Brca2 hereditary breast cancer pathophenotype

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134946 BREA ART.NO 905-96 ORD.NO 230303.Z

Address for offprints and correspondence: J.N. Marcus, Department of Pathology, St. Luke’s Hospital, 232 S. Woods Mill Road, Chester-field, MO 63017, USA; Phone: (314)8512927; Fax: (314)8516830; E-mail: [email protected]

Breast Cancer Research and Treatment 44: 275–277, 1997. 1997 Kluwer Academic Publishers. Printed in the Netherlands.

Brief communication

BRCA2 hereditary breast cancer pathophenotype

Joseph N. Marcus,1 Patrice Watson,2 David L. Page,3 Steven A. Narod,4 Patricia Tonin,5 Gilbert M. Lenoir,6

Olga Serova,6 and Henry T. Lynch2

1Department of Pathology, St. Luke’s Hospital, Chesterfield, MO; 2Department of Preventive Medicine andPublic Health, Creighton University School of Medicine, Omaha; 3Department of Pathology, VanderbiltUniversity School of Medicine, Nashville, USA; 4Women’s College Hospital, Toronto, Ontario Canada;5Department of Medicine, McGill University, Montreal, Quebec, Canada; 6International Agency for Researchon Cancer, Lyon, France

Key words: BCRA1, BCRA2, familial breast cancer, hereditary breast cancer, pathology, DNA cytometry,tubular-lobular group

Summary

Four BRCA2 hereditary breast cancer (HBC) families manifested significant excesses of ‘tubular-lobulargroup’ (TLG) invasive carcinomas and lobular carcinoma in situ/atypical lobular hyperplasia in comparisonto BRCA1-HBC cases.

Introduction

Mutations in the BRCA1 and BRCA2 genes ac-count in roughly equal proportion for most here-ditary breast cancer (HBC), which comprises 4–9%of all breast cancer cases [1]. Because BRCA2 wasonly recently isolated [2], not much is known aboutthe tumor phenotype. Here we present preliminaryevidence for distinctive pathologic features ofBRCA2-HBC as compared with BRCA1-HBC.

Methods

We have now identified BRCA2 mutations in fourHBC families that are part of an ongoing double-blind study of HBC histopathology and DNA cy-tometry [1]. There were 13 individuals with 17 in-vasive breast cancers (four of them bilateral) whichwere analyzed for the features listed in the Table.

Seventy-five invasive BRCA1 cancers in 65 individ-uals from 19 families with BRCA1 mutations wereavailable for comparison. Details of pathology andDNA cytometry methods can be found in ref. 1.

For analysis, invasive lobular, tubular, tubulo-lobular, and cribriform special type carcinomaswere considered together as a ‘tubular-lobulargroup’ (TLG) as before [1], because of their inter-related clinical, pathologic, epidemiologic, andmolecular genetic characteristics. Specifically,these special types have a) clinically less aggressivebehavior in their pure forms, b) similar morpholog-ic features including low grade nuclei and a hybridform, tubulolobular carcinoma [3], c) significant,coordinately increased relative frequencies oflobular or tubular types in the settings of high riskcountries, prior benign breast biopsy, fibrocysticchanges, nulli-parity, and bilateral breast cancer [4],d) near-significant associations with a positive fam-ily history of breast cancer [4, 5], and e) virtually no



276 JN Marcus et al.

Table 1. Pathobiologic profile of BRCA2 and BRCA1 Hereditary Breast Cancer (HBC) cases

Phenotype BRCA2-HBC BRCA1-HBC p value

Tubular-lobular group (TLG) 5/17 (29.4) 5/75 (6.7) 0.017TLG or TLG features 9/17 (52.9) 7/75 (9.3) 0.0002Any LCIS/ALH 4/17 (23.5) 2/75 (2.7) 0.01TLG or TLG features or any LCIS/ALH 11/17 (64.7) 7/75 (9.3) 0.0001Ductal carcinoma grade 3 2/12 (16.7) 30/48 (62.5) 0.008Diploidy 8/13 (61.5) 8/60 (13.3) 0.0008DNA index 1.71 ± 0.27 (5) 1.58 ± 0.36 (49) 0.19S phase fraction (of diploids), % 3.5 ± 2.9 (8) 3.2 ± 1.7 (8) 0.83S phase fraction (of aneuploids), % 7.5 ± 3.3 (5) 16.0 ± 6.4 (48) 0.005

Abbreviations: HBC: hereditary breast cancer; TLG: tubular-lobular group; LCIS/ALH: lobular carcinoma in situ/atypical lobularhyperplasia.Entries are number of cases with phenotype/total cases (percent), or mean and standard deviation (sample size).P values are respectively computed from 2-tailed Fisher’s test or Mann-Whitney U test.

somatic alteration of the BRCA1 region on chro-mosome 17q in lobular type, in contrast to frequentalterations in invasive ductal carcinomas [6].

