Impact of Age at Primary Breast Cancer on Contralateral Breast Cancer Risk in BRCA1/2 Mutation Carriers
Open accessAbstract
Purpose: To determine prospectively overall and age-specific estimates of contralateral breast cancer (CBC) risk for young patients with breast cancer with or without BRCA1/2 mutations. Patients and Methods: A cohort of 6,294 patients with invasive breast cancer diagnosed under 50 years of age and treated between 1970 and 2003 in 10 Dutch centers was tested for the most prevalent BRCA1/2 mutations. We report absolute risks and hazard ratios within the cohort from competing risk analyses. Results: After a median follow-up of 12.5 years, 578 CBCs were observed in our study population. CBC risk for BRCA1 and BRCA2 mutation carriers was two to three times higher than for noncarriers (hazard ratios, 3.31 [95% CI, 2.41 to 4.55; P < .001] and 2.17 [95% CI,1.22 to 3.85; P = .01], respectively). Ten-year cumulative CBC risks were 21.1% (95% CI, 15.4 to 27.4) for BRCA1, 10.8% (95% CI, 4.7 to 19.6) for BRCA2 mutation carriers and 5.1% (95% CI, 4.5 to 5.7) for noncarriers. Age at diagnosis of the first breast cancer was a significant predictor of CBC risk in BRCA1/2 mutation carriers only; those diagnosed before age 41 years had a 10-year cumulative CBC risk of 23.9% (BRCA1: 25.5%; BRCA2: 17.2%) compared with 12.6% (BRCA1: 15.6%; BRCA2: 7.2%) for those 41 to 49 years of age (P = .02); our review of published studies showed ranges of 24% to 31% before age 40 years (BRCA1: 24% to 32%; BRCA2:17% to 29%) and 8% to 21% after 40 years (BRCA1: 11% to 52%; BRCA2: 7% to 18%), respectively. Conclusion: Age at first breast cancer is a strong risk factor for cumulative CBC risk in BRCA1/2 mutation carriers. Considering the available evidence, age-specific risk estimates should be included in counseling.
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- Findingown data§ Results
After a median follow-up of 12.5 years, 578 contralateral breast cancers were observed in the study population.
“After a median follow-up of 12.5 years, 578 CBCs were observed in our study population.”
- Also stated in: § CBC Risk in Comparison With the Breast Cancer Incidence of the Dutch Female Population Younger Than Age 50 Years · plain
“After a median follow-up of 12.5 years, 578 CBCs were observed in our study population, resulting in a significantly increased SIR of 3.01 (95% CI, 2.77 to 3.27) compared with breast cancer rates in the general Dutch female population.”
Quote in the paperSubstantial claim - Also stated in: § CBC Risk in Comparison With the Breast Cancer Incidence of the Dutch Female Population Younger Than Age 50 Years · plain
- Findingown data
A positive family history of breast cancer was associated with a marginally significant increased contralateral breast cancer risk in BRCA1/2 mutation carriers (HR 2.11; 95% CI 0.98-4.55; P = .06).
“A positive family history of breast cancer was associated with an increased CBC risk in noncarriers (HR, 1.65; 95% CI, 1.25 to 2.18; P = .001)and with a marginally significant risk increase in BRCA1/2 mutation carriers (HR, 2.11; 95% CI, 0.98 to 4.55; P = .06;Table 2).”
Quote in the paperNot a substantial claim - Findingown data
The highest contralateral breast cancer risk was in BRCA1/2 mutation carriers diagnosed before age 41 with a positive family history, with a 10-year cumulative risk of 38.1% (95% CI 23.5-52.6).
“The highest risk of CBC was found in BRCA1/2 mutation carriers who were diagnosed with a first breast cancer before age 41 years and who had a positive family history of breast cancer at that time, with a 10-year cumulative CBC risk of 38.1% (95% CI, 23.5 to 52.6; Data Supplement; Table 2).”
Quote in the paperSubstantial claim - Findingown data
BRCA2 mutation carriers diagnosed before age 41 had a 10-year cumulative contralateral breast cancer risk of 17.2% (95% CI 5.4-34.7).
“For BRCA1 and BRCA2 mutation carriers separately, the 10-year cumulative CBC risks for those diagnosed before age 41 years were 25.5% (95% CI, 17.4 to 34.4) and 17.2% (95% CI, 5.4 to 34.7), respectively, and for those 41 to 49 years old, 15.6% (95% CI, 8.5 to 24.5) and 7.2% (95% CI, 1.9 to 17.5), respectively.”
Quote in the paperSubstantial claim - Findingcitation
The systematic review included 21 published studies that reported 10-year cumulative contralateral breast cancer risk estimates for BRCA1 and/or BRCA2 mutation carriers.
“In short: 21 published studies reported 10-year cumulative CBC risk estimates for BRCA1 and/or BRCA2 mutation carriers.”
Quote in the paperNot a substantial claim
- Findingown data
There was statistically significant effect modification by BRCA1/2 carrier status for the age effect on contralateral breast cancer risk (P interaction = .05).
“This age effect was not seen in noncarriers (Fig 1A; HR, 1.06; 95% CI, 0.89 to 1.28; P = .50),and there was a statistically significant effect modification when comparing BRCA1/2 carriers with noncarriers (P interaction = .05;Table 2).”
Quote in the paperSubstantial claim - Findingown data
BRCA1 mutation carriers had a higher contralateral breast cancer risk than noncarriers, with an age-adjusted hazard ratio of 3.31 (95% CI 2.41-4.55; P < .001).
“Carriers of a BRCA1 or a BRCA2 mutation were at a significantly increased CBC risk compared with noncarriers, with age-adjusted HRs of 3.31 (95% CI, 2.41 to 4.55; P ,.001) and 2.17 (95% CI, 1.22 to 3.85; P = .01),respectively (Data Supplement).”
Quote in the paperSubstantial claim - Findingown data
BRCA1/2 mutation carriers diagnosed at ages 40-49 had a 10-year cumulative contralateral breast cancer risk of 12.6% (95% CI 7.4-19.3).
