Abstract
Purpose:
Advanced breast cancer (BC) at diagnosis is common in sub-Saharan Africa (SSA), including among women living with HIV (WLWH). In public hospitals across South Africa (SA), 10–15% of women present with stage IV BC, compared to <5% in the United States (US); 20% of new BC diagnoses in SA are in WLWH. We evaluated the impact of HIV on overall survival (OS) among women with stage IV BC.
Methods:
We conducted a prospective cohort study of women diagnosed with stage IV BC between February 2, 2015 and September 18, 2019 at six public hospitals in SA. Multivariate Cox regression models were used to estimate the association of HIV status on OS.
Results:
Among 550 eligible women, 147 (26.7%) were WLWH. Compared to HIV-negative BC patients, WLWH were younger (median age 45 vs. 60 years, p<0.001), predominantly black (95.9% vs. 77.9%, p<0.001), and more likely to have hormone receptor-negative (hormone-negative) BC (32.7% vs. 22.6%, p=0.016). Most women received systemic cancer-directed therapy (80.1%). HIV status was not associated with treatment or OS (Hazard Ratio (HR) 1.13 [95%CI 0.89–1.44]). On exploratory subgroup analysis, WLWH and hormone-negative BC had shorter OS compared to HIV-uninfected women (1-year OS: 27.1% vs. 48.8%, p=0.003; HR 1.94 [95%CI 1.27–2.94]; p=0.002), which was not observed for hormone receptor positive BC.
Conclusion:
HIV-status was not associated with worse OS in women with stage IV BC in SA and cannot account for the poor survival in this cohort. Subgroup analysis revealed that WLWH with hormone-negative BC had worse OS, which warrants further investigation.
Keywords: Breast Cancer, metastatic, HIV, sub-Saharan Africa
Introduction
South Africa (SA) has the largest HIV-infected population in the world (6.4 million people, 23.2% of adult women) and approximately 20% of women diagnosed with breast cancer (BC) across public hospitals in SA are women living with HIV (WLWH) [1, 2]. Late stage at BC diagnosis is also common in SA, with 10–15% of women presenting with metastatic (stage IV) BC, compared to <5% in the US [3–5].
Prior studies suggest that outcomes for stage IV BC patients in sub-Saharan Africa (SSA), including SA, are worse than in the US, although direct comparisons across studies from different settings are difficult to make [4, 6–11]. Studies have also demonstrated that HIV-infection adversely affects survival, both in the US and in HIV-endemic settings [11–15]; in 2019 Coghill et al [12] showed that WLWH with stage I-III BC in the US had higher overall mortality than HIV-uninfected women (Hazard Ratio (HR) 1.85 [95%CI 1.68–2.04], adjusted for treatment), and in 2020, McCormack et al [11] showed that among BC patients from five countries in SSA (14.4% with stage IV BC), WLWH had increased mortality compared to HIV-negative women (HR 1.48 [95%CI 1.22–1.81], age and stage adjusted). Multiple US studies have also shown that HIV-positive patients with cancer are less likely to receive cancer-directed therapy compared to HIV-negative patients [13, 16, 17]; in 2016 Suneja et al [17] reported that WLWH and BC were more than two times less likely to receive cancer treatment (Odds Ratio (OR) 2.14 [95%CI 1.16–3.98]) and that among HIV patients with cancer, stage IV was a strong predictor for not receiving cancer treatment (OR 2.60 [95%CI 1.93–3.51]).
Despite evidence from high-income countries, it is not known whether WLWH who present with stage IV BC in resource constrained healthcare settings receive equal treatment as their HIV-negative counterparts, and to our knowledge no studies have reported on whether survival in this population differs by HIV status. This topic is of significant clinical importance in HIV-endemic healthcare settings with high rates of advanced BC, such as the SA public healthcare system.
Using data from the South African Breast Cancer and HIV Outcomes (SABCHO) study [18], our group has previously shown that HIV status did not impact BC tumor characteristics or the quality of localized BC treatment received in SA [19–21]. The objective of the current study was to determine the association between HIV status and OS in stage IV BC when controlling for demographic and clinical factors, including treatment.
Methods
Data Source
The SABCHO study began enrolling women from six public health hospitals in SA in February 2015 [18]. Eligible women were >18 years old, newly diagnosed with BC, had no history of other cancers, received BC care at a study hospital, and signed informed consent. The participating hospitals were Chris Hani Baragwanath Academic Hospital (CHBAH), Johannesburg; Charlotte Maxeke Johannesburg Academic Hospital (CMJAH), Johannesburg; Grey’s Hospital (Grey’s), Pietermaritzburg; Ngwelezana Hospital (Ngwelezana), Empangeni; and Addington Hospital / Inkosi Albert Luthuli Central Hospital (analyzed as one site), Durban. Data was collected on patient demographics, tumor characteristics, BC treatments, and outcomes in a web-based electronic medical records system.
Patient Population
We identified all female patients who were diagnosed with de novo stage IV BC who enrolled in the SABCHO study between February 2, 2015 and September 18, 2019. All women had complete blood count, liver function tests, basic metabolic panel, chest X-ray and abdominal ultrasound as part of routine staging work up. Bone scans, other X-rays, and CT scans were done on an as-needed basis. Stage IV BC was defined as BC metastasis beyond the ipsilateral axilla relative to the primary tumor. We excluded patients without a confirmed pathologic diagnosis of BC, known BC hormone receptor status, or known HIV status.