Further, TLG carcinomas are frequently associ-ated with lobular carcinoma in situ (LCIS) and/oratypical lobular hyperplasia (ALH), which are riskmarkers for synchronous, metachronous, and bilat-eral invasive breast cancers [7–9]. About two-thirdsof invasive lobular carcinomas have associatedLCIS/ALH, significantly more than for invasiveductal carcinomas, approaching 90% in the classicalform [10]. Moreover, the invasive carcinomas whicharise in follow-up of primary LCIS/ALH are pre-dominantly lobular and tubular types [7–9]. In theanalysis, we note accompanying LCIS/ALH andcarcinomas with TLG ‘features’ (10–50% TLG tu-mor composition).

Results and discussion

Most of the BRCA2-HBCs were TLG type or hadTLG features (Table 1). Specifically, there was onelobular, one tubular, two tubulolobular, and onecribriform carcinoma, while four other carcinomashad features of lobular type. These TLG and TLG‘features’ cancers were significantly more commonin BRAC2-HBC (p = 0.0002). There was also ahigher prevalence of accompanying LCIS/ALH(p = 0.01), which was identified in all four BRCA2

families. Combined as a superset, carcinomas ofTLG type, TLG ‘features’, and LCIS/ALH are instriking excess in BRCA2-HBC (Table 1).

The four BRCA2 families are part of a largergroup of 24 families in our resource that currentlylack features of BRCA1-HBC based on the absenceof BRCA1mutations, 17q linkage, absence of ovari-an cancer affected (80% of HBC families with ovar-ian cancer cases are expected to be BRCA1 [11]), orpresence of BRCA2 mutations or 13q linkage. Wefind a significant TLG carcinoma excess in thisgroup compared to non-HBCs which persists aftersubtraction of the four BRCA2 families [ref. 1 andunpublished data]. The excess is likely be due to yetunidentified BRCA2 families that are expected inthis group, or to a mimic phenotype of a separatecancer predisposition gene(s).

In contrast to BRCA2-HBC, BRCA1-HBC casesare significantly more likely to be high grade, aneu-ploid, and highly proliferative (high aneuploid Sphase fraction (Table 1). These results are similar toour earlier findings for a ‘BRCA1-related’ HBCgroup that was not defined by mutations exclusive-ly, and which was compared to breast cancers atlarge [1, 12]. Higher grades in BRCA1-HBC alsohave been reported elsewhere [13].

We had the opportunity to assess additionalmembers of IARC 2932, the first family in which aBRCA2 mutation was identified [1, 2], although un-like the rest of the data set, these new cases were not



BCRA2 hereditary breast cancer pathophenotype 277

viewed double-blind. LCIS/ALH was ubiquitous,present in nine of 11 affected individuals in thisfamily.

We do not find the high tumor grades and prolif-eration rates that have been reported in five Icelan-dic BRCA2 families [14]. However, the sample sizesboth here and in that abstract report are small.Larger studies will be needed to confirm trends andassess heterogeneity in the BRCA2 phenotype. Ourcurrent data show distinctive pathobiologic differ-ences between BRCA1 and BRCA2-HBC and sug-gest that TLG invasive carcinomas and lobular neo-plasia may be phenotypic markers of BRCA2-HBC.

Acknowledgements

Supported by grants from the National Cancer In-stitute (RO1CA 48802 and RO1CA 50468), HealthFuture Foundation, Nebraska Health DepartmentCancer and Smoking Diseases Research (LB595),Council for Tobacco Research (1297E), and Na-tional Cancer Institute of Canada Breast CancerResearch Inititative.

References

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7. McDivitt RW, Hutter RVP, Foote FW, Stewart FW: In situlobular carcinoma. A prospective follow-up study indicatingcumulative patient risks. JAMA 201: 96–100, 1967

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11. Narod SA, Ford D, Devilee P, Barkadottir RB, Lynch HT,Smith SA et al.: An evaluation of genetic heterogeneity in145 breast-ovarian cancer families. Am J Hum Genet 56:254–264, 1995

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13. Eisinger F, Stoppa-Lyonnet D, Longy M, Kerangueven F,Noguchi T, Bailly C, Vincent-Salomon A, Jaquemier J, Birn-baum D, Sobol H: Germ line mutation at BRCA1 affects thehistoprognostic grade in hereditary breast cancer. CancerRes 56: 471–474, 1996

14. Sigurdsson H, Agnarsson BA, Jonasson JG, Bjornsdottir IB,Barkardottir RB, Gudlaugsdottir S, Egilsson V: Worse sur-vival among breast cancer patients in families carrying theBRCA2 susceptibility gene. Breast Cancer Res Treat 37(Suppl): 33, 1996

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Brca2 hereditary breast cancer pathophenotype