“The 10-year cumulative risk of CBC for BRCA1/ 2 mutation carriers diagnosed with a first breast cancer before age 41 years was 23.9% (95% CI, 16.7 to 31.8) compared with 12.6% (95% CI, 7.4 to 19.3) for those 40 to 49 years old at diagnosis (Fig 1B; HR, 1.89; 95% CI,1.09 to 3.29; P = .02).”
Quote in the paperSubstantial claim - Findingown data
A positive family history of breast cancer was associated with increased contralateral breast cancer risk in noncarriers (HR 1.65; 95% CI 1.25-2.18; P = .001).
“A positive family history of breast cancer was associated with an increased CBC risk in noncarriers (HR, 1.65; 95% CI, 1.25 to 2.18; P = .001)and with a marginally significant risk increase in BRCA1/2 mutation carriers (HR, 2.11; 95% CI, 0.98 to 4.55; P = .06;Table 2).”
Quote in the paperNot a substantial claim - Findingown data
In BRCA1 mutation carriers alone, the age effect on contralateral breast cancer risk was not statistically significant (HR 1.77; 95% CI 0.93-3.38; P = .08).
“mutation carriers alone also showed the effect of age, but it was not statistically significant (P interaction = .14;age at diagnosis , 41 years v age at diagnosis 41 to 49 years; HR BRCA1 , 1.77; 95% CI, 0.93 to 3.38; P = .08;Data Supplement).”
Quote in the paperNot a substantial claim - Findingown data
The hazard ratio for contralateral breast cancer comparing BRCA1/2 carriers diagnosed before age 41 with those diagnosed at 40-49 was 1.89 (95% CI 1.09-3.29; P = .02).
“The 10-year cumulative risk of CBC for BRCA1/ 2 mutation carriers diagnosed with a first breast cancer before age 41 years was 23.9% (95% CI, 16.7 to 31.8) compared with 12.6% (95% CI, 7.4 to 19.3) for those 40 to 49 years old at diagnosis (Fig 1B; HR, 1.89; 95% CI,1.09 to 3.29; P = .02).”
Quote in the paperSubstantial claim - Findingown data
BRCA1 mutation carriers aged 41-49 had a 10-year cumulative contralateral breast cancer risk of 15.6% (95% CI 8.5-24.5).
“For BRCA1 and BRCA2 mutation carriers separately, the 10-year cumulative CBC risks for those diagnosed before age 41 years were 25.5% (95% CI, 17.4 to 34.4) and 17.2% (95% CI, 5.4 to 34.7), respectively, and for those 41 to 49 years old, 15.6% (95% CI, 8.5 to 24.5) and 7.2% (95% CI, 1.9 to 17.5), respectively.”
Quote in the paperSubstantial claim - Findingown data
In this study, with unselected mutation carriers and accounting for competing risks, the 10-year contralateral breast cancer risk for BRCA1/2 mutation carriers was 18%.
“In our own study with unselected mutation carriers and accounting for competing risks, we found a 10-year CBC risk for BRCA1/2 mutation carriers of 18%.”
Quote in the paperSubstantial claim - Findingown data
In BRCA1/2 mutation carriers, adjuvant systemic therapy was associated with a non-significant suggestion of decreased contralateral breast cancer risk (HR 0.65; 95% CI 0.37-1.17; P = .15).
“Adjuvant systemic therapy (any type) given for the first breast cancer decreased the risk of CBC in noncarriers.In BRCA1/2 mutation carriers, there was also a suggestion of a decreased risk, but the effect was not statistically significant (systemic therapy v no systemic therapy: HR noncarriers , 0.74; 95% CI, 0.61 to 0.91; P ,.001; HR BRCA1/2 , 0.65; 95% CI, 0.37 to 1.17; P = .15;Table 2).”
Quote in the paperNot a substantial claim - Findingown data
The 10-year cumulative contralateral breast cancer risk was 5.1% (95% CI 4.5-5.7) for noncarriers.
“The 10-year cumulative CBC risk was 5.1% (95% CI, 4.5 to 5.7) for noncarriers, 21.1% (95% CI, 15.4 to 27.4) for BRCA1 mutation carriers, and 10.8% (95% CI, 4.7 to 19.6) for BRCA2 mutation carriers (Fig 1A; Data Supplement).”
Quote in the paperSubstantial claim - Findingown data
Adjuvant systemic therapy for the first breast cancer decreased contralateral breast cancer risk in noncarriers (HR 0.74; 95% CI 0.61-0.91; P < .001).
“Adjuvant systemic therapy (any type) given for the first breast cancer decreased the risk of CBC in noncarriers.In BRCA1/2 mutation carriers, there was also a suggestion of a decreased risk, but the effect was not statistically significant (systemic therapy v no systemic therapy: HR noncarriers , 0.74; 95% CI, 0.61 to 0.91; P ,.001; HR BRCA1/2 , 0.65; 95% CI, 0.37 to 1.17; P = .15;Table 2).”
Quote in the paperNot a substantial claim - Findingown data
The 10-year contralateral breast cancer risk for BRCA1/2 mutation carriers with a family history of breast cancer was 25%.
“which was similar to the 10-year CBC risk observed in our study for mutation carriers with a family history of breast cancer (25%; Table 2).”
Quote in the paperNot a substantial claim - Findingown data
The overall standardized incidence ratio for contralateral breast cancer in the study population compared with the general Dutch female population was 3.01 (95% CI 2.77-3.27).
“After a median follow-up of 12.5 years, 578 CBCs were observed in our study population, resulting in a significantly increased SIR of 3.01 (95% CI, 2.77 to 3.27) compared with breast cancer rates in the general Dutch female population.”
Quote in the paperSubstantial claim - Findingown data
BRCA1 mutation carriers diagnosed before age 41 had a 10-year cumulative contralateral breast cancer risk of 25.5% (95% CI 17.4-34.4).
“For BRCA1 and BRCA2 mutation carriers separately, the 10-year cumulative CBC risks for those diagnosed before age 41 years were 25.5% (95% CI, 17.4 to 34.4) and 17.2% (95% CI, 5.4 to 34.7), respectively, and for those 41 to 49 years old, 15.6% (95% CI, 8.5 to 24.5) and 7.2% (95% CI, 1.9 to 17.5), respectively.”