Covariates and Outcomes
Data was collected on patient age at diagnosis, self-reported race/ethnicity, HIV status, highest level of education, body mass index (BMI), performance status, treatment hospital, BC clinical T-stage, Ki67 proliferation index, grade, hormone and HER2 receptor status, site of metastatic disease, systemic therapy (receipt of any chemotherapy and/or endocrine therapy), chemotherapy drugs received (none, anthracycline, taxane, anthracycline and taxane, or other), and surgical resection of primary breast mass. Patients with equivocal HER2 testing by immunohistochemistry (i.e., HER2 2+ with missing confirmatory HER2 fluorescence in situ hybridization testing) were treated as HER2 negative. Data on receipt of HER2 targeted therapy was not collected, as such agents are not available for treatment of metastatic BC in South African public hospitals. For WLWH, CD4 count, HIV viral load, and time on anti-retroviral therapy (ART) were recorded at enrollment. A wealth index was derived from a survey of household wealth, including questions on electricity and water sources, toilet facilities, and ownership of various amenities, as previously described [21]. Patients were grouped into wealth quintiles using the first principal component of a principal component analysis of survey responses. Treatment and outcome data were collected through June 30, 2020. Patients were contacted every 3 months after enrollment to determine vital status. If the patient, next of kin, and other provided person of contact were unable to be reached for two consecutive follow up calls, we searched publicly available administrative data to try and determine vital status for that patient. If no additional information about vital status could be obtained, the patient was censored at last date she was known to be alive. Overall survival (OS) was defined as time from first diagnostic biopsy to death from any cause.
Statistical Analysis
Descriptive statistics were used to report baseline demographic and clinical characteristics; we used the chi-squared test (χ2) for categorical variables and the Mann-Whitney U test for continuous variables to evaluate differences between patients based on HIV status. We used Kaplan-Meier curves to estimate OS by HIV in the overall cohort and by hormone receptor status; we compared mortality using the log-rank test. In an exploratory analysis we compared OS in WLWH by baseline HIV characteristics (i.e.: CD4 count, time on ART, and HIV viral load). We report sensitivity analyses for black women only for all comparisons.
We tested all variables for association with OS using univariable Cox proportional hazard models, and all variables with a p-value <0.1 (i.e., ethnicity, performance status, treatment hospital, T-stage, tumor grade, hormone and HER2 receptor status, Ki67, site of metastatic disease, receipt of chemotherapy, endocrine therapy, systemic therapy and surgery) were considered for a multivariable Cox model for the entire cohort. Ultimately, we excluded self-reported race/ethnicity due to high co-linearity with HIV, excluded tumor grade due to a high number of missing values and co-linearity with Ki67, and included only the composite treatment variable systemic therapy. We included age and HIV status in our final model as the literature shows that they impact BC survival. We used our final model to analyze the full cohort and to perform sensitivity analysis on the subset of only black women. Exploratory subgroup analysis was also performed by hormone receptor status. All statistical analyses were done using R version 1.3.1093. The study was approved by the University of the Witwatersrand Human Research Ethics Committee and the Institutional Review Board of Columbia University.
Results
Baseline Characteristics
Between February 2, 2015 and September 18, 2019, we enrolled 3,560 women in the SABCHO cohort. Of these, we excluded 2,992 women diagnosed with stage I-III BC, 6 with duplicate identification numbers, 4 with unknown hormone receptor status, and 8 with unknown HIV status. Of the remaining 550 eligible women, 147 were WLWH (26.7%).
The overwhelming majority of WLWH self-identified as black (95.9% vs. 77.9% in the HIV-negative cohort, p<0.001). The population of WLWH differed from uninfected women on multiple baseline characteristics; these differences persisted when the analysis was restricted to black women only (Table 1). In the entire cohort, WLWH were younger at diagnosis (age <50 years: 63.9% vs. 24.3%, p<0.001), more likely to have completed secondary education (77.6% vs. 60.8%, p<0.001), and less likely to be in the highest wealth index (5.4% vs. 24.8%, p<0.001). Fewer WLWH than HIV-uninfected women had hormone receptor-positive (hormone-positive) BC (67.3% vs. 77.4%, p=0.02) and visceral metastases were more common in WLWH (59.9% vs. 50.1%, p=0.043). The rate of HER2 positive BC was equal between the two groups (25.3% overall).
Table 1:
Baseline Characteristics of Women with Stage IV Breast Cancer Enrolled in the SABCHO cohort (2015–2019), stratified by HIV status and Self-Identified Ethnicity
| All Women | Black Women | |||||||
|---|---|---|---|---|---|---|---|---|
| HIV − (N=403) | HIV + (N=147) | Total (N=550) | p-value | HIV − (N=314) | HIV + (N=141) | Total (N=455) | p-value | |
| Age (years) | < 0.001 | < 0.001 | ||||||
| <50 | 98 (24.3%) | 94 (63.9%) | 192 (34.9%) | 78 (24.8%) | 91 (64.5%) | 169 (37.1%) | ||
| >/=50 | 305 (75.7%) | 53 (36.1%) | 358 (65.1%) | 236 (75.2%) | 50 (35.5%) | 286 (62.9%) | ||
