagnosis, year at diagnosis, or ER status of the first BC with BRCA1 or BRCA2 PV carrier status when evaluating associations with CBC, OC, or non-breast/ovarian cancer risks. CBC, OC, and nonbreast/ovarian cancer HRs remained similar after adjusting for chemotherapy, radiotherapy, and hormonal therapy (Data Supplement, Table S9), and after including females that tested negative for a PV in one gene after predictive testing, and were untested for PVs in the other gene, in the BRCA1/BRCA2 PV noncarrier group (Data Supplement, Table S10).
Table 3. Associations Between BRCA1/BRCA2 PV Carrier Status and SPC Risks, Adjusted for Age and Calendar Year at First BC Diagnosis, and Estrogen Receptor Status of First BC Diagnosis.
| Cancer Site and BRCA1/2 PV Carrier Status | Females, No. | Person-Years | Events, No. | HR (95% CI) |
|---|---|---|---|---|
| Contralateral breast SPCs | ||||
| Noncarriers | 20,035 | 70,434 | 257 | 1.00 (reference category) |
| BRCA1 PV carriers | 1,713 | 3,737 | 57 | 3.60 (2.65 to 4.90) |
| BRCA2 PV carriers | 1,587 | 4,015 | 38 | 2.40 (1.70 to 3.40) |
| Ovarian SPCs | ||||
| Noncarriers | 20,764 | 79,470 | 30 | 1.00 (reference category) |
| BRCA1 PV carriers | 1,730 | 4,325 | 40 | 33.0 (19.1 to 57.1) |
| BRCA2 PV carriers | 1,601 | 4,169 | 20 | 12.0 (6.70 to 21.5) |
| Nonbreast/ovarian SPCs | ||||
| Noncarriers | 21,543 | 87,814 | 424 | 1.00 (reference category) |
| BRCA1 PV carriers | 1,840 | 7,971 | 45 | 1.45 (1.05 to 2.01) |
| BRCA2 PV carriers | 1,750 | 8,016 | 48 | 1.24 (0.92 to 1.68) |
| ColorectalSPCs | ||||
| Noncarriers | 21,543 | 87,814 | 63 | 1.00 (reference category) |
| BRCA1 PV carriers | 1,840 | 7,971 | 14 | 2.93 (1.53 to 5.62) |
| BRCA2 PV carriers | 1,750 | 8,016 | 6 | 1.06 (0.45 to 2.49) |
| EndometrialSPCs | ||||
| Noncarriers | 21,543 | 87,814 | 49 | 1.00 (reference category) |
| BRCA1 PV carriers | 1,840 | 7,971 | 6 | 1.87 (0.73 to 4.74) |
| BRCA2 PV carriers | 1,750 | 8,016 | 4 | 0.86 (0.30 to 2.44) |
| Pancreatic SPCs | ||||
| Noncarriers | 21,543 | 87,814 | 19 | 1.00 (reference category) |
| BRCA1 PV carriers | 1,840 | 7,971 | 2 | 1.84 (0.36 to 9.32) |
| BRCA2 PV carriers | 1,750 | 8,016 | 6 | 3.56 (1.34 to 9.48) |
Abbreviations: BC, breast cancer; HR, hazard ratio; PV, pathogenic variant; SPC, second primary cancer.
Male BRCA2 PV carriers had higher CBC and prostate SPC risks than BRCA1/BRCA2 PV noncarriers (CBC: HR, 13.1 [95% CI, 1.19 to 146]; prostate: HR, 5.61 [95% CI, 1.96 to 16.0]; Data Supplement, Table S8).
Incidence Rates and Cumulative Risks
The 10-year cumulative CBC risks were 16% (95% CI, 8.7 to 22) in BRCA1 PV carriers, 12% (95% CI, 6.5 to 18) in BRCA2 PV carriers, and 3.6% (95% CI, 2.9 to 4.2) in noncarriers. The corresponding OC and combined nonbreast/ovarian SPC risks were 6.3% (95% CI, 2.8 to 9.7), 3.0% (95% CI, 1.3 to 4.6), and 0.4% (95% CI, 0.1 to 0.6), and 7.8% (95% CI, 4.6 to 11), 6.2% (95% CI, 3.6 to 8.7), and 4.9% (95% CI, 4.2 to 5.6). Ten-year cumulative risk (CR) and incidence estimates are presented in Table 4, with 10-year Kaplan-Meier curves provided in Figure 2.
