Selection bias influences reported contralateral breast cancer incidence and survival in high risk non-BRCA1/2 patients.
OBJECTIVE
The results of studies comparing survival in familial and sporadic breast cancer (BC) are inconsistent. A higher incidence of contralateral breast cancer (CBC) has been reported in familial BC. Ascertainment bias may influence both the reported familial CBC and survival.


METHODS
We assessed CBC incidence, distant disease free (DDFS) and overall survival (OS) in 327 BC patients who had > or =3 breast and/or ovarian cancers in the family but no BRCA1/2 gene mutation (non-BRCA1/2). They were matched to 327 sporadic controls for year and age at detection. To correct for ascertainment bias, we analyzed also separately the results (1) Of the 250 non-BRCA1/2 patients with DNA testing performed before diagnosis or within 2 years ('unselected') and (2) Of the 77 with testing > or =2 years after diagnosis (late-tested).


RESULTS
Median follow-up of non-BRCA1/2 patients was 6.1 yrs. Ten years CBC incidence was 11% in non-BRCA1/2 versus 6% in sporadic patients (p = 0.002). At multivariate analysis CBC incidence was increased in late-tested non-BRCA1/2 (HR 4.6; p = 0.001) not in 'unselected' (HR 1.8; p = 0.1). Increased CBC occurred in non-BRCA1/2 patients mainly before genetic testing, suggesting ascertainment bias. Tumors were < or =T1 in 62% of non-BRCA1/2 versus 50% of sporadic patients (p = 0.003), node-negative in 55% versus 52% respectively (p = 0.5). After correction for stage and therapy, OS did not differ between 'unselected' non-BRCA1/2 and sporadic patients (HR 0.8; p = 0.3), but was improved in late-tested non-BRCA1/2.


CONCLUSIONS
Overall survival and contralateral breast cancer incidence were similar in 'unselected' non-BRCA1/2- and sporadic patients. Reports of higher CBC incidence and better survival in non-BRCA1/2 patients may substantially be caused by DNA testing selection-bias.
Tilanus-Linthorst
Madeleine M A
MM
Department of Surgical Oncology, Erasmus University Medical Centre, Rotterdam, The Netherlands. m.tilanus-linthorst@erasmusmc.nl
Bartels
Karina C M
KC
Alves
Celina
C
Bakri
Bonnie
B
Crepin
Ellen
E
van den Ouweland
Ans
A
Klijn
Jan G M
JG
Meijers-Heijboer
Hanne
H
Brekelmans
Cecile T M
CT
D000328:Adult; D019313:BRCA1 Protein / Q000235:genetics; D024682:BRCA2 Protein / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics / Q000401:mortality*; D005260:Female; D006801:Humans; D015994:Incidence; D015412:Mastectomy, Segmental / Q000379:methods; D008875:Middle Aged; D009367:Neoplasm Staging; D011379:Prognosis; D012307:Risk Factors; D015983:Selection Bias; D015996:Survival Rate
D019313:BRCA1 Protein; D024682:BRCA2 Protein