| Race/Ethnicity | < 0.001 | |||||||
| Black | 314 (77.9%) | 141 (95.9%) | 455 (82.7%) | 314 (100.0%) | 141 (100.0%) | 455 (100.0%) | ||
| Others | 89 (22.1%) | 6 (4.1%) | 95 (17.3%) | - | - | - | ||
| Education | 0.001 | < 0.001 | ||||||
| Primary | 156 (38.7%) | 33 (22.4%) | 189 (34.4%) | 133 (42.4%) | 32 (22.7%) | 165 (36.3%) | ||
| Secondary | 245 (60.8%) | 114 (77.6%) | 359 (65.3%) | 179 (57.0%) | 109 (77.3%) | 288 (63.3%) | ||
| Missing | 2 (0.5%) | 0 (0.0%) | 2 (0.4%) | 2 (0.6%) | 0 (0.0%) | 2 (0.4%) | ||
| Wealth Index | < 0.001 | 0.010 | ||||||
| 1 | 69 (17.1%) | 39 (26.5%) | 108 (19.6%) | 60 (19.1%) | 31 (22.0%) | 91 (20.0%) | ||
| 2 | 72 (17.9%) | 39 (26.5%) | 111 (20.2%) | 55 (17.5%) | 36 (25.5%) | 91 (20.0%) | ||
| 3 | 75 (18.6%) | 36 (24.5%) | 111 (20.2%) | 59 (18.8%) | 32 (22.7%) | 91 (20.0%) | ||
| 4 | 87 (21.6%) | 25 (17.0%) | 112 (20.4%) | 64 (20.4%) | 27 (19.1%) | 91 (20.0%) | ||
| 5* | 100 (24.8%) | 8 (5.4%) | 108 (19.6%) | 76 (24.2%) | 15 (10.6%) | 91 (20.0%) | ||
| Body Mass Index | 0.063 | 0.010 | ||||||
| <25 | 97 (24.1%) | 51 (34.7%) | 148 (26.9%) | 65 (20.7%) | 50 (35.5%) | 115 (25.3%) | ||
| 25–30 | 107 (26.6%) | 30 (20.4%) | 137 (24.9%) | 82 (26.1%) | 29 (20.6%) | 111 (24.4%) | ||
| >30 | 166 (41.2%) | 52 (35.4%) | 218 (39.6%) | 136 (43.3%) | 49 (34.8%) | 185 (40.7%) | ||
| Missing | 33 (8.2%) | 14 (9.5%) | 47 (8.5%) | 31 (9.9%) | 13 (9.2%) | 44 (9.7%) | ||
| Hospital | 0.059 | 0.425 | ||||||
| Durban | 111 (27.5%) | 26 (17.7%) | 137 (24.9%) | 57 (18.2%) | 24 (17.0%) | 81 (17.8%) | ||
| CHBAH | 100 (24.8%) | 43 (29.3%) | 143 (26.0%) | 96 (30.6%) | 41 (29.1%) | 137 (30.1%) | ||
| CMJAH | 90 (22.3%) | 28 (19.0%) | 118 (21.5%) | 74 (23.6%) | 26 (18.4%) | 100 (22.0%) | ||
| Greys | 90 (22.3%) | 42 (28.6%) | 132 (24.0%) | 77 (24.5%) | 42 (29.8%) | 119 (26.2%) | ||
| Ngwelazane | 12 (3.0%) | 8 (5.4%) | 20 (3.6%) | 10 (3.2%) | 8 (5.7%) | 18 (4.0%) | ||
| Performance Status | 0.309 | 0.450 | ||||||
| 0 & 1 | 304 (75.4%) | 117 (79.6%) | 421 (76.5%) | 237 (75.5%) | 111 (78.7%) | 348 (76.5%) | ||
| 2 – 4 | 99 (24.6%) | 30 (20.4%) | 129 (23.5%) | 77 (24.5%) | 30 (21.3%) | 107 (23.5%) | ||
| T stage | 0.192 | 0.237 | ||||||
| T0-T3 | 101 (25.1%) | 45 (30.6%) | 146 (26.5%) | 77 (24.5%) | 42 (29.8%) | 119 (26.2%) | ||
| T4 | 302 (74.9%) | 102 (69.4%) | 404 (73.5%) | 237 (75.5%) | 99 (70.2%) | 336 (73.8%) | ||
| Grade | 0.275 | 0.910 | ||||||
| 1 | 16 (4.0%) | 4 (2.7%) | 20 (3.6%) | 12 (3.8%) | 4 (2.8%) | 16 (3.5%) | ||
| 2 | 163 (40.4%) | 67 (45.6%) | 230 (41.8%) | 136 (43.3%) | 64 (45.4%) | 200 (44.0%) | ||
| 3 | 118 (29.3%) | 48 (32.7%) | 166 (30.2%) | 101 (32.2%) | 47 (33.3%) | 148 (32.5%) | ||
| Missing | 106 (26.3%) | 28 (19.0%) | 134 (24.4%) | 65 (20.7%) | 26 (18.4%) | 91 (20.0%) | ||
| Hormone Receptor | 0.016 | 0.043 | ||||||
| Positive | 312 (77.4%) | 99 (67.3%) | 411 (74.7%) | 240 (76.4%) | 95 (67.4%) | 335 (73.6%) | ||
| Negative | 91 (22.6%) | 48 (32.7%) | 139 (25.3%) | 74 (23.6%) | 46 (32.6%) | 120 (26.4%) | ||
| HER2 Receptor | 0.082 | 0.136 | ||||||
| Negative | 309 (76.7%) | 102 (69.4%) | 411 (74.7%) | 237 (75.5%) | 97 (68.8%) | 334 (73.4%) | ||
| Positive | 94 (23.3%) | 45 (30.6%) | 139 (25.3%) | 77 (24.5%) | 44 (31.2%) | 121 (26.6%) | ||
| Ki67 Index | 0.259 | 0.315 | ||||||
| </=20 | 175 (43.4%) | 53 (36.1%) | 228 (41.5%) | 126 (40.1%) | 49 (34.8%) | 175 (38.5%) | ||
| >20 | 223 (55.3%) | 91 (61.9%) | 314 (57.1%) | 185 (58.9%) | 89 (63.1%) | 274 (60.2%) | ||
| Missing | 5 (1.2%) | 3 (2.0%) | 8 (1.5%) | 3 (0.01%) | 3 (0.02%) | 6 (0.01%) | ||
| Metastatic Site | 0.043 | 0.030 | ||||||
| Non-visceral | 201 (49.9%) | 59 (40.1%) | 260 (47.3%) | 157 (50.0%) | 55 (39.0%) | 212 (46.6%) | ||
| Visceral | 202 (50.1%) | 88 (59.9%) | 290 (52.7%) | 157 (50.0%) | 86 (61.0%) | 243 (53.4%) | ||
| Time to diagnosis | 0.142 | 0.218 | ||||||
| <6 months | 172 (42.7%) | 75 (51.0%) | 247 (44.9%) | 134 (42.7%) | 70 (49.6%) | 204 (44.8%) | ||
| ≥6 months | 228 (56.6%) | 72 (49.0%) | 300 (54.5%) | 177 (56.4%) | 71 (50.4%) | 248 (54.5%) | ||
| Missing | 3 (0.7%) | 0 (0.0%) | 3 (0.5%) | 3 (1.0%) | 0 (0.0%) | 3 (0.7%) | ||
| CD4 count | - | - | ||||||
| <250 cells/mm3 | - | 16 (11.7%) | - | - | 15 (11.4%) | - | ||
| ≥250 cells/mm3 | - | 121 (88.3%) | - | - | 117 (88.6%) | - | ||
| Missing | - | 10 | - | - | 9 | - | ||
| HIV Viral Load | - | - | ||||||
| Undetected | - | 66 (50.4%) | - | - | 65 (51.2%) | - | ||
| Detected | - | 65 (49.6%) | - | - | 62 (48.8%) | - | ||
| Missing | - | 16 | - | - | 14 | - | ||
| On ART | - | - | ||||||
| No | - | 36 (24.5%) | - | - | 34 (24.1%) | - | ||
| Yes | - | 111 (75.5%) | - | - | 107 (75.9%) | - | ||
| ART (years) | - | - | ||||||
| Median (IQR) | - | 6 (3.0–9.0) | - | - | 6.0 (3.0–9.0) | - | ||
ART = antiretroviral therapy, IQR=interquartile range
Wealthiest
Among the 147 WLWH in our cohort, 111 women (75.5%) were already on antiretroviral therapy (ART) at time of BC diagnosis, and the remaining 36 women were initiated on ART at BC diagnosis. At time of BC diagnosis, the median duration of ART treatment among WLWH was 6 years [interquartile range (IQR) 3 to 9 years], the median CD4 cell count was 490 cells/mm3 [IQR 340–720], and 66 women (49.6%) had an undetectable HIV viral load (Table 1). There were no differences in the baseline HIV treatment and immune status of WLWH, stratified by BC hormone receptor status, except that WLWH diagnosed with hormone-negative BC were more likely to have an undetectable HIV viral load, compared to WLWH diagnosed with hormone-positive BC (62.2% vs. 44.2%, p=0.050).