Table 4. Incidence Rates, 10-Year CRs, and Associated Statistics for SPC Risks.
| FU Time Elapsed | Total Person-Years | BC Survivors, No. | O, No. | Inc (95% CI) | CR (95% CI) |
|---|---|---|---|---|---|
| Contralateral breast SPCs in BRCA1 PV carriers | |||||
| <5 years | 3,095 | 1,713 | 44 | 142 (105 to 189) | 5.6 (3.6 to 7.5) |
| 5-10 years | 485 | 208 | 11 | 227 (120 to 393) | 16 (8.7 to 22) |
| Contralateral breast SPCs in BRCA2 PV carriers | |||||
| <5 years | 3,249 | 1,587 | 26 | 80.0 (53.5 to 115) | 3.2 (1.8 to 4.7) |
| 5-10 years | 558 | 221 | 11 | 197 (105 to 341) | 12 (6.5 to 18) |
| Contralateral breast SPCs in BRCA1/BRCA2 PV noncarriers | |||||
| <5 years | 57,283 | 20,035 | 202 | 35.3 (30.6 to 40.4) | 1.7 (1.5 to 2.0) |
| 5-10 years | 11,256 | 5,170 | 47 | 41.8 (31.1 to 55.0) | 3.6 (2.9 to 4.2) |
| Ovarian SPCs in BRCA1 PV carriers | |||||
| <5 years | 3,708 | 1,730 | 38 | 102 (73.6 to 139) | 4.1 (2.6 to 5.7) |
| 5-10 years | 443 | 211 | 2 | 45.1 (8.99 to 145) | 6.3 (2.8 to 9.7) |
| Ovarian SPCs in BRCA2 PV carriers | |||||
| <5 years | 3,487 | 1,601 | 19 | 54.5 (33.9 to 83.3) | 2.5 (1.1 to 3.9) |
| 5-10 years | 529 | 205 | 1 | 18.9 (1.72 to 88.2) | 3.0 (1.3 to 4.6) |
| Ovarian SPCs in BRCA1/BRCA2 PV noncarriers | |||||
| <5 years | 65,116 | 20,764 | 24 | 3.69 (2.42 to 5.39) | 0.2 (0.1 to 0.2) |
| 5-10 years | 12,515 | 5,899 | 5 | 4.03 (1.53 to 8.83) | 0.4 (0.1 to 0.6) |
| Nonbreast/ovarian SPCs in BRCA1 PV carriers | |||||
| <5 years | 5,944 | 1,840 | 26 | 43.7 (29.2 to 63.1) | 2.1 (1.3 to 3.0) |
| 5-10 years | 1,540 | 652 | 16 | 104 (61.8 to 165) | 7.8 (4.6 to 11) |
| Nonbreast/ovarian SPCs in BRCA2 PV carriers | |||||
| <5 years | 5,983 | 1,750 | 34 | 56.8 (40.0 to 78.4) | 2.8 (1.8 to 3.8) |
| 5-10 years | 1,586 | 649 | 9 | 56.7 (28.0 to 104) | 6.2 (3.6 to 8.7) |
| Nonbreast/ovarian SPCs in BRCA1/BRCA2 PV noncarriers | |||||
| <5 years | 70,649 | 21,543 | 300 | 42.5 (37.9 to 47.5) | 2.2 (1.9 to 2.5) |
| 5-10 years | 14,753 | 6,793 | 93 | 63.0 (51.2 to 76.9) | 4.9 (4.2 to 5.6) |
Abbreviations: BC, breast cancer; CR, cumulative risk; FU, follow-up; Inc, incidence per 10,000 person-years; O, second primaries observed; PV, pathogenic variant; SPC, second primary cancer.
FIG 2.
Ten-year cumulative second primary cancer risk curves, stratified by BRCA1 and BRCA2 PV carrier status: (A) CBC, (B) OC, and (C) nonbreast/ovarian cancer. CBC, contralateral breast cancer; CR, cumulative risk; FU, follow-up; OC, ovarian cancer; PV, pathogenic variant.
Within each carrier group, the incidence estimates during a 5-year period for CBC, OC, and nonbreast/ovarian cancer were somewhat higher for those diagnosed with their first BC before 2013 than those diagnosed in 2013 or later (Data Supplement, Table S11).
Discussion
To our knowledge, this study is one of the first to examine nonbreast cancer risks4–6 and one of the largest to examine CBC risks3,7,8 after BC in female BRCA1/BRCA2 PV carriers. It is also the first, to our knowledge, to investigate associations between germline pathogenic variation and SPC risks after male BC. To our knowledge, it is the first study based on a linkage of germline testing laboratory data to population-scale electronic health records (EHRs), minimizing selection biases common in recruitment-based cohort studies.23 It is based on very high-quality registry data.11–14 This work offers proof of principle that linkages of genetic testing laboratory data to population-scale EHRs allow estimation of understudied cancer risks in novel cohorts.
