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Familial Invasive Breast Cancers: Worse Outcome Related to BRCA1 Mutations

From the Departments of Oncology Genetics, Biostatistics, Radiotherapy, Surgery, Pharmacology, Medical Oncology, and Pathology, Institut Curie, Paris, France.

Address reprint requests to Dominique Stoppa-Lyonnet, MD, PhD, Service de Génétique Oncologique, Institut Curie, 26 Rue d’Ulm, F75248 Paris, France; email dominique.lyonnet{at}curie.net

	ABSTRACT

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PURPOSE: Although all studies confirm that BRCA1 tumors are highly proliferative and poorly differentiated, their outcomes remain controversial. We propose to examine, through a cohort study, the pathologic characteristics, overall survival, local recurrence, and metastasis-free intervals of 40 patients with BRCA1 breast cancer.

PATIENTS AND METHODS: A cohort of 183 patients with invasive breast cancer, treated at the Institut Curie and presenting with a familial history of breast and/or ovarian cancer, were tested for BRCA1 germ-line mutation. Tumor characteristics and clinical events were extracted from our prospectively registered database.

RESULTS: Forty BRCA1 mutations were found among the 183 patients (22%). Median follow-up was 58 months. BRCA1 tumors were larger in size (P = .03), had a higher rate of grade 3 histoprognostic factors (P = .002), and had a higher frequency of negative estrogen (P = .003) and progesterone receptors (P = .002) compared with non-BRCA1 tumors. Overall survival was poorer for carriers than for noncarriers (5-year rate, 80% v 91%, P = .002). Because a long time interval between cancer diagnosis and genetic counseling artificially increases survival time due to unrecorded deaths, the analysis was limited to the 110 patients whose diagnosis-to-counseling interval was less than 36 months (19 BRCA1 patients and 91 non-BRCA1 patients). The differences between the BRCA1 and non-BRCA1 groups regarding overall survival and metastasis-free interval were dramatically increased (49% v 85% and 18% v 84%, respectively). Multivariate analysis showed that BRCA1 mutation was an independent prognostic factor.

CONCLUSION: Our results strongly support that among patients with familial breast cancer, those who have a BRCA1 mutation have a worse outcome than those who do not.

	INTRODUCTION

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IDENTIFICATION OF women with a high risk of breast cancer, or women affected with a breast cancer linked to genetic predisposition, has become possible thanks to the cloning of the BRCA1 and BRCA2 genes and to the worldwide diffusion of genetic testing.^1-4 However, the management of women at risk and the treatment of affected women are still to be determined. Management and treatment are greatly dependent upon the outcome of BRCA-associated tumors, ie, overall survival, local recurrence rate, and risk of metastasis.

Most studies analyzing histoprognostic factors have reported that BRCA1 breast cancers are characterized by a high histologic grade due to a high mitotic index and by a lack of estrogen and progesterone receptor expression.^5-8 On the other hand, BRCA2-associated tumors and non–BRCA1/BRCA2 familial breast tumors present histoprognostic features similar to those of sporadic cases,^7-10 which leads one to expect that the prognosis of breast cancers linked to BRCA1 gene alterations is worse than that of sporadic cases and possibly worse than that of tumors associated with other predisposing genes.

However, survival studies of patients with BRCA1 breast cancers have reported rather controversial results. One has reported a significantly better prognosis¹¹ and three have shown no difference.^6,12,13 Three other studies have reported a trend toward a worse prognosis,^14-16 and three have shown an adverse outcome.^17-19 Possible biases in the selection of case groups as well as of control groups for the five case-control studies,^{6,11,12,14,16} the small number of BRCA1 mutation carriers in three cohort studies,^17-19 the combination of BRCA1 and BRCA2 mutation carriers in the case group in three cohort studies,^13,15,19 and the lack of genetic testing in affected relatives^12-14,16 may have led to inconclusive or inaccurate results.

In this study, we examined the pathologic characteristics, overall survival, local recurrence, and metastasis-free intervals of 40 breast cancer patients with BRCA1 mutations identified in a cohort of 183 familial breast cancer patients.

