Breast cancer receptor status and stage at diagnosis in over 1,200 consecutive public hospital patients in Soweto, South Africa: a case series

Breast cancer receptor status, most commonly defined by estrogen-receptor (ER), progesterone-receptor (PR), and human epidermal growth factor receptor 2 (HER2) status in the clinical setting, has major implications for breast cancer prevention strategies and patient management [1, 2]. Studies of these markers in African women with breast cancer in sub-Saharan Africa (SSA) have had extremely variable findings; reported percentages of estrogen receptor negative (ERN) tumors range from 30% to 40% [3‐5] to >70% [6‐9]; in comparison, corresponding percentages in the United States are 35% in breast cancer patients aged 40 and decline to 15% to 20% by age 70, and are slightly higher in black than in white American women [10]. In SSA, for example, in 75 Ghanaian breast cancer patients, 76% were (ERN) based on receptor testing carried out on formalin-fixed paraffin-embedded specimens obtained in Ghana and transported to the United States for receptor assessment [9]. Similarly, in 500 tumor blocks from Nigeria and Senegal, half were triple negative [7]. At the other end of the spectrum, 27% of tumors were ERN among 192 Nigerian breast cancer patients in a setting in which immunohistochemistry (IHC) was routinely conducted prospectively at diagnosis [3]. The latter study is consistent with recent related results from breast cancers diagnosed in the United States in African-born women, of which 30% of tumors with known receptor status were ERN [11].

A well-known pitfall of ER testing is that results are highly sensitive to biopsy-tissue fixation and processing procedures. These factors have led to false negatives worldwide, as highlighted in the Consensus Recommendations on Estrogen Receptor Testing in Breast Cancer by Immunohistochemistry [12]. Ideally, receptor status is determined on biopsy specimens obtained before preoperative neoadjuvant chemotherapy, and IHC is conducted within a short time-frame to avoid antigen degradation [13]. Receptor-status data from some previous SSA studies may have been vulnerable to such biases because of a lack of routine receptor testing conducted at diagnosis. Additionally, if receptor status is determined from mastectomy tissue taken after neoadjuvant chemotherapy, the tumor phenotype may have evolved from its original status. Conversely, overall ERN proportions may be relatively high because of the relatively young population age-structure; ERN disease is more common in younger cases.

Knowledge of the receptor-status distribution among breast cancer patients in SSA is needed, given the uncertainty present and to improve our understanding of tumor biology, prevention targets, and prognosis. To begin to meet this need, we analyzed unique data from a large (>1,200) consecutive breast cancer case series from a public setting in South Africa where receptor status, including HER2, was routinely measured at diagnosis on prechemotherapy biopsy specimens. We examined breast cancer receptor status in relation to demographic and clinical characteristics and compared age-stratified ER status in black South African women with that in US white and black women. A formal assessment of missing receptor status, and racial comparisons between black, white, colored, and Asian South African women were also performed.

Over a period of 5 years 9 months, 1,247 breast cancers were diagnosed: 12 (1.0%) in men, and 19 (1.5%) carcinoma in situ in women (all were DCIS) were excluded hereafter (Table 1). The present analyses are restricted to the 1,216 women with invasive breast cancer, of whom 90% were black South African women, and the remaining 10% were white, colored, or Asian. Mean age at diagnosis was 55.3 years (standard deviation (SD) 14.3). Of the patients, 23% were diagnosed at stage I/IIA, 24% at stage IIB, and more than half (54%) at stages III/IV. About 89% were moderately/poorly differentiated (grade 2/3) tumors. Clinical notes mentioned ductal carcinoma for 80% of women, lobular in 4.2%, medullary/mucinous in 3.0%, inflammatory in 1.6%, papillary in 2.3%, and Paget disease for 0.6% (data not in tables).

In this large systematic study of breast cancer receptor status measured at diagnosis in a South African public hospital, we observed that (a) the majority (63%) of tumors were ER positive in black breast cancer patients, and triple-negatives constituted one fifth of tumors, that is, an overall subtype distribution not excessively different from that in the West, especially to that of US black women older than 50; (b) black women were more likely than nonblack women to have ERN or triple-negative breast cancer, and PRN and HER2P proportions were relatively high; (c) in the absence of any organized screening program, a decline occurred in the proportion of late-stage breast cancers in a population that previously had a very high proportion of late-stage presentation, suggesting possibilities for downstaging in low-resource settings. These combined observations indicate that very late-stage aggressive tumors may not be inherent features of the breast cancer burden throughout SSA. They suggest that, combined with appropriate and timely treatment, improvements in breast cancer survival rates may be realistic targets in this and comparable settings.