Quote in the paperSubstantial claim - Findingown data
The 10-year cumulative contralateral breast cancer risk was 10.8% (95% CI 4.7-19.6) for BRCA2 mutation carriers.
“The 10-year cumulative CBC risk was 5.1% (95% CI, 4.5 to 5.7) for noncarriers, 21.1% (95% CI, 15.4 to 27.4) for BRCA1 mutation carriers, and 10.8% (95% CI, 4.7 to 19.6) for BRCA2 mutation carriers (Fig 1A; Data Supplement).”
Quote in the paperSubstantial claim - Findingown data
The age effect on contralateral breast cancer risk was not observed in noncarriers (HR 1.06; 95% CI 0.89-1.28; P = .50).
“This age effect was not seen in noncarriers (Fig 1A; HR, 1.06; 95% CI, 0.89 to 1.28; P = .50),and there was a statistically significant effect modification when comparing BRCA1/2 carriers with noncarriers (P interaction = .05;Table 2).”
Quote in the paperSubstantial claim - Findingown data
BRCA1/2 mutation carriers diagnosed before age 41 had a 10-year cumulative contralateral breast cancer risk of 23.9% (95% CI 16.7-31.8).
“The 10-year cumulative risk of CBC for BRCA1/ 2 mutation carriers diagnosed with a first breast cancer before age 41 years was 23.9% (95% CI, 16.7 to 31.8) compared with 12.6% (95% CI, 7.4 to 19.3) for those 40 to 49 years old at diagnosis (Fig 1B; HR, 1.89; 95% CI,1.09 to 3.29; P = .02).”
Quote in the paperSubstantial claim - Findingown data
Of all patients, 4.3% carried a BRCA1 (n = 200) and/or BRCA2 (n = 71) mutation.
“Of all patients, 4.3% were identified as carrying a BRCA1 (n = 200) and/ or a BRCA2 (n = 71) mutation.”
Quote in the paperNot a substantial claim - Findingown data
BRCA2 mutation carriers had a higher contralateral breast cancer risk than noncarriers, with an age-adjusted hazard ratio of 2.17 (95% CI 1.22-3.85; P = .01).
“Carriers of a BRCA1 or a BRCA2 mutation were at a significantly increased CBC risk compared with noncarriers, with age-adjusted HRs of 3.31 (95% CI, 2.41 to 4.55; P ,.001) and 2.17 (95% CI, 1.22 to 3.85; P = .01),respectively (Data Supplement).”
Quote in the paperSubstantial claim - Findingown data
The 10-year cumulative contralateral breast cancer risk was 21.1% (95% CI 15.4-27.4) for BRCA1 mutation carriers.
“The 10-year cumulative CBC risk was 5.1% (95% CI, 4.5 to 5.7) for noncarriers, 21.1% (95% CI, 15.4 to 27.4) for BRCA1 mutation carriers, and 10.8% (95% CI, 4.7 to 19.6) for BRCA2 mutation carriers (Fig 1A; Data Supplement).”
Quote in the paperSubstantial claim - Findingown data
BRCA2 mutation carriers aged 41-49 had a 10-year cumulative contralateral breast cancer risk of 7.2% (95% CI 1.9-17.5).
“For BRCA1 and BRCA2 mutation carriers separately, the 10-year cumulative CBC risks for those diagnosed before age 41 years were 25.5% (95% CI, 17.4 to 34.4) and 17.2% (95% CI, 5.4 to 34.7), respectively, and for those 41 to 49 years old, 15.6% (95% CI, 8.5 to 24.5) and 7.2% (95% CI, 1.9 to 17.5), respectively.”
Quote in the paperSubstantial claim - Findingcitation
Five previous studies reported 10-year contralateral breast cancer risks for subgroups based on age at first breast cancer diagnosis.
“Five previous studies 13,19,21,27,36 reported 10-year CBC risks for subgroups based on age at first breast cancer diagnosis (Fig 2B).”
Quote in the paperNot a substantial claim - Findingown data
In this study, the highest contralateral breast cancer risk was found in BRCA1/2 mutation carriers diagnosed at a young age who also had a family history of breast cancer, with a 10-year cumulative risk of 38.1% (95% CI, 23.5 to 52.6).
“In our study, we found the highest CBC risk in BRCA1/2 mutation carriers diagnosed at young ages who also had a family history of breast cancer (10-year cumulative CBC risk of 38.1% [95% CI, 23.5 to 52.6]).”
Quote in the paperSubstantial claim - Study design and conductreasoning
Because not all known BRCA1/2 mutations were tested, some mutation carriers may have been misclassified as noncarriers.
“Because we were unable to test for all known BRCA1/2 mutations, some BRCA1/2 mutation carriers may have been misclassified as noncarriers.”
Quote in the paperNot a substantial claim - Interpretationown data
The study's contralateral breast cancer risk estimates are at the lower end of previously published ranges.
“Again, our risk estimates are at the lower end of the range of previously published risk estimates.”
Quote in the paperNot a substantial claim - Study design and conductown data
Including time-dependent interactions with oophorectomy, other second primaries, local recurrence, regional recurrence, and adjustment for treatment did not substantially alter the results.
“Including time-dependent interactions with oophorectomy, other second primaries of breast (ipsilateral) or ovaries, local recurrence, regional recurrence, and adjustment for treatment given for the first breast cancer did not substantially alter the results (Data Supplement).”
Quote in the paperNot a substantial claim - Interpretationown data
The overall 10-year contralateral breast cancer risk for unselected BRCA1/2 mutation carriers is around 18%.
“In conclusion, the overall 10-year CBC risk for unselected BRCA1/2 mutation carriers will be around 18%, whereas for”
Quote in the paperSubstantial claim - Study design and conductown data
The number of BRCA2 mutation carriers in the cohort was too small to draw firm conclusions about the effect of age in BRCA2 mutation carriers.