	PATIENTS AND METHODS

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Cohort Inclusion Criteria
From January 1991 to July 1998, women affected with breast cancer and regularly followed at the Institut Curie were invited to attend the family cancer clinic of our institute if they presented with a family history of breast or ovarian cancer. All information regarding the family cancers, age at cancer diagnosis, and age at death or current age were obtained as reported in our previous study.²⁰

Molecular testing was proposed to women who presented with one of the following family criteria: (i) two first-degree relatives affected with cancer, with at least one with invasive breast cancer before 41 years or one with ovarian cancer at any age, and (ii) at least three first- or second-degree relatives from the same lineage affected with invasive breast or ovarian cancer at any age. The index case was one of the affected family members. After the patients were informed about the aims and limits of breast cancer genetic testing, blood samples were collected with their written consent.

BRCA1 Genetic Testing
Screening of BRCA1 for point mutations or small rearrangements was performed through analysis of genomic DNA with the denaturing gradient gel electrophoresis method according to the conditions described previously.²⁰ In short, BRCA1 gene screening was performed on the 22 coding exons and their flanking intron-exon junctions. The gene was investigated by use of a total of 35 different amplifications. The average size of the amplicons was 300 base pairs. Polymerase chain reaction products showing an electrophoretic variant pattern were directly sequenced on both strands using the fluorometric method with automated sequencing procedures (dRhodamine Terminator Cycle Sequencing Ready Reaction and ABI377 DNA sequencer; Applied Biosystems, Inc, Foster City, CA).

Mutations leading to putative truncated products, and three missense mutations (Cys47Tyr, Ala1708Glu, and Arg1751Gln), were considered to be associated with a biologic deleterious effect.²⁰

Patient Treatments
Treatment strategies were aimed at preserving the breast whenever possible. Patients with small tumors were treated with wide surgical excision of the primary tumor and axillary node dissection followed by breast irradiation and regional node irradiation when nodes were involved. In patients with large tumors, either chemotherapy or radiotherapy was delivered first, after diagnosis on a core biopsy. The initial treatment was followed, according to the clinical response, by surgery when residual tumor was detectable or by complementary radiotherapy alone. Finally, a mastectomy was performed up front in case of multifocal tumor or if it was the patient’s choice.

Forty-three percent of tumors were treated with wide excision followed by radiotherapy. Thirty-three percent were treated with up-front chemotherapy and 8% with up-front radiotherapy. Finally, in 16% of cases, a mastectomy was performed. Overall, in 74% of cases, breast-conserving treatment was used.

Registration of Patient and Tumor Characteristics
Age at onset, menopausal status, clinical stage (according to International Union Against Cancer criteria), pathologic findings, Bloom and Richardson histologic grade, mitotic index, hormone receptor status, time interval between diagnosis and genetic counseling, treatments, follow-up, local recurrences, metastases, and vital statistics were prospectively registered in the Institut Curie’s breast cancer database.²¹

Statistical Analysis
², Fisher’s exact test, and Student’s t test were used to compare patient and tumor characteristics. Survival was determined from the date of diagnosis to the date of death or last follow-up. Metastasis-free and breast local recurrence–free intervals were defined as the periods from the date of diagnosis to the date of first distant metastasis or first local recurrence, respectively; patients were censored at the time of death or last follow-up. Kaplan-Meier estimates were generated for BRCA1 and non-BRCA1 breast cancer patients and compared using the log-rank test.²²

The influence of BRCA1 mutation, adjusted for other prognostic factors, was assessed in a multivariate analysis by the Cox proportional hazards model,²³ in a forward stepwise regression procedure. Age, tumor size, clinical nodal status, estrogen and progesterone receptor status, and Scarff-Bloom-Richardson grading were entered in the model.

	RESULTS

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From January 1991 to July 1998, all 183 patients presenting with breast cancer who met the cohort criteria agreed to give a blood sample for molecular testing. A germ-line deleterious BRCA1 mutation was identified in 40 patients (22%) belonging to 36 different families. Among the 40 identified mutations, 27 (68%) were different and were scattered on the entire coding sequence of the gene.

Patient characteristics are summarized according to their BRCA1 status in Table 1. The two groups were well balanced for age and menopausal status. The rate of synchronous contralateral breast cancer was 5% in both groups. The median time interval between cancer diagnosis and genetic counseling was 40 months (range, 1 to 158 months; mean, 47 months) for the BRCA1 patients versus 17 months (range, 1 to 166 months; mean, 37 months) for the non-BRCA1 patients (P = .20).