Breast Cancer Treatment
The majority of women in our cohort (80.9%) received systemic anti-cancer therapy (endocrine therapy, chemotherapy, or both), with no difference by HIV status. There were also no differences by HIV status for receipt of chemotherapy, palliative surgery of the primary tumor, or hormonal therapy (hormone-positive BC only) (Table 2). HER2-directed therapies are not available for the treatment of women with metastatic BC in the South African public hospitals, thus no women in our cohort received such therapies. Among the 105 patients who did not receive any systemic therapy, 59 (56.2%) died prior to receiving the first dose of prescribed therapy. Although more WLWH were not recommended for systemic therapy than HIV-uninfected women, the absolute difference was small and did not reach statistical significance (17.6% vs. 7.0% of those not receiving therapy, p=0.062).
Table 2:
Treatment Characteristics of Women with Stage IV Breast Cancer Enrolled in the SABCHO cohort (2015–2019), stratified by HIV status and Self-Identified Ethnicity
| All Women | Black Women | |||||||
|---|---|---|---|---|---|---|---|---|
| HIV − (N=403) | HIV + (N=147) | Total (N=550) | p-value | HIV − (N=314) | HIV + (N=141) | Total (N=455) | p-value | |
| Systemic Therapy | 0.146 | 0.257 | ||||||
| Yes* | 332 (82.4%) | 113 (76.9%) | 445 (80.9%) | 255 (81.2%) | 108 (76.6%) | 363 (79.8%) | ||
| No | 71 (17.6%) | 34 (23.1%) | 105 (19.1%) | 59 (18.8%) | 33 (23.4%) | 92 (20.2%) | ||
| Reason For No Systemic Therapy | 0.062 | 0.073 | ||||||
| (N=71) | (N=34) | (N=105) | (N=59) | (N=33) | (N=92) | |||
| Died | 40 (56.3%) | 19 (55.9%) | 59 (56.2%) | 34 (57.6%) | 19 (57.6%) | 53 (57.6%) | ||
| Local therapy only | 6 (8.5%) | 0 (0.0%) | 6 (5.7%) | 5 (8.5%) | 0 (0.0%) | 5 (5.4%) | ||
| Not recommended | 5 (7.0%) | 6 (17.6%) | 11 (10.5%) | 5 (8.5%) | 6 (18.2%) | 11 (12.0%) | ||
| Refused | 16 (22.5%) | 4 (11.8%) | 20 (19.0%) | 12 (20.3%) | 3 (9.1%) | 15 (16.3%) | ||
| Missing | 4 (5.6%) | 5 (14.7%) | 9 (8.6%) | 3 (5.1%) | 5 (15.2%) | 8 (8.7%) | ||
| Time to Systemic Treatment | 0.101 | 0.268 | ||||||
| (N=332) | (N=113) | (N=455) | (N=255) | (N=108) | (N=363) | |||
| <6 months | 225 (67.8%) | 67 (59.3%) | 292 (65.6%) | 169 (66.3%) | 65 (60.2%) | 234 (64.5%) | ||
| ≥6 months | 107 (32.2%) | 46 (40.7%) | 153 (34.4%) | 86 (33.7%) | 43 (39.8%) | 129 (35.5%) | ||
| Chemotherapy | 0.205 | 0.807 | ||||||
| Yes | 214 (53.1%) | 87(59.2%) | 301 (54.7%) | 181 (57.6%) | 83(58.9%) | 264 (58.0%) | ||
| No | 189 (46.9%) | 60(40.8%) | 249 (45.3%) | 133 (42.4%) | 58(41.1%) | 191 (42.0%) | ||
| Palliative Breast Surgery | 0.311 | 0.222 | ||||||
| Yes | 48 (11.9%) | 13(8.8%) | 61 (11.1%) | 39 (12.4%) | 12(8.5%) | 51 (11.2%) | ||
| No | 355 (88.1%) | 134 (91.2%) | 489 (88.9%) | 275 (87.6%) | 129 (91.5%) | 404 (88.8%) | ||
| Hormonal Therapy (Hormone-positive) | 0.481 | 0.239 | ||||||
| (N=312) | (N=99) | (N=411) | (N=240) | (N=95) | (N=335) | |||
| Yes | 212 (67.9%) | 71(71.7%) | 283 (68.9%) | 153 (63.8%) | 67(70.5%) | 220 (65.7%) | ||
| No | 100 (32.1%) | 28(28.3%) | 128 (31.1%) | 87 (36.2%) | 28(29.5%) | 115 (34.3%) | ||
| Chemotherapy Received | 0.049 | 0.126 | ||||||
| (N=214) | (N=87) | (N=301) | (N=181) | (N=83) | (N=264) | |||
| Anthracycline + Taxane | 44 (20.6%) | 29 (33.3%) | 73 (24.3%) | 39 (21.5%) | 27 (32.5%) | 66 (25.0%) | ||
| Anthracycline | 120 (56.1%) | 47 (54.0%) | 167 (55.5%) | 100 (55.2%) | 45 (54.2%) | 145 (54.9%) | ||
| Taxane | 43 (20.1%) | 10 (11.5%) | 53 (17.6%) | 36 (19.9%) | 10 (12.0%) | 46 (17.4%) | ||
| Other | 7 (3.3%) | 1 (1.1%) | 8 (2.7%) | 6 (3.3%) | 1 (1.2%) | 7 (2.7%) | ||
| Median (IQR) Follow Up Time in Months | 14.8 (6.5–25.4) | 10.5 (4.4–23.0) | 14.2 (5.5–25.0) | 0.063 | 14.4 (5.3–24.0) | 10.5 (4.1–22.9) | 13.5 (4.7–24.0) | 0.210 |
Chemotherapy, endocrine therapy, or both.