“Unfortunately, we could not draw firm conclusions about the effect of age in BRCA2 mutation carriers because the number of BRCA2 mutation carriers in our cohort was too small.”
Quote in the paperSubstantial claim - Study design and conductown data
Adjustment for time interactions with oophorectomy, other second primaries, local recurrence, regional recurrence, and treatment did not alter the carrier-versus-noncarrier hazard ratio results.
“Adjustment for time interactions with oophorectomy, other second primaries of breast (ipsilateral) or ovaries, local recurrence, regional recurrence, and adjustment for treatment given for the first breast cancer did not alter these results (Data Supplement).”
Quote in the paperNot a substantial claim - Interpretationown data
Age at first breast cancer is a strong risk factor for cumulative contralateral breast cancer risk in BRCA1/2 mutation carriers.
“ConclusionAge at first breast cancer is a strong risk factor for cumulative CBC risk in BRCA1/2 mutation carriers.”
Quote in the paperSubstantial claim - Interpretationnone given
This cohort study is the first large study unselected for family history that reports unbiased contralateral breast cancer risk estimates for BRCA1 and BRCA2 mutation carriers separately in comparison with noncarriers.
“To our knowledge, this cohort study is the first large study unselected for family history that reports unbiased CBC risk estimates for BRCA1 and BRCA2 mutation carriers separately in comparison with noncarriers.”
Quote in the paperSubstantial claim - Study design and conductnone given
The study was unable to test for all known BRCA1/2 mutations.
“Because we were unable to test for all known BRCA1/2 mutations, some BRCA1/2 mutation carriers may have been misclassified as noncarriers.”
Quote in the paperNot a substantial claim - Interpretationown data
Age at diagnosis of the first breast cancer is an important predictor of contralateral breast cancer risk in BRCA1/2 mutation carriers.
“Furthermore, based on our study and those published previously, age at primary breast cancer diagnosis is an important predictor of the CBC risk in BRCA1/2 mutation carriers”
Quote in the paperSubstantial claim- Rests on an assumption: The risk estimates from this study and previously published studies are comparable and can be combined to describe a range of contralateral breast cancer risks.
- Interpretationreasoning
The finding of the highest contralateral breast cancer risk in young BRCA1/2 mutation carriers with a family history is consistent with previously published risk estimates, which were based mainly on BRCA1/2 carriers recruited through clinical genetic centers.
“This is in concordance with previously published risk estimates, which were based mainly on BRCA1/2 carriers recruited through CGCs, ie, those with a substantial family history.”
Quote in the paperNot a substantial claim - Study design and conductown data
Missing data on systemic therapy and family history in a large proportion of women made the numbers in subanalyses small.
“Because of missing data regarding systemic therapy and family history in a large proportion of women (Data Supplement), the numbers in these subanalyses are small.”
Quote in the paperSubstantial claim
- May combine two claims. 23
- Classified as probably not a substantial claim. 9
- The quote only partly states this claim. 2
May combine two claims.
FindingcitationAcross published studies, the reported 10-year contralateral breast cancer risks ranged from 16.6% to 40% for BRCA1/2, 20.4% to 42% for BRCA1, and 10.1% to 30% for BRCA2 mutation carriers.
“the range of reported 10-year CBC risks was 16.6% to 40% for BRCA1/2, 20.4% to 42% for BRCA1, and 10.1% to 30% for BRCA2 mutation carriers, with our results at the lower end of the ranges.”
Quote in the paperNot a substantial claimMay combine two claims.
FindingcitationFor BRCA1/2 mutation carriers combined, previously reported 10-year cumulative contralateral breast cancer risks ranged from 23.7% to 30.7% for diagnosis before age 40 and from 8.4% to 21% for diagnosis after age 40.
“For BRCA1/2 mutation carriers combined, the range of 10-year cumulative CBC risks reported was 23.7% to 30.7% (BRCA1: 24% to 32%; BRCA2: 17% to 29%) for mutation carriers diagnosed with a first breast cancer before age 40 years, and 8.4% to 21% (BRCA1: 11% to 52%; BRCA2: 7% to 18%) for those older than age 40 years.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataIncluding age as a linear factor showed similar results, with per-year hazard ratios of 1.00 for noncarriers and 0.97 for BRCA1/2 carriers (P interaction = .20).
“Including age as a linear factor showed similar results (per year increase: HR, 1.00; 95% CI, 0.98 to 1.01; P = .54and HR, 0.97; 95% CI, 0.93 to 1.01; P = .10for noncarriers and BRCA1/2, respectively; P interaction = .20).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataAge at first breast cancer diagnosis was a significant predictor of contralateral breast cancer risk in BRCA1/2 mutation carriers but not in noncarriers.
“Age at diagnosis of the first breast cancer was a significant predictor of CBC risk in BRCA1/2 mutation carriers only; those diagnosed before age 41 years had a 10-year cumulative CBC risk of 23.9% (BRCA1: 25.5%; BRCA2: 17.2%) compared with 12.6% (BRCA1: 15.6%; BRCA2: 7.2%) for those 41 to 49 years of age (P = .02)”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataStandardized incidence ratios for contralateral breast cancer were highest among younger patients and during the first 5 years of follow-up for both BRCA1/2 mutation carriers and noncarriers.
“Both for BRCA1/2 mutation carriers and noncarriers, SIRs were highest for younger patients and in the first 5 years of follow-up.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataIn this study, the proportion of patients with contralateral breast cancer was 8.7% among noncarriers, 22.5% among BRCA1 mutation carriers, and 16.9% among BRCA2 mutation carriers.
“Event of interest: CBC | 521 | 8.7 | 45 | 22.5 | , .001 | 16.9 | .01 |”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataThe data suggest that BRCA1 and BRCA2 are different entities regarding contralateral breast cancer risk, with different standardized incidence ratios over time and higher cumulative risk for BRCA1 than BRCA2.
“However, the data of our study suggest that BRCA1 and BRCA2 are also different entities regarding the CBC risk (different SIRs for the time periods and higher cumulative CBC risk for BRCA1 over BRCA2).”