Based on >1,000 receptor-characterized tumors, ER positivity (65% overall and 63% in black women) in South African breast cancer patients was consistent with that of black American women older than 50 years and very similar to a Nigerian study (65%), which was also based on IHC at diagnosis, and to others in South Africa and Sudan [3‐5]. However, several African studies have reported that fewer than 40% of tumors were ERP [6‐9, 23]. One of the latter studies also observed that TRNs constituted >50% of tumors, compared with 20% observed here.

Several factors may contribute to these differences, including the age of breast cancer patients, stage at diagnosis, histopathologic methods, differential underlying risk-factor distributions, and ERP and ERN incidence rates and genetic heterogeneity across this vast continent. The average age at breast cancer diagnosis of 55 years in the present study is between 6 and 10 years older than that in most previous studies of receptor status from SSA [3, 6‐9] and may contribute to the lower ERN proportion in our study, although ERP tumors dominated even at premenopausal ages in Soweto. As expected, more late-stage tumors were ERN, as such tumors have more-aggressive growth, and tumor progression is associated with a loss of estrogen expression [24]. The latter factor may have also contributed to the lower ERN proportion in our study than in other SSA studies, as stage at diagnosis was earlier (54% stage III/IV in Soweto versus >80% in other studies). As the study design in a case series and incidence rates cannot be calculated, the lower ERN proportion in Soweto than in some other SSA settings may result from similar incidence rates of ERN breast cancer, but a higher incidence rate of ERP disease in Soweto. Urban South African women are more westernized than their counterparts elsewhere in Africa (for example, smaller family size, greater use of hormonal contraception) [25], which may have led to real increases in incidence rates for ERP breast cancer and thus to a larger total breast cancer burden with a greater proportion of ERP cases. Differences in findings within Africa may also have been influenced by specimen collection or storage conditions (detailed in the introduction). Notably, the studies with IHC conducted at diagnosis that are less affected by antigen degradation have shown that ERP tumors predominate. Additionally, nuclear-staining cutoffs in some historical studies were 10% or 11% [3, 8], as per the guidelines at the time, whereas 1% was used here. Applying the higher cutoff to our data, the ERN percentage would have increased from 35% to 43%. Determination of receptor-status relative frequencies in other African settings, including rural populations, is needed. Furthermore, as no single outright majority subtype exists, receptor classification is needed for clinical decision making, but is not always available in SSA. That the majority of tumors in this study were the better-prognosis ERP tumors is, meanwhile, an encouraging feature of this burden. Research is needed into whether the more-favorable prognostic profile in Sowetan breast cancer patients confers survival gains.

Although the majority breast cancer burden in this study was postmenopausal and ERP, nevertheless, one in three tumors was poorer-prognosis HER2P enriched or TRNs. The real HER2P percentage may be even higher, as 26% of tumors had a 2⁺ IHC HER2 staining score, and previous unpublished work at CHBAH comparing IHC and FISH HER2 status found that 50% of IHC HER2 2+ stains were FISH HER2P. Regardless of the HER2 assessment method, the percentage of HER2P tumors is higher than in several other reports in Africa [3, 7]. Thus, affordable treatment for HER2P tumors, by trastuzumab or other agents, is needed in this setting. Additionally, the proportion of tumors that were PRN (48%) was higher than in US data today and before the introduction of screening (33% to 39% PRN at age 50) [26]. Reexamination of these proportions in Africa, and an investigation of their drivers, are needed.