Overall Survival
The median follow-up for the entire cohort was 14.2 months (IQR (inter quartile range), 5.5–25.1 months). At the time of data analysis, 428 women had died (77.8%). The unadjusted 1-year OS was 57.5% [95%CI 53.2–61.5] for all women, and 55.2% [95%CI 50.5–59.7] for black women. There was a trend toward shorter OS among WLWH in the entire cohort, but this did not meet the statistical significance cut off (1-year OS for all women: 48.8% [95%CI 40.5–56.6] vs. 60.7% [95%CI 55.7–65.3] for HIV-infected vs. HIV-uninfected, p=0.09; Figure 1). Among black women there was no difference in OS by HIV-status (1-year OS for black women: 48.8% [95%CI 40.3–56.7] vs. 58.1% [95%CI 52.4–63.4]; p=0.29).
Fig. 1.
Overall Survival in Women with Stage IV Breast Cancer Enrolled in the SABCHO cohort (2015–2019), by HIV status
In an exploratory analysis, OS did not differ by HIV status among women with hormone-positive BC (Figure 2A: 1-year OS 59.4% [50.5–70.0%] vs. 64.1% [59.0–69.7%] for HIV-infected vs. uninfected women, p=0.95). However, WLWH with hormone receptor-negative (hormone-negative) BC had a shorter OS compared to HIV-uninfected women (Figure 2B: 1-year OS 27.1% [17.0–43.1%] vs. 48.8% [39.5–60.3%], p=0.003). A similar trend was observed in the subgroup analysis of black women only. We further explored OS among women living with HIV by baseline HIV characteristics (CD4 count, time on ART and HIV viral load) and found no differences (Supplementary Figure 1).
Fig. 2.
Overall Survival in Women with Stage IV Breast Cancer Enrolled in the SABCHO cohort (2015–2019), by Hormone Receptor and HIV status
(A) Hormone-Positive Breast Cancer
(B) Hormone-Negative Breast Cancer
Multivariate Analysis
Our final multivariate model for OS included HIV status, age, treatment hospital, performance status, T-stage, hormone receptor status, HER2 receptor status, Ki67, metastatic site, receipt of systemic treatment and palliative surgery. HIV status was not associated with OS (HR 1.13 [95%CI 0.89–1.44], p=0.32), while worse performance status, hormone-negative BC, Ki67 >20%, T4 disease, and visceral metastasis were. Receipt of systemic therapy and locoregional therapy with palliative surgery were associated with better survival. The multivariate analysis did not differ substantially for black women only (Table 3). There remained no association between HIV and worse OS among black women (HR 1.08 [95% CI 0.84–1.40], p=0.55).
Table 3:
Multivariate Cox Proportional Hazard Ratio Model of Risk Factors for Mortality in Women with Stage IV Breast Cancer Enrolled in the SABCHO cohort (2015–2019), stratified by Self-Identified Ethnicity
| All Women | Black Women | |||
|---|---|---|---|---|
| Events (N) | 421/542* | 351/449** | ||
| HR (95% CI) | P-value | HR (95% CI) | P-value | |
| HIV | ||||
| Negative | 1.00 | 1.00 | ||
| Positive | 1.13 (0.89–1.44) | 0.32 | 1.08 (0.84–1.40) | 0.55 |
| Age (years) | ||||
| <50 | 1.00 | 1.00 | ||
| ≥50 | 1.16 (0.93– 1.46) | 0.20 | 1.20 (0.94–1.53) | 0.15 |
| Hospitals | ||||
| Durban | 1.00 | 1.00 | ||
| CHBAH | 1.36 (1.00–1.86) | 0.049 | 1.28 (0.89–1.83) | 0.18 |
| CMJAH | 1.14 (0.83–1.56) | 0.42 | 1.14 (0.79–1.65) | 0.48 |
| Greys | 1.18 (0.87–1.61) | 0.29 | 1.05 (0.73–1.51) | 0.81 |
| Ngwelazane | 1.12 (0.64–1.95) | 0.69 | 1.07 (0.58–1.98) | 0.82 |
| Performance Status | ||||
| 0 – 1 | 1.00 | 1.00 | ||
| 2 – 4 | 2.01 (1.60–2.53) | <0.001 | 2.09 (1.63–2.68) | <0.001 |
| T stage | ||||
| T0-T3 | 1.00 | 1.00 | ||
| T4 | 1.60 (1.27–2.02) | <0.001 | 1.56 (1.20–2.01) | 0.001 |
| Hormone Receptor | ||||
| Positive | 1.00 | 1.00 | ||
| Negative | 1.39 (1.10–1.76) | 0.006 | 1.46 (1.13–1.87) | 0.003 |
| HER2 Receptor | ||||
| Negative | 1.00 | 1.00 | ||
| Positive | 1.07 (0.85–1.35) | 0.56 | 1.07 (0.83–1.37) | 0.60 |
| KI67 Index | ||||
| ≤20 | 1.00 | 1.00 | ||
| >20 | 1.47 (1.18–1.83) | 0.001 | 1.51 (1.19–1.93) | 0.001 |
| Metastatic site | ||||
| Non-visceral | 1.00 | 1.00 | ||
| Visceral | 1.31 (1.06–1.61) | 0.01 | 1.34 (1.07–1.69) | 0.01 |
| Had surgery | ||||
| No | 1.00 | 1.00 | ||
| Yes | 0.50 (0.35–0.72) | <0.001 | 0.44 (0.29–0.67) | <0.001 |
| Had systemic therapy | ||||
| No | 1.00 | 1.00 | ||
| Yes | 0.12 (0.09–0.16) | <0.001 | 0.12 (0.09–0.17) | <0.001 |
8 observations deleted due to missingness
6 observations deleted due to missingness
We performed an exploratory subgroup analysis by BC hormone receptor status and found that, in a multivariate model including HIV status, age, performance status, metastatic site, palliative surgery, and receipt of chemotherapy, HIV-positive status was associated with worse OS among women with hormone-negative BC (HR 1.94 [95%CI 1.27–2.94], p=0.002), but not among women with hormone-positive BC (HR 1.24 [95%CI 0.92–1.66], p=0.15).