Quote in the paperSubstantial claimMay combine two claims.
Study design and conductcitationOnly a few patients received hormonal treatment, so the effect of hormonal therapy could not be studied separately.
“However, only a few patients received hormonal treatment: in the time period of this study, only postmenopausal women with estrogen receptor-positive disease were considered for adjuvant hormonal therapy in the Netherlands.53 Therefore, we were unable to study the effect of hormonal therapy separately.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [53] Rutgers EJ, 2002, Ned Tijdschr Geneeskd
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims. The quote only partly states this claim.
InterpretationreasoningThe variation in reported contralateral breast cancer risk estimates is large, reflecting heterogeneity of breast cancer in different groups and methodologic aspects.
“The variation in all reported risk estimates is large, which reflects the heterogeneity of breast cancer in the different groups (and thus the differential effect of various factors, such as treatment),”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationOnly three studies accounted for competing risks in their analyses, which is important to prevent risk overestimation.
“Furthermore, only three studies accounted for competing risks in their analyses, which is important to prevent risk overestimation.51”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [51] source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
InterpretationreasoningAssuming equal penetrance of untested rare mutations, the misclassification may have led to a slight underestimation of contralateral breast cancer risks.
“Assuming these rare mutations are of equal penetrance, this may have led to a slight underestimation of the CBC risks (M.K. Schmidt, personal communication, March 2015).”
Quote in the paperNot a substantial claim- The authors state this as an assumption: The untested rare BRCA1/2 mutations have penetrance equal to that of the tested mutations.
May combine two claims.
InterpretationreasoningAlmost all published studies suffered from potential selection and testing bias, including selected high-risk BRCA1/2 mutation carriers, and may therefore have overestimated contralateral breast cancer risk.
“Almost all published studies suffered from potential selection and testing bias, including”
Quote in the paperSubstantial claimMay combine two claims.
InterpretationcitationFour studies including selected patients and accounting for competing risks reported higher 10-year contralateral breast cancer risk estimates (21%-27%), similar to the risk observed in this study for mutation carriers with a family history of breast cancer (25%).
“Four studies including”
Quote in the paperNot a substantial claim0 of 4 sources checkedMay combine two claims.
Interpretationown dataAdjustment for treatment and other follow-up events did not alter the results, indicating that the age effect on contralateral breast cancer risk cannot be explained by differential treatment effects in younger and older patients.
“Adjustment for treatment given for the first breast cancer and other events during follow-up (eg, locoregional recurrences) did not alter these results, indicating that these effects cannot be explained by a differential treatment effect in younger and older patients.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown dataAdjustment for estrogen receptor status of the first breast cancer did not alter the results.
“In addition, adjustment for the estrogen receptor status of the first breast cancer did not alter the results (data not shown).”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationown dataFamily history is a predictor of contralateral breast cancer risk in both noncarriers and BRCA1/2 mutation carriers.
“We observed that family history is a predictor of CBC risk in both noncarriers and mutation carriers, which is in line with previous literature.19,21”
Quote in the paperNot a substantial claim0 of 2 sources checkedMay combine two claims.
InterpretationcitationThe 10-year contralateral breast cancer risk estimates for BRCA1/2 mutation carriers in this study are of the same magnitude as previously published estimates (13%-42%), with BRCA2 carriers tending to be in the lower part of the range.
“The 10-year CBC risk estimates for BRCA1/2 mutation carriers found in this study are of the same magnitude as those published previously, ie,13% to 42%, with BRCA2 mutation carriers tending to be in the lower part of this range.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
Study design and conductown dataAbsolute overall and subgroup risk estimates were derived using cumulative incidence curves accounting for competing risks.
“Absolute overall and subgroup risk estimates for BRCA1/2 mutation carriers and noncarriers were derived using cumulative incidence curves accounting for competing risks.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown dataBRCA1/2 mutation analysis tested for 92 variants representing approximately 64% of BRCA1/2 mutations prevalent in families in the Netherlands.
“BRCA1/2 mutation analysis included testing for 92 variants representing approximately 64% of the BRCA1/2 mutations prevalent in families in the Netherlands, using Allelic discrimination or Fragment length analyses; Sanger sequencing was used for confirmation of mutations”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductcitationFamily history data were gathered from clinical charts and may be of lower quality, although sufficient correlation with Clinical Genetic Center data was previously shown.
“Furthermore, the family history data we used were gathered from the clinical charts, and may therefore be of lower quality, even though previously we showed sufficient correlation with data from the Clinical Genetic Center.48”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [48] source
Not checked in the free run.
May combine two claims.
Interpretationown dataFor BRCA1/2 mutation carriers diagnosed with a first breast cancer before age 40, the 10-year cumulative contralateral breast cancer risk ranges from 23.7% to 30.7% (BRCA1: 24% to 32%; BRCA2: 17% to 29%).
“with a range of 10-year cumulative CBC risks of 23.7% to 30.7% for mutation carriers diagnosed with the first breast cancer before age 40 years (BRCA1: 24% to 32%; BRCA2: 17% to 29%)”
Quote in the paperSubstantial claim- Rests on an assumption: The risk estimates from this study and previously published studies are comparable and can be combined to describe a range of contralateral breast cancer risks.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductcitationA large proportion of patients were diagnosed before 1995, so many BRCA1/2 mutation carriers were unaware of their mutation status at diagnosis.
“Importantly, because a large proportion of patients were diagnosed before 1995, many BRCA1/2 mutation carriers were unaware of their mutation status at diagnosis.42,48”
Quote in the paperNot a substantial claim0 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductown dataPatients without germline DNA were from earlier diagnosis years but had an age distribution similar to patients with sufficient germline DNA.
“Patients without germline DNA were from earlier years of breast cancer diagnosis, but had an age distribution similar to patients with germline DNA of sufficient quality.”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationown dataFor BRCA1/2 mutation carriers diagnosed with a first breast cancer after age 40, the 10-year cumulative contralateral breast cancer risk ranges from 8.4% to 21% (BRCA1: 11% to 52%; BRCA2: 7% to 18%).