In females, we found elevated CBC, ovarian, and nonbreast/ovarian SPC risks in BRCA1/BRCA2 PV carriers, colorectal and endometrial SPC risks in BRCA1 PV carriers, and pancreatic SPC risks in BRCA2 PV carriers, relative to the general English population, as measured by the SIRs. These increased SIRs cannot be fully attributed to BRCA1/BRCA2 PVs as some of the increase will reflect the effect of cancer risk factors associated with having survived a first BC, such as common genetic variation24,25 and nongenetic factors such as treatment effects.19,26 The ascertainment process will also partly explain the elevated SIRs, as those tested for BRCA1/BRCA2 PVs are typically highly selected on the basis of criteria such as cancer FH.20 Nevertheless, the BRCA1/BRCA2 SIR estimates were much higher than the corresponding SIRs for noncarriers, and the HR estimates comparing carriers and noncarriers were elevated at most sites with increased SIR estimates. Since the carrier and noncarrier groups in the HR estimations were ascertained in similar fashions and composed of survivors of BC, the effects of the ascertainment process and BC-associated SPC risk factors will likely be attenuated when comparing carriers with noncarriers. This suggests that much of the excess SPC risks are attributable to BRCA1/BRCA2 PVs. However, the HR estimates may be biased if cancer FH differs between carriers and noncarriers in this cohort. Unfortunately, cancer FH data were unavailable. Notably, the female CBC HR estimates for both BRCA1 and BRCA2 PV carriers were consistent with two recent cohort studies.3,7
We found higher CBC SIRs for female BRCA1 PV carriers younger than 45 years at first BC diagnosis compared with those diagnosed when older. This is consistent with population-level observations19 and could be explained by the higher proportion of ER-negative BC18,19 or more extensive BC FH26,27 in BRCA1 PV carriers younger at BC diagnosis. We found no other notable SIR differences by age at first BC diagnosis in BRCA1/BRCA2 PV carriers.
The 10-year cumulative CBC, OC, and nonbreast/ovarian cancer risk estimates are applicable to carriers and tested noncarriers ascertained through clinical genetics centers, and the CBC risk estimates for BRCA1/BRCA2 PV carriers were broadly consistent with a large previous study with similar ascertainment criteria.8 However, they would overestimate the risks in BRCA1/BRCA2 PV carriers unselected for cancer FH, emphasizing the importance of integrating FH in the counseling and risk estimation process.20
The male BRCA2 PV carrier CBC SIR was greater than the corresponding HR, indicating that FH may partly account for the elevated risk, consistent with previous research.28 The prostate cancer SIR was consistent with previous research,29 and similar to the corresponding HR.
The SIR, HR, and CR estimates in BRCA1/BRCA2 PV carriers may be inflated by surveillance bias, as cancer surveillance may be heightened after a positive BRCA1/BRCA2 PV test.20 The SIR estimates may be additionally prone to such bias owing to heightened surveillance in survivors of BC relative to the general population.20 In addition, the low nonbreast/ovarian/prostate SPC counts may mean some analyses were underpowered, particularly in males. Furthermore, the median FU of under 4 years and median age of 46 years at first BC diagnosis may have precluded the identification of associations with later-or older-onset cancers. Finally, since the criteria for a genetic testing referral changed in 2013,30 the influence of FH on the estimates may differ between those tested for BRCA1/2 PVs before 2013 and in 2013 or later. Analyses were adjusted for first BC diagnosis year when estimating HRs and SIRs. However, the absolute incidence estimates were somewhat higher for those diagnosed before 2013 than those diagnosed in 2013 or later. This may also reflect improvements in clinical management over time (Data Supplement Table S11).
The elevated CBC/OC cancer risks, together with previous results,3,5,7,8 suggest that females found to carry BRCA1/BRCA2 PVs may wish to consider risk-reducing options such as contralateral mastectomy and risk-reducing bilateral salpingo-oophorectomy after BC. These recommendations are consistent with results from previous studies.31,32
We also found increased CBC and prostate cancer risks in male BRCA2 PV carriers and elevated colorectal and pancreatic cancer risks in female BRCA1 and BRCA2 PV carriers. Although these results were based on low SPC counts, previous findings of elevated first primary risks at the breast and prostate in male BRCA2 PV carriers, colorectal cancer in female BRCA1 PV carriers, and pancreatic cancer in female BRCA2 PV carriers33 suggest these associations may be true.
In conclusion, we estimated combined and site-specific relative and absolute SPC risks in BRCA1/2 PV carriers after BC. We investigated risk variability by age at diagnosis and ER status of the first BC in females. This study demonstrates the value of population-scale EHR linkages, and that survivors of BC carrying BRCA1/BRCA2 PVs are at elevated cancer risks.