Discussion
In this study we report survival in a large prospective cohort of predominantly black African women (26.7% WLWH) diagnosed with stage IV BC in six different public hospitals in SA. BC stage at diagnosis is a strong predictor of survival [11], and our results from a resource constrained setting confirm that this population has very poor outcomes. We analyzed the effect of HIV on the survival of women with stage IV BC in an effort to understand whether HIV infection contributes to the poor prognosis in this patient population.
On adjusted multivariate analysis HIV-infection was not associated with OS in stage IV BC patients (HR 1.13 [95%CI 0.89–1.44], p=0.32). On exploratory subgroup analysis, HIV was associated with worse OS in women with hormone-negative BC (1-year OS 27.1% vs. 48.8%, p=0.003; HR 1.94 [95%CI 1.27–2.94], p=0.002), but not in women with hormone-positive BC (1-year OS 59.4% vs. 64.1%, p=0.95; HR 1.24 [95%CI 0.92–1.66], p=0.15).
Contrary to our results, studies that either limited analysis to women with localized BC only, or analyzed cohorts with only a small percentage of women with stage IV BC, have consistently shown that HIV negatively impacts survival [12–14]. For example, a study using the National Cancer Data Base in the US reported higher mortality after BC diagnosis in 957 WLWH compared to HIV-uninfected women (HR 1.85 [95%CI 1.68–2.04]) [12], and a study analyzing linked US registries of HIV/AIDs and cancer patients reported higher BC-specific mortality among 314 WLWH compared to HIV-uninfected women (HR 2.61 [95%CI 2.06–3.31]) [14]. Greater all-cause mortality was also seen among 315 WLWH in the prospective African Breast Cancer Disparities Outcome study (HR 1.48 [95%CI 1.22–1.81]) [11], and in a prospective study of 19 WLWH compared to 81 HIV-uninfected BC patients in Malawi (HR 5.15 [95%CI 1.58–16.76]) [15]. In contrast, in our analysis of women with stage IV BC in SA, HIV infection was not associated with OS.
A possible explanation for our results is that WLWH have poor tolerance to chemotherapy, leading to dose delays and dose reductions that impact survival in localized BC patients but not in stage IV BC. Receipt of adjuvant chemotherapy at a minimum relative dose intensity of 85% is associated with improved disease-free survival and OS in localized BC [22–24]; conversely dose delays and dose reductions of cytotoxic chemotherapy have not been shown to adversely affect survival in stage IV BC [25]. A retrospective study from Memorial Sloan Kettering Cancer Center supports the notion that WLWH do not tolerate cytotoxic treatment as well as HIV-uninfected women, with WLWH treated for BC needing more dose reductions and experiencing more chemotherapy delays due to toxicity (56% vs 30%, p=0.03) [26].
Poor tolerance to chemotherapy among WLWH may also explain results from our exploratory analysis, which revealed a differential effect of HIV on BC survival by hormone receptor status. Although WLWH in our cohort were just as likely as HIV-uninfected women to initiate systemic anti-cancer therapy, we did not capture data on chemotherapy doses, dose reductions, or dose delays, and thus were unable to compare tolerance of cytotoxic treatment between HIV-infected and uninfected women. If dose reductions and/or delays of cytotoxic therapy were more common among WLWH, we would expect this to have the greatest impact on survival of women with hormone-negative BC, as demonstrated in our results. Multiple randomized controlled trials comparing upfront chemotherapy followed by hormonal therapy versus hormonal therapy alone in metastatic hormone-positive BC have failed to show an OS advantage for upfront chemotherapy [27–29]. Thus, dose reductions of cytotoxic chemotherapy in WLWH with hormone-positive stage IV BC are less likely to impact OS, compared to reductions in hormone-negative BC, where endocrine therapy is ineffective.
We also considered whether the results of our exploratory analysis may be driven by more women with uncontrolled HIV in the hormone receptor positive BC subgroup compared to the hormone receptor negative subgroup. However, there was no difference in the median CD4 count, percent of women on ART, and median time on ART among WLWH, stratified by BC hormone receptor status. Additionally, overall survival among WLWH stratified by baseline HIV characteristics (CD4 count, time on ART and HIV viral load) showed no difference in the overall cohort (Supplementary Figure 1) or when the cohort was stratified by BC hormone receptor status. Thus, it is unlikely that the difference in OS by HIV status in the hormone-negative versus hormone-positive BC groups can be explained by a difference in the baseline HIV treatment or immune status of WLWH.
Although HIV positive status was not associated with worse OS in our overall stage IV BC population, several known prognostic factors, such as T-stage, Ki67 index, hormone receptor subtype, performance status, site of metastatic disease, and systemic treatment, had the expected impact on OS (Table 3). Our findings are consistent with studies showing that prognostic factors in stage IV BC are similar to those in localized BC, and that the initial site of metastatic disease impacts OS [6, 30, 31]. In addition to systemic therapy, locoregional therapy with palliative surgery was also associated with improved OS in our cohort; this finding must be interpreted with caution due to selection bias whereby fit patients without visceral metastases are more likely to undergo surgery [6, 32]. The randomized controlled trial ECOG-ACRIN E2018 showed that there is no difference in OS between women with stage IV BC randomized to locoregional resection and systemic therapy versus systemic therapy alone [33].