“and 8.4% to 21% for those diagnosed after age 40 years (BRCA1: 11% to 52%; BRCA2: 7% to 18%; Fig 3).”
Quote in the paperSubstantial claim- Rests on an assumption: The risk estimates from this study and previously published studies are comparable and can be combined to describe a range of contralateral breast cancer risks.
May combine two claims. The quote only partly states this claim.
Interpretationown dataAmong mutation carriers selected through clinical genetic centers, the 10-year cumulative contralateral breast cancer risk is somewhat higher, approximately 21% to 27%, with BRCA2 carriers at the lower end and BRCA1 carriers at the higher end.
“selected”
Quote in the paperNot a substantial claim- Rests on an assumption: The risk estimates from this study and previously published studies are comparable and can be combined to describe a range of contralateral breast cancer risks.
May combine two claims.
Study design and conductown dataAlthough the cohort was large, it included a relatively small number of BRCA1/2 mutation carriers, especially BRCA2 mutation carriers.
“Although the cohort in this study is large, a relatively small number of BRCA1/2 mutation carriers were included, especially accounting for BRCA2 mutation carriers.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductown dataThe analyses corrected for prophylactic measures, although the effect on contralateral breast cancer prevention was not an endpoint in the article.
“In the analyses we corrected for prophylactic measures, although the effect on CBC prevention 49,50 was not an end point in this article.”
Quote in the paperNot a substantial claim0 of 2 sources checked
The authors state this as an assumption.
The untested rare BRCA1/2 mutations have penetrance equal to that of the tested mutations.
“Assuming these rare mutations are of equal penetrance, this may have led to a slight underestimation of the CBC risks (M.K. Schmidt, personal communication, March 2015).”
The paper relies on this without support.
Genetic testing for BRCA1/2 mutations is being performed increasingly.
“Because genetic testing is performed increasingly, it is important to be able to provide precise and unbiased risk estimates of CBC for a patient with BRCA1/2-associated breast cancer.”
The paper relies on this without support.
The risk estimates from this study and previously published studies are comparable and can be combined to describe a range of contralateral breast cancer risks.
“Furthermore, based on our study and those published previously, age at primary breast cancer diagnosis is an important predictor of the CBC risk in BRCA1/2 mutation carriers, with a range of 10-year cumulative CBC risks”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
BRCA1 mutation carriers have an actual greater cancer risk than BRCA2 mutation carriers.
“BRCA1 mutation carriers have an actual greater cancer risk than BRCA2 mutation carriers [33, 56].”
From Fear of cancer recurrence in breast cancer survivors carrying a BRCA1 or 2 genetic mutation : a cross-sectional study (2024) · cites this paper as [33]
The Discussion reports a higher 10-year contralateral breast cancer risk for BRCA1 than BRCA2 mutation carriers in this cohort (21.1% versus 10.8%). The claim says “cancer risk” generally, but the study concerns contralateral breast cancer after a first breast cancer diagnosis in patients diagnosed before age 50; it does not establish a higher overall cancer risk. (LLM, conf=0.86)
Experimental — accuracy not yet measuredThe risk of recurrence is higher in carriers of the BRCA1 than BRCA2 gene mutation.
“Since the risk of recurrence is higher in carriers of the BRCA1 than BRCA2 gene mutation [33]”
From Fear of cancer recurrence in breast cancer survivors carrying a BRCA1 or 2 genetic mutation : a cross-sectional study (2024) · cites this paper as [33]
The Discussion reports a higher 10-year risk of contralateral breast cancer in BRCA1 carriers (21.1%) than in BRCA2 carriers (10.8%). But the Statistical Analysis section defines that outcome as a second primary cancer and treats local and regional recurrences separately. The paper therefore supports the comparison for contralateral breast cancer, not for recurrence. (LLM, conf=0.86)
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Competing-risk study counts disagree
MinorThe discussion first says only three published studies accounted for competing risks, then describes four selected-patient studies that did so.
“Furthermore, only three studies accounted for competing risks in their analyses, which is important to prevent risk overestimation.”
“Four studies including "selected" patients and accounting for competing risks reported higher risk estimates, ranging from 21% to 27%, 12,24,31,34”
The older age group has conflicting lower bounds
MinorThe same 12.6% risk is assigned to patients aged 40-49 in one passage and 41-49 in another. The first definition also overlaps with the group diagnosed before age 41.
“23.9% (95% CI, 16.7 to 31.8) compared with 12.6% (95% CI, 7.4 to 19.3) for those 40 to 49 years old at diagnosis”
“23.9% (BRCA1: 25.5%; BRCA2: 17.2%) compared with 12.6% (BRCA1: 15.6%; BRCA2: 7.2%) for those 41 to 49 years of age”
The carrier age comparison cites the noncarrier panel
MinorThe results cite Figure 1B for an age-stratified comparison of BRCA1/2 carriers, but the figure caption identifies panel B as the noncarrier comparison and panel C as the carrier comparison.
“The 10-year cumulative risk of CBC for BRCA1/ 2 mutation carriers diagnosed with a first breast cancer before age 41 years was 23.9% (95% CI, 16.7 to 31.8) compared with 12.6% (95% CI, 7.4 to 19.3) for those 40 to 49 years old at diagnosis (Fig 1B; HR, 1.89; 95% CI,1.09 to 3.29; P = .02).”
“(B) Cumulative incidence curves showing the risk of CBC for noncarriers stratified according to the age at diagnosis of the first breast cancer, ie, patients diagnosed at ages 41 to 49 years and younger than 41 years.(C) Cumulative incidence curves showing the risk of CBC for BRCA1/2 mutation carriers stratified according to the age at diagnosis of the first breast cancer”
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“Though BRCA1/2 mutation carriers are at increased risk of developing a contralateral breast cancer (24) and tamoxifen treatment has been shown to be protective (38), we found no evidence for worse survival attributable to second primary breast cancer within BRCA1/2 mutation carriers.”