Supplementary Material
Context.
Key Objective
Second primary cancer (SPC) risks after breast cancer (BC) in BRCA1/BRCA2 pathogenic variant (PV) carriers are unclear. This study investigates associations between BRCA1/BRCA2 PVs and SPCs in a novel, population-scale linkage of electronic health records from the National Health Service England and genetic testing data from clinical laboratories across England.
Knowledge Generated
Elevated risks were found for SPCs at the contralateral breast/ovary in female BRCA1/BRCA2 PV carriers, colorectum in female BRCA1 PV carriers, pancreas in female BRCA2 PV carriers, and contralateral breast/prostate in male BRCA2 PV carriers. Risks were particularly elevated in females younger at first BC diagnosis.
Relevance (K.D. Miller)
Patients found to have PV in BRCA1/BRCA2 face difficult decisions including considering prophylactic surgery and enhanced screening. The more detailed information on second cancer risks provided by this analysis facilitates crucial shared decision making.*
*Relevance section written by JCO Senior Deputy Editor Kathy D. Miller, MD.
Support
Supported by the CRUK Catalyst Award CanGene-CanVar (C61296/A27223) and the Cancer Research UK grant PPRPGM-Nov20\100002, and was supported by core funding from the NIHR Cambridge Biomedical Research Centre (NIHR203312). C.H. is supported by a Wellcome Trust Clinical Research Training Fellowship (Ref 203924/Z/16/Z).
Footnotes
Prior Presentation
Presented at the Festival of Genomics and Biodata, London, England, January 24-25, 2024; the Cancer Research UK Future Leaders City of London Annual Symposium, London, England, January 29-30, 2024; the Cancer Research UK Data-Driven Conference, Manchester, England, February 27-28, 2024; and the American Association of Cancer Research Annual Meeting, San Diego, CA, April 5-10, 2024.
Authors’ Disclosures of Potential Conflicts of Interest
Disclosures provided by the authors are available with this article at DOI https://doi.org/10.1200/JCO.24.01146.
Author Contributions
Conception and design: Isaac Allen, Eva Morris, Clare Turnbull, Marc Tischkowitz, Paul Pharoah, Antonis C. Antoniou
Financial support: Clare Turnbull, Marc Tischkowitz, Antonis C. Antoniou
Administrative support: Bethany Torr, Marc Tischkowitz Provision of study materials or patients: Marc Tischkowitz Collection and assembly of data: Lucy Loong, Tameera Rahman, Sophie Allen, Alice Garrett, Bethany Torr, Andrew Bacon, Sophie Jose, Sally Vernon, Joanna Pethick, Francesco Santaniello, Shilpi Goel, Katrina Lavelle, Fiona McRonald, Eva Morris, Steven Hardy
Data analysis and interpretation: Isaac Allen, Hend Hassan, Yvonne Walburga, Catherine Huntley, Andrew Bacon, Craig Knott, Ying-Wen Wang, Fiona McRonald, Diana Eccles, Eva Morris, Paul Pharoah, Antonis C. Antoniou, Margreet Lüchtenborg
Manuscript writing: All authors
Final approval of manuscript: All authors
Accountable for all aspects of the work: All authors
Authors’ Disclosures of Potential Conflicts of Interest
Second Primary Cancer Risks After Breast Cancer in BRCA1 and BRCA2 Pathogenic Variant Carriers
The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I 5 Immediate Family Member, Inst 5 My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/authors/author-center.
Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments).
Tameera Rahman
Employment: Health Data Insight
Travel, Accommodations, Expenses: Health Data Insight
Bethany Torr Employment: Novartis
Stock and Other Ownership Interests: Novartis
Diana Eccles
Employment: University Hospitals Southampton NHS Foundation Trust
Research Funding: AstraZeneca
Clare Turnbull
Consulting or Advisory Role: Roche
Speakers’ Bureau: AstraZeneca
Paul Pharoah
Patents, Royalties, Other Intellectual Property: The PREDICT breast cancer prognostic model is licensed to OncoAssist by the University of Cambridge. I receive a share of the fees
Expert Testimony: Shook, Hardy, BCON
Antonis C. Antoniou
Patents, Royalties, Other Intellectual Property: Listed as creator of the BOADICEA model, which has been licensed by Cambridge Enterprise for commercial purposes
No other potential conflicts of interest were reported.
Data Sharing Statement
A data sharing statement provided by the authors is available with this article at DOI https://doi.org/10.1200/JCO.24.01146.
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Data Availability Statement
A data sharing statement provided by the authors is available with this article at DOI https://doi.org/10.1200/JCO.24.01146.