While it is difficult to compare survival across studies, we do note that the median and 1-year OS of our cohort is significantly shorter than that reported in the US and other low and middle-income countries [6, 34]; social determinants of health, including poverty, distance to treatment hospital, and diagnostic delays, are likely contributing. In addition, lack of access to HER2-directed therapies, CDK4/6 inhibitors, and later lines of cytotoxic chemotherapy is another important consideration in this setting. Our findings concur with prior studies, which have not found HIV to be a major contributor to the poor survival of women with BC in SSA [11].
Strengths and Limitations
Our study has multiple strengths, including a large prospective cohort made up of >25% HIV-positive women, very little missing information, and minimal loss to follow up. This is one of the most complete datasets of stage IV BC patients treated in SSA, and one of very few studies providing information on HIV treatment and immune status of WLWH and BC. Our study provides crucial information for providers who routinely care for WLWH with advanced BC. Our dataset is compiled from six different public hospitals in SA, minimizing the chances that our results are due to differential treatment of HIV-positive patients in a single institution.
Our results should be considered within the limitations of our dataset and study design. Our cohort is comprised of predominantly black African women treated in a resource constrained setting, and our findings may or may not be readily applicable to WLWH in well-resourced healthcare settings, where there is greater availability of first-line targeted BC therapies as well as access to multiple lines of treatment at time of progression. Although our dataset included cancer treatment data and allowed us to control for treatment initiation, data on dose reductions and dose delays were not captured. We were, therefore, unable to take into account these clinically relevant treatment factors, which may have differed according to HIV status.
In addition, although we report that WLWH in our cohort were younger than HIV-negative women at time of BC diagnosis (median age 45 vs. 60 years, p<0.001), this finding should be interpreted with caution, as we were unable to adjust for the differences in age distribution between these two populations, which may have changed our results. For example, in a large analysis from the US that adjusted for age distribution differences between the HIV-positive and HIV-negative populations, there was no difference in age at BC diagnosis between WLWH and HIV-negative women (median observed age among AIDs population of 44.5 years compared to an expected age in the general population of 46 years, p=0.177)[35]. Future studies comparing WLWH and HIV-negative women with BC should adjust for differences in population age distribution. Finally, we do not have details on the exact antiretroviral therapies that WLWH were treated, and thus are unable to explore differences in survival among WLWH treated with protease inhibitor-based versus non-nucleoside reverse transcriptase inhibitor-based regimens.
Conclusions
In this prospective study of women diagnosed with stage IV BC in SA, anti-cancer treatment did not differ by HIV status and HIV status was not associated with overall survival (HR 1.13 [95%CI 0.89–1.44], p=0.32). However, on exploratory subgroup analysis HIV-infected women with hormone-negative stage IV BC had a significantly shorter overall survival compared to HIV-uninfected women, a difference not seen in women with hormone-positive disease. This is a novel finding that warrants further investigation and validation; future studies should collect detailed treatment information on chemotherapy types and doses received.
Supplementary Material
Supplementary Fig.1 Overall Survival in HIV-Positive Women with Stage IV Breast Cancer Enrolled in the SABCHO cohort (2015–2019), by baseline HIV characteristics
(A) CD4 count
(B) Length of Time on Antiretroviral Treatment
(C) HIV Viral Load at Breast Cancer Diagnosis
Funding:
This study was funded by NIH grant (NCI R01CA192627 and R01CA250012) to Drs. Jacobson, Joffe, Neugut and Ruff; a University of Witwatersrand/South African Medical Research Council / University of the Witwatersrand Common Epithelial Cancer Research Centre grant to Dr. Ruff; and Dr. Neugut is funded in part by CCSG P30 CA13696. Dr. O’Neil is a K12 Scholar supported by the National Cancer Institute of the National Institutes of Health under Award Number K12CA226330. Dr. Pumpalova is funded by NIH T32 training grant (T32 CA094061) awarded to the Department of Epidemiology at the Columbia University Mailman School of Public Health.
Conflicts of interest/Competing interests:
Dr. Neugut has received consulting fees from Otsuka, United Biosource Corp, Hospira, Eisai, and GlaxoSmithKline, and is on the medical advisory board of EHE Intl. He has also received research funding from Otsuka. Dr. Ruff has received honoraria from Sanofi, Amgen, and Roche and research funding from Amgen, Sanofi, Merck and Novartis. All other authors declare they have no conflicts of interest.
List of Abbreviations:
- ART
antiretroviral therapy
- BC
breast cancer
- BMI
body mass index
- IQR
interquartile range
- HR
hazard ratio
- OS
overall survival
- SA
South Africa
- SABCHO
South African Breast Cancer and HIV Outcomes study
- SSA
sub-Saharan Africa
- US
United States of America
- WLWH
women living with HIV
Footnotes
Ethics approval: Approval was obtained from the ethics committees of Columbia University and the University of Witwatersrand. The procedures used in this study adhere to the tenets of the Declaration of Helsinki.
Consent to participate: Informed consent was obtained from all individual participants included in the study.
Availability of data and material:
The datasets generated during an/or analyzed during the current study are available from the corresponding author in reasonable request.
