Breast Cancer Genetic Testing Among African Patients With Breast Cancer

Abstract

This population-based study of Ghanian women with a family history of breast cancer analyzes breast cancer gene mutations to determine whether the triple-negative breast cancer phenotype is a risk factor for mutation carrier status.

Population-based incidence rates of breast cancers that yield negative testing results for estrogen receptors, progesterone receptors, and human epidermal growth factor receptor 2 biomarkers (triple-negative breast cancer [TNBC]) are 2-fold higher among African American women compared with white American women, and TNBC is a risk factor for breast cancer gene 1 (BRCA1) mutation carrier status that is independent of an individual’s family history. These patterns, coupled with data revealing an increased frequency of TNBC among western, sub-Saharan Africans, suggest that African ancestry is associated with hereditary susceptibility for TNBC. Resources for collecting and analyzing germline DNA from blood and/or saliva specimens to evaluate for BRCA mutations are limited in low- and middle-income countries in Africa, and transporting specimens to laboratories in more affluent countries is challenging. Recent studies suggest that DNA extraction from formalin-fixed, paraffin-embedded tumor specimens is feasible and accurate, thereby providing a readily available resource for genetic studies. We report the results from a study motivated by the educational and research efforts of an international multidisciplinary breast cancer partnership. Selected BRCA mutations were analyzed among Ghanaian patients with breast cancer, exploring the effectiveness of collaborations between surgeons, oncologists, pathologists, and geneticists in assessing the genetics of breast cancer in low- and middle-income countries in Africa.

Methods

This study was approved by the Committee on Human Research Publication institutional review board for the Komfo Anokye Teaching Hospital and Kwame Nkrumah University of Science and Technology. The study population consisted of women with a family history of breast cancer who had received a diagnosis of locally advanced disease and were treated from September 2009 to August 2011 at Komfo Anokye Teaching Hospital in Kumasi, Ghana, with neoadjuvant chemotherapy followed by definitive breast/axillary surgery. Formalin-fixed paraffin-embedded samples were obtained from surgical resection specimens, and DNA was extracted from deparaffinized tissues and genotyped for 3 common BRCA mutations: BRCA1 185delAG, BRCA1 5382insC, and BRCA2 6174delT (Inqaba Biotechnical Industries Ltd). The process of obtaining patient consent and tissue studies was completed by Ghanaian medical staff.

Results

Of 521 patients, 94 (18.0%) met inclusion criteria and consented to participate (Table 1). Thirty-six (38.3%) were younger than 45 years and 37 (39.3%) were age 45 to 60 years at diagnosis. Fourteen (14.8%) had delivered fewer than 3 babies. Sixty-six (70.2%) had T4 disease and 12 (12.8%) had T3 disease at diagnosis. Thirty-one cases (33.0%) were ER positive, 18 (19.2%) were PR positive, 8 (8.5%) were human epidermal growth factor receptor 2 positive, and 57 (60.6%) had TNBC. DNA genotyping identified BRCA mutations in 58 cases (61.7%) overall, BRCA1 185delAG mutations in 44 cases (47.3%), BRCA1 5382insC mutations in 41 cases (44.1%), and BRCA2 6174delT mutations in 44 cases (47.3%). Forty-six patients (48.9%) had multiple mutations. Table 2 shows BRCA mutation status stratified by breast cancer phenotype, revealing that BRCA mutations were more common among cases of TNBC compared with non-TNBC tumors (87.7% vs 21.6%, P < .001).

Table 1. Distribution of Age, Parity, and the Menopausal Stage of 94 Participants.

Characteristic	No. (%)
Age, y
<45	36 (38.3)
45-60	37 (39.3)
61-80	21 (22.3)
Parity
0-2	14 (14.8)
3-4	44 (46.8)
>5	36 (38.3)
Menopausal status
Premenopausal	37 (39.3)
Perimenopausal	14 (14.8)
Postmenopausal	34 (36.1)
Unknown	9 (9.5)

Table 2. Associations Between Breast Cancer Phenotype and BRCA Mutations Among 94 Ghanaian Patients With a Family History of Breast Cancer.

Mutation	No. (%)
	ER-Positive, 31 (33.0)	PR-Positive, 18 (19.2)	HER2/Neu-Positive, 8 (8.5)	TNBC, 57 (60.6)
BRCA1 185delAG 44 (47.3%)	1 (3.2)	1 (5.6)	4 (50)	39 (68.4)
BRCA1 5382insC 41 (44.1%)	1 (3.2)	1 (5.6)	4 (50)	36 (63.2)
BRCA2 6174delT 44 (47.3%)	3 (9.7)	2 (11.1)	4 (50)	37 (65.0)

Abbreviations: BRCA, breast cancer gene; ER, estrogen receptor; HER2/neu-positive, human epidermal growth factor receptor 2; PR, progesterone receptor; TNBC, triple-negative breast cancer.

Discussion

Breast cancer gene mutations account for approximately 5% to 10% of breast cancers in the general population but are detected in up to 43% of young patients with TNBC. The TNBC phenotype is therefore a risk factor for mutation carrier status. Little to our knowledge is known about BRCA mutation frequency among women with African ancestry worldwide, despite higher rates of TNBC present among African American and western sub-Saharan African populations. Fackenthal et al reported BRCA1/2 mutations among 11% of Nigerian patients with breast cancer, unselected for age and family history; Francies et al confirmed that TNBC is a risk factor for hereditary breast cancer susceptibility in South Africa. To our knowledge, few other investigators have overcome the barriers of specimen acquisition and genotyping expenses to additionally characterize BRCA mutations in Africa. We demonstrated the feasibility of BRCA testing in Ghana through geneticists, surgeons, and pathologists collaborating to use surgical specimen resources for these studies; we furthermore confirmed an association between TNBC and high risk for BRCA mutations.