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Risk factors for metachronous contralateral breast cancer: A systematic review and meta-analysis
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“Data collection has been described previously [22], in short: information about diagnosis and treatment, for example, histological tumour grade, stage, adjuvant chemotherapy and endocrine systemic treatment (before summer 2005 no adjuvant trastuzumab was administered), oestrogen (ER) and…”
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“Moreover, we have comprehensive clinicopathological data and follow-up including prophylactic surgeries available.(16,17) A large proportion of the patients in our cohort were diagnosed before 1995 and did not know their mutation status at the time of diagnosis, and therefore had an unaffected choice of treatment.”
BackgroundMethodInfluentialSelf-citationBilateral Mastectomy in Women With Unilateral Breast Cancer
Lim, D. W., Metcalfe, K. A., & Narod, S. A. (2021) · JAMA Surgery · doi:10.1001/jamasurg.2020.6664 · Cited by 52 · see citing works
EBCC-13 manifesto: Balancing pros and cons for contralateral prophylactic mastectomy
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Differences in Ovarian and Other Cancers Risks by Population and BRCA Mutation Location
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Prediction and clinical utility of a contralateral breast cancer risk model
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“The cumulative CBC incidences we observed in BRCA1 and BRCA2 mutation carriers were comparable with the results from earlier studies [1,2].”
BackgroundResultInfluentialSelf-citationBRCA-CRisk: A Contralateral Breast Cancer Risk Prediction Model for BRCA Carriers
Sun, J., Chu, F., Pan, J., Zhang, Y., Yao, L., Chen, J., Hu, L., Zhang, J., Xu, Y., Wang, X., et al. (2022) · Journal of Clinical Oncology · doi:10.1200/jco.22.00833 · Cited by 31 · see citing works
“These findings are in line with the observations from other studies regarding CBC risks in BRCA1/2 carriers.(1,6,7,30,31) Mutation locations of BRCA1/2 genes might be associated with breast or ovarian cancer risk.”
ResultAkdeniz, D., Klaver, M. M., Smith, C. Z. A., Koppert, L. B., & Hooning, M. J. (2020) · Cancer Causes & Control · doi:10.1007/s10552-020-01284-2 · Cited by 30 · see citing works
Self-citationPigment Epithelium-Derived Factor Plays a Role in Alzheimer's Disease by Negatively Regulating Aβ42
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The impact of coding germline variants on contralateral breast cancer risk and survival
Morra, A., Mavaddat, N., Muranen, T., Ahearn, T. U., Allen, J., Andrulis, I. L., Auvinen, P., Becher, H., Behrens, S., BLOMQVIST, C. P., et al. (2023) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2023.02.003 · Cited by 26 · see citing works
“Carriers of PTVs and pathogenic/likely pathogenic MSVs in BRCA1 and BRCA2 had approximately a 2- and 3-fold increased CBC risk, respectively, as reported previously.(25,30) The larger HR estimates in women with an ER-negative first BC for BRCA1 and in women with ER-positive first BC for BRCA2 probably reflect the fact…”
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Self-citationRate of BRCA mutation in patients tested under NCCN genetic testing criteria
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“BRCA1 and BRCA2 (BRCA1/2 hereafter) are two such genes, with estimated lifetime risk of breast cancer between 41%– 90%(3-7) and increased risk of contralateral breast cancer between 10%–40%.(8,9) Bilateral mastectomy in women with BRCA1/2-associated breast cancer markedly reduces the risk of contralateral breast cance…”
BackgroundAn overview of the research progress of BRCA gene mutations in breast cancer
Wan, A., Zhang, G., Ma, D., Zhang, Y., & Qi, X. (2023) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2023.188907 · Cited by 23 · see citing works
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for the TFGT Collaborative Group, Meiser, B., Quinn, V. F., Mitchell, G., Tucker, K., Watts, K., Rahman, B., Peate, M., Saunders, C. M., Geelhoed, E. A., et al. (2018) · European Journal of Human Genetics · doi:10.1038/s41431-017-0057-3 · Cited by 18 · see citing works
Genetic testing in women with breast cancer: implications for treatment
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“The Dutch study mentioned above [24] showed a significantly higher 10-year cumulative contralateral breast cancer risk of 23.”
BackgroundShelton, C. H., Ruiz, A., Shelton, L., Montgomery, H., Freas, K., Ellsworth, R. E., Poll, S. R., Pineda‐Alvarez, D., Heald, B., Esplin, E. D., et al. (2023) · Annals of Surgical Oncology · doi:10.1245/s10434-023-14394-3 · Cited by 16 · see citing works
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“reported that a younger onset age of the rst breast cancer was associated with a signi cantly elevated risk of CBC in patients with BRCA mutations [9, 24].”
BackgroundResultInfluentialLv, Z., Wang, H., Liu, X.-P., Jin, L., Shen, R., Wang, X., Kong, B., Qu, H., Li, F., & Yang, Q. (2017) · Cellular Physiology and Biochemistry · doi:10.1159/000479542 · Cited by 14 · see citing works
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“The risk of contralateral breast cancer among women with P or LP in BRCA1 or BRCA2 is two to three times higher than those without P or LP in BRCA1 or BRCA2 and ranges up to 36% at 15 years after diagnosis,(13,14) with greatest risk among those who were younger than 50 years at initial diagnosis and/or with first-degr…”
BackgroundGenetic Factors in the Locoregional Management of Breast Cancer
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“8% and 5% for gBRCA1, gBRCA2 mutation carriers and non-carriers respectively [61].”
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“Because BRCA1 and BRCA2 pathogenic germline variants have distinct functional effects, we also evaluated the effects of RT separately within these groups (20-22).”
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“Surveillance with MRI alternating with mammography is a recommended option in BRCA1/2 carriers (33-35).”
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Management of Women with a Hereditary Predisposition for Breast Cancer
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“It is known, that the risk of developing contralateral breast cancer is higher in gBRCA1/2 mutation carriers [4].”
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“[25].”
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“5% for non-carriers) [1, 42, 43], which can be managed by contralateral radical mastectomy.”