A predominance of bettERNprognosis luminal A and B tumors and the strong downstaging trend over time suggest that late stage at diagnosis in the South African setting may be driven to a greater extent by nonbiologic determinants of stage at diagnosis rather than by the predominance of an inherent aggressive rapidly growing tumor, but must be confirmed in other studies. Luminal A and B tumors, both ERP tumors, have good 5-year survival (about 90%) compared with <80% for HER2P and TRN tumors in US settings [18]. Whether subtype-specific tumors have different prognoses still must be investigated within African populations, but given the downstaging trends observed in this South African setting, the potential impact on lives saved can be estimated, assuming external stage-specific 5-year survival rates [27]. Of 1,000 women diagnosed with this improvement would result in an additional 80 women alive 5 years after diagnosis. The reasons for the observed downstaging are likely to be multifactorial, including factors at both the individual and health-system levels (for example, improving public awareness through media campaigns, faster referral, and a dedicated tertiary hospital breast clinic that was increasing in volume and ease of access). Importantly, these trends occurred within a resource-limited setting and without population-based screening, and demonstrate that earlier presentation is achievable in similar settings.

Further research is needed to evaluate the relative contributions to downstaging of all components of a woman’s journey from first noticing symptoms to diagnosis at CHBAH.

Black women were more likely to have ERNnegative tumors than were white, colored, or Asian South African breast cancer patients. Despite wide confidence intervals, the odds ratios for TRN, HER2P enriched, and luminal B versus luminal A tumors for black versus nonblack women were 2.0 (95% CI, 1.1 to 3.8), 2.2 (1.0 to 4.9), and 1.0 (0.6 to 1.8) (reciprocals of those already provided in Table 4), estimates that are remarkably similar to those found for African American versus non-African American women in the Carolina Breast Cancer Study (ORs of 2.1, 1.8, and 0.9, respectively) [18]. Racial differences in the South African study are unlikely to be due to differential early detection by screening mammography because women with medical aid coverage of screening mammograms are unlikely to be directed to CHBAH for diagnosis. Women with positive findings on screening mammography are likely to remain within the private sector for diagnostic workup and treatment. Indeed, all the women for whom we had referral information had been referred from a local health clinic or doctor, hospital, or were self-referrals.

The age distributions for ERN and PRP tumors in Soweto showed a dip in frequency distribution at age 60, which corresponds to the Clemmesen hook and reflects a plateauing of incidence rates at postmenopausal ages [20, 21]. HER2P tumors also displayed this feature of a younger age peak at age 50 and a dip at age 60; their age distribution was virtually equivalent to quite a distinct population (for example, in Hawaii [17]). However, differences in age distributions by ER-receptor status were not as pronounced as have been observed in high-risk populations such as the United States (younger distribution for ERN tumors) [17, 21]; thus ER proportions by age would benefit from re-investigation in other large breast cancer case series from Africa. Higher rates of ERP cancers at older ages in the United States are likely to account for this difference, because the major lifestyle transitions (early menarche, low parity, late childbearing, postmenopausal weight gain, less breastfeeding) are stronger risk factors for ERP breast cancer, and screening is more likely to detect these tumors [28]. In US, white and black women incidence rates of ERP breast cancer have increased, whereas for ERN tumors, they have decreased during the past 2 decades [10], driving an increasing percentage of ERP cancers over time and with age. In the same way, South Africa may be at an earlier stage of a breast cancer transition that will see an increasing rate of ERP disease as younger cohorts with less-traditional reproductive profiles reach postmenopausal ages.

This study is unique for this setting in terms of the sample size, IHC performed at diagnosis on prechemotherapy biospecimens in quality-controlled laboratories, and inclusion of HER2 expression. Analytically, we carefully assessed the influence of the 11% unknown receptor status; they were more likely to be ERN, as they were advanced tumors. The study is essentially a hospital-based case series, but it is likely to have fewer problems of underdiagnosis and thus a skewed patient profile that misrepresents the true population burden in rural and in lower-resource settings. The case series is likely to be representative of breast cancers in the public health sector of Soweto, as CHBAH provides affordable care and is easily accessible and known to the geographically close population (78% live within 25 km).

Although a greater proportion of black than nonblack South African women had ERN or TRN breast cancer, in all racial groups in this urban South African setting, breast tumors were predominantly ERP. We observed a strong trend of earlier stage at diagnosis over a 5–year period. Further research is needed to assess subtype-specific risk factors and subtype-specific survival in this setting. These findings provide initial indications that late-stage aggressive breast cancers may not be an inherent feature of the sub-Saharan African breast cancer burden.