View larger version (23K): [in this window] [in a new window]   Fig 1. Overall survival according to BRCA1 status for (A) all 183 patients (BRCA1 carriers, n = 40; noncarriers, n = 143; 5-year rate, 80% in carriers v 91% in noncarriers, P = .002) and (B) the 110 patients who had genetic counseling within 36 months of diagnosis (BRCA1 carriers, n = 19; noncarriers, n = 91; 5-year rate, 49% in carriers v 85% in noncarriers, P = .0001).

View larger version (23K): [in this window] [in a new window]   Fig 2. Local recurrence–free interval according to BRCA1 mutation status for (A) all 183 patients (BRCA1 carriers, n = 40; noncarriers, n = 143; 5-year rate, 83% in carriers v 85% in noncarriers, P = .16) and (B) the 110 patients who had genetic counseling within 36 months of diagnosis (BRCA1 carriers, n = 19; noncarriers, n = 91; 5-year rate, 54% in carriers v 79% in noncarriers, P = .11).

View larger version (23K): [in this window] [in a new window]   Fig 3. Metastasis-free interval according to BRCA1 mutation status for (A) all 183 patients (BRCA1 carriers, n = 40; noncarriers, n = 143; 5-year rate, 67% in carriers v 86% in noncarriers, P = .22) and (B) the 110 patients who had genetic counseling within 36 months of diagnosis (BRCA1 carriers, n = 19; noncarriers, n = 91; 5-year rate, 18% in carriers v 84% in noncarriers, P = .0001).

To test whether BRCA1 was an independent prognostic factor of overall survival and metastasis-free interval, a multivariate analysis was performed on the subgroup of 110 patients, using a Cox model with a stepwise procedure. The unadjusted relative risk (RR) of death associated with BRCA1 mutation was 5.1. After adjustment for clinical nodal status, the RR was 3.5 (95% confidence interval, 1.3 to 9.7; Table 3). Tumor size, estrogen receptor status, and histoprognostic grade did not contribute to the improvement of the model. The unadjusted RR of metastasis associated with BRCA1 mutation was 3.5. After adjustment for clinical nodal status and estrogen receptor status, the RR was 2.6 (95% confidence interval, 1.0 to 6.5; Table 4). No other variable contributed significantly to the improvement of the model.

View this table: [in this window] [in a new window]   Table 3. Multivariate Cox Regression Model of Overall Survival in 110 Patients With 36 Months Between Diagnosis and Genetic Counseling

View this table: [in this window] [in a new window]   Table 4. Multivariate Cox Regression Model of Metastasis-Free Interval in 110 Patients With 36 Months Between Diagnosis and Genetic Counseling

	DISCUSSION

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Our cohort study was performed on familial breast cancer cases. The high rates of metachronous bilateral tumors and synchronous contralateral tumors similarly observed in both patient groups underscore the breast cancer predisposition condition of the patients. With respect to genetics, the non-BRCA1 familial breast cancer cases are probably a heterogeneous group: it may comprise BRCA2 mutation carriers, carriers of a gene(s) still unidentified, sporadic cases with a family history of breast cancer occurring by chance, and finally some carriers of BRCA1 mutations that escaped detection. Our study therefore shows that BRCA1 breast cancers are associated with a worse prognosis than non-BRCA1 familial cancers. In addition, since the 5-year survival rate for non-BRCA1 patients was 91%, which is similar to that for large series in our institution²¹ and in the Surveillance, Epidemiology, and End Results database,²⁴ these results strongly suggest that the prognosis in BRCA1 breast cancer is also worse than that in sporadic cases. An independent study (W.D. Foulkes, personal communication, June 2000) found a significantly short median metastasis-free interval for BRCA1/BRCA2 mutation carriers compared with noncarriers in both univariate (P = .002) and multivariate (P = .05) analyses, thereby supporting our observations.