BackgroundManagement of patients with BRCA mutation from the point of view of a breast surgeon
Riis, M. L. H. (2021) · Annals of Medicine and Surgery · doi:10.1016/j.amsu.2021.102311 · Cited by 6 · see citing works
Risk Management for BRCA1/BRCA2 Mutation Carriers Without and With Breast Cancer
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Estimating Contralateral Breast Cancer Risk
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Beratung junger Frauen mit hereditärer Belastung für Brust- und Eierstockkrebs
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“Anhand einer umfangreichen Untersuchung des Konsortiums konnte gezeigt werden, dass das Risiko für eine kontralaterale Erkrankung vom jeweils verändertenGen und individuellen Ersterkrankungsalter abhängt [2, 14].”
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BRCA mutation in breast cancer patients: Prognostic impact and implications on clinical management
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“BRCA1 mutation carriers have an actual greater cancer risk than BRCA2 mutation carriers [33, 56].”
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“BRCAwt and BRCA1 vs. BRCA2), considering different BC recurrence risks and, according to age at diagnosis, addressing questionable risk-reducing effects in older (> 50 years) patients [2, 25, 28–30].”
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“6% in carriers who were first diagnosed at 41 to 49 years [22].”
BackgroundResultBreast Cancer in the Young Patient: Review of Therapy and Treatment Considerations
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“This risk is higher in individuals diagnosed at a younger age [20], reinforcing the impact of early-onset breast cancer on the probability of a second primary malignancy in the contralateral breast.”
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“Genetic factors, particularly mutations in the BRCA1 and BRCA2 genes [27, 59], considerably raise the risk of getting breast cancer.”
Technical and Analytical Approach for Breast Reconstruction With IMAP Propeller Flap
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“17,18 According to a recent meta-analysis 19 some risk factors have been described as predictors of a moderately increased risk of CBC (ie, radiotherapy for primary breast cancer [PBC] at a young age).”
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“1) [27–29].”
Self-citationCase 7-2020: A 52-Year-Old Man with a Mass in the Left Breast
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Surgical Management of Early-Onset Breast Cancer Among Young BRCA1 and BRCA2 Carriers
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“[17] Several factors may account for this discrepancy.”
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“[6].”
Prophylaxie chirurgicale mammaire chez les patientes à très haut risque de cancer du sein
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“This risk is strongly impacted by characteristics such as germline mutation status [4], racial or ethnic background [5], age at initial diagnosis [6], and menopau‑ sal status [7–10].”
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Saule, C., & Mouret‐Fourme, E. (2023) · La Presse Médicale Formation · doi:10.1016/j.lpmfor.2023.10.019
Risk-Reducing Surgery for Breast Cancer
Benson, J. R., Muktar, S., & Jatoi, I. (2023) · Springer eBooks · doi:10.1007/978-981-19-7630-8_7
- Authors
- van den Broek, A. J., van ’t Veer, L. J., Hooning, M. J., Cornelissen, S., Broeks, A., Rutgers, E. J., Smit, V. T. H. B. M., Cornelisse, C. J., van Beek, M., Janssen-Heijnen, M. L., Seynaeve, C., Westenend, P. J., Jobsen, J. J., Siesling, S., Tollenaar, R. A. E. M., van Leeuwen, F. E., & Schmidt, M. K.
- Affiliations
- Alexandra J. van den Broek, Laura J. van ’t Veer, Sten Cornelissen, Annegien Broeks, Emiel J. Rutgers, Flora E. van Leeuwen, and Marjanka K. Schmidt, Netherlands Cancer Institute-Antoni van Leeuwenhoek, Amsterdam; Maartje J. Hooning and Caroline Seynaeve, Erasmus MC Cancer Institute, Rotterdam; Vincent T.H.B.M. Smit, Cees J. Cornelisse, and Rob A.E.M. Tollenaar, Leiden University Medical Center, Leiden; Mike van Beek, PAMM, Catharina Hospital, Eindhoven; Maryska L. Janssen-Heijnen, Netherlands...
- Leiden University Medical Center (NL)
- ORCID
- Venue
- Journal of Clinical Oncology
- Published
- 2016-02-10
- Volume
- 34
- Issue
- 5
- Pages
- 409-418
- ISSN
- 0732-183X (ISSN-L)
- 1527-7755
- OpenAlex
- W2218994245
- Cited by
- 104
- References
- 56
- Citations by year
- 2026: 6 · 2025: 7 · 2024: 9 · 2023: 8 · 2022: 8 · 2021: 14 · 2020: 13 · 2019: 12 · 2018: 12 · 2017: 12 · 2016: 2 · 2013: 1
- FWCI
- 5.93
- Type
- journal article
- Language
- en
- Open access
- green
- research.utwente.nl
- Licence
- other-oa
- Locations
- Journal of Clinical Oncology (publishedVersion)
- PubMed (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion)
- University of Twente Research Information (acceptedVersion, other-oa)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Leiden Repository (Leiden University) (submittedVersion)
- University of Twente Research Information (submittedVersion, other-oa)
- Funders
- Universiteit Leiden
- KWF Kankerbestrijding (DCS-NKI 2009-4363, 2007-3839, DCS-NKI 2001‐2423, NKI 2009-4363, DCS-NKI 2007-3839, 2009 4363, NKI 2007–3839)
- Leids Universitair Medisch Centrum
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › BRCA gene mutations in cancer
- Health Sciences › Medicine › Epidemiology › Multiple and Secondary Primary Cancers
- Health Sciences › Medicine › Pathology and Forensic Medicine › Breast Lesions and Carcinomas
- Keywords
- contralateral breast cancer, BRCA1 mutation, BRCA2 mutation, young women with breast cancer, hereditary breast cancer, cumulative risk, competing risk analysis, age-specific risk
- MeSH terms
- Adult, Age Factors, Breast Neoplasms, DNA Mutational Analysis, Female, Follow-Up Studies, Heterozygote, Humans, Middle Aged, Mutation, Neoplasm Staging, Netherlands, Prognosis, Retrospective Studies, Prevalence, Neoplasms, Second Primary, Risk Assessment, BRCA1 Protein, Genetic Predisposition to Disease, BRCA2 Protein
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