Retrospective studies addressing the question of disease prognosis are exposed to the common pitfall of the selection bias toward survival. Both the design of our study (based on a cohort study) and the selection of patients who had had genetic counseling within 36 months after diagnosis considerably limited this bias. Indeed, the bias consisted of excluding from genetic analysis patients who were dead at the time of genetic counseling. The impact of this bias was demonstrated by the increased difference in outcome when the analysis was limited to the 110 patients whose time interval between diagnosis and genetic counseling was less than 3 years. Studies from Foulkes et al¹⁷ and, more recently, Robson et al¹⁹ and our previous study focusing on early-onset breast cancer¹⁸ tried to avoid this bias by performing germ-line BRCA1 mutation screening either on tumor samples^17,19 or on lymphocytes of patients with a very small interval between diagnosis and counseling.¹⁸ Hence, they were able to demonstrate a statistically significant difference between BRCA1 and non-BRCA1 patients, although the number of patients was small. Two other studies^15,16 tried to limit this bias by removing probands from the case group and showed a trend toward worse prognosis in BRCA patients. In addition, it has to be observed that, when the whole cohort is taken into account, the median time interval between diagnosis and genetic counseling in the BRCA1 patients was longer than that in non-BRCA1 patients (40 months v 17 months), as was the follow-up (88 months v 56 months). These differences reflect the common efforts of such studies to find probands with a high probability of being carriers of breast cancer–predisposing genes, and therefore the tendency for their selection in long retrospective time periods, which obviously increases the selection bias toward survival. This bias, known as the Neyman bias, was recently described in a review of BRCA breast cancer prognosis by Phillips et al.²⁵ The Neyman bias could explain the paradoxical reported observations that BRCA1 patients have tumors with adverse histoprognostic features without impaired survival.^12-16 Indeed, histoprognostic characteristics are known at the time of diagnosis and are therefore insensitive to a time-dependent selection bias.

The multivariate analysis showed that even though clinical nodal status was the prognostic factor associated with the highest relative risk of death and short metastasis-free interval, BRCA1 mutation status remained an independent prognostic factor. Moreover, due to the design of the study being based on selection of patients by familial criteria only, clinical stage presentation was not expected to be biased. Therefore, we hypothesize that the more advanced clinical stage observed in BRCA1 patients likely reflects the biologic characteristics of BRCA1 tumors.

Breast local recurrence rates were not significantly different in the two groups. However, we must be cautious regarding the rate of local recurrences in BRCA1 patients because it may change with the increases in number of patients and follow-up. Indeed, a longer follow-up period could allow us to observe a high rate of second independent ipsilateral tumors, which is expected with breast cancer predisposition and as reported by Turner et al,²⁶ who studied the frequency of BRCA1 mutation carriers in a group of women with bilateral breast cancer.

In conclusion, our results strongly support that among familial breast cancer patients, those with a BRCA1 mutation have a worse outcome those who do not have a mutation. The precise influence of BRCA1 mutations on prognosis will be determined from the follow-up of BRCA1 mutation carriers prospectively registered in cohort studies. However, these new data may already be taken into account when discussing the management of healthy women carriers of a BRCA1 mutation.

	APPENDIX Institut Curie Breast Cancer Group

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The members of the Institut Curie Breast Cancer Group are as follows: B. Asselain, P. Beuzeboc, D. Bourgeois, E. Bourstyn, F. Brunin, F. Campana, J.Y. Charvolin, K.B. Clough, P. de Crémoux, A. de La Rochefordière, V. de Margerie, R. Dendale, V. Diéras, T. Dorval, B. Dubray, J.M. Extra, M.C. Falcou, F. Fitoussi, A. Fourquet, C. Gautier, J.N. Guglielmina, J.P. Hamelin, C. Jaulerry, M. Jouve, H. Magdelénat, M. Meunier, V. Mosseri, E. Mouret-Fourme, C. Nos, T. Palangié, J.Y. Pierga, P. Pouillart, R.J. Salmon, X. Sastre-Garau, P. Schlienger, S. Scholl, D. Stoppa-Lyonnet, F. Thibault, P. This, P. Vielh, J.R. Vilcoq, A. Vincent-Salomon, and B. Zafrani.

	ACKNOWLEDGMENTS

 
We are indebted to the patients for their participation in the study. We are grateful to Isabelle Eugène for her daily and efficient support in the organization of the genetic clinic. We thank Sabine Pagès, and Virginie Caux for the genetic testing of patients. We thank Anne de Henning for the linguistic revision of the manuscript.

	REFERENCES

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Submitted February 17, 2000; accepted July 14, 2000.

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