References:
- 1.Shisana O, Rehle T, Simbayi L, et al. (2014) South African National HIV Prevalence, Incidence and Behaviour Survey, 2012. Cape Town: HSRC Press [Google Scholar]
- 2.Phakathi B, Cubasch H, Nietz S, et al. (2019) Clinico-pathological characteristics among South African women with breast cancer receiving anti-retroviral therapy for HIV. Breast 43:123–129 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Howlader N, Noone A, Krapcho M, et al. (2019) SEER Cancer Statistics Review, 1975–2017. Bethesda, MD [Google Scholar]
- 4.Jedy-Agba E, McCormack V, Adebamowo C, Dos-Santos-Silva I (2016) Stage at diagnosis of breast cancer in sub-Saharan Africa: a systematic review and meta-analysis. Lancet Glob Heal 4:e923–35 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Dickens C, Joffe M, Jacobson J, et al. (2014) Stage at breast cancer diagnosis and distance from diagnostic hospital in a periurban setting: A South African public hospital case series of over 1,000 women. Int J Cancer 135:2173–2182 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Soares LR, Freitas-Junior R, Curado MP, et al. (2020) Low Overall Survival in Women With De Novo Metastatic Breast Cancer: Does This Reflect Tumor Biology or a Lack of Access to Health Care? JCO Glob Oncol 679–687 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Adisa AO, Arowolo OA, Akinkuolie AA, et al. (2011) Metastatic breast cancer in a Nigerian tertiary hospital. Afr Health Sci 11:279–84 [PMC free article] [PubMed] [Google Scholar]
- 8.Aitelhaj M, LKhoyaali S, Rais G, et al. (2016) First line chemotherapy plus trastuzumab in metastatic breast cancer HER2 positive - Observational institutional study. Pan Afr Med J 24: [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Weiner CM, Mathewos A, Addissie A, et al. (2018) Characteristics and follow-up of metastatic breast cancer in Ethiopia: A cohort study of 573 women. The Breast 42:23–30 [DOI] [PubMed] [Google Scholar]
- 10.Joko-Fru WY, Miranda-Filho A, Soerjomataram I, et al. (2020) Breast cancer survival in sub-Saharan Africa by age, stage at diagnosis and human development index: A population-based registry study. Int J Cancer 146:1208–1218 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.McCormack V, McKenzie F, Foerster M, et al. (2020) Breast cancer survival and survival gap apportionment in sub-Saharan Africa (ABC-DO): a prospective cohort study. Lancet Glob Heal 8:e1203–e1212 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Coghill AE, Han X, Suneja G, et al. (2019) Advanced stage at diagnosis and elevated mortality among US patients with cancer infected with HIV in the National Cancer Data Base. Cancer 125:2868–2876 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Coghill AE, Suneja G, Rositch AF, et al. (2019) HIV Infection, Cancer Treatment Regimens, and Cancer Outcomes Among Elderly Adults in the United States. JAMA Oncol 5: [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Coghill AE, Shiels MS, Suneja G, Engels EA (2015) Elevated Cancer-Specific Mortality Among HIV-Infected Patients in the United States. J Clin Oncol 33:2376–2383 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Youngblood VM, Nyirenda R, Nyasosela R, et al. (2020) Outcomes and prognostic factors for women with breast cancer in Malawi. Cancer Causes Control 31:393–402 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Suneja G, Shiels MS, Angulo R, et al. (2014) Cancer Treatment Disparities in HIV-infected Individuals in the United States. J Clin Oncol 32:2344–2350. 10.1200/JCO.2013.54.8644 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Suneja G, Lin CC, Simard EP, et al. (2016) Disparities in cancer treatment among patients infected with the human immunodeficiency virus. Cancer 122:2399–2407. 10.1002/cncr.30052 [DOI] [PubMed] [Google Scholar]
- 18.Cubasch H, Ruff P, Joffe M, et al. (2017) South African Breast Cancer and HIV Outcomes Study: Methods and Baseline Assessment. J Glob Oncol 3:114–124 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Cubasch H, Joffe M, Hanisch R, et al. (2013) Breast cancer characteristics and HIV among 1,092 women in Soweto, South Africa. Breast Cancer Res Treat 140:177–186 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Langenhoven L, Barnardt P, Neugut AI, Jacobson JS (2016) Phenotype and Treatment of Breast Cancer in HIV-Positive and -Negative Women in Cape Town, South Africa. J Glob Oncol 2:284–291 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.O’Neil DS, Nietz S, Buccimazza I, et al. (2019) Neoadjuvant Chemotherapy Use for Nonmetastatic Breast Cancer at Five Public South African Hospitals and Impact on Time to Initial Cancer Therapy. Oncologist 24:933–944 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Chirivella I, Bermejo B, Insa A, et al. (2009) Optimal delivery of anthracycline-based chemotherapy in the adjuvant setting improves outcome of breast cancer patients. Breast Cancer Res Treat 114:479–84 [DOI] [PubMed] [Google Scholar]
- 23.Bonadonna G, Valagussa P (1981) Dose-Response Effect of Adjuvant Chemotherapy in Breast Cancer. N Engl J Med 304:10–15. 10.1056/nejm198101013040103 [DOI] [PubMed] [Google Scholar]
- 24.Budman DR, Berry DA, Cirrincione CT, et al. (1998) Dose and dose intensity as determinants of outcome in the adjuvant treatment of breast cancer. J Natl Cancer Inst 90:1205–11. 10.1093/jnci/90.16.1205 [DOI] [PubMed] [Google Scholar]
- 25.Denduluri N, Lyman GH, Wang Y, et al. (2018) Chemotherapy Dose Intensity and Overall Survival Among Patients With Advanced Breast or Ovarian Cancer. Clin Breast Cancer 18:380–386 [DOI] [PubMed] [Google Scholar]
- 26.Parameswaran L, Taur Y, Shah MK, et al. (2014) Tolerability of Chemotherapy in HIV-Infected Women with Breast Cancer: Are There Prognostic Implications? AIDS Patient Care STDS 28:358–364 [DOI] [PubMed] [Google Scholar]
- 27.Rossof A, Gelman R, Creech R (1982) Randomized Evaluation of Combination Chemotherapy vs. Observation alone Following Response or Stabilization after Oophorectomy for Metastatic Breast Cancer in Premenopausal Women. Am J Clin Oncol 5:253–259 [DOI] [PubMed] [Google Scholar]
- 28.Glick JH, Creech RH, Torri S, et al. (1980) Randomized clinical trial of tamoxifen plus sequential CMF chemotherapy versus tamoxifen alone in postmenopausal women with advanced breast cancer. Cancer 45:735–741 [DOI] [PubMed] [Google Scholar]
- 29.Bezwoda WR, Derman D, De Moor NG, et al. (1982) Treatment of metastatic breast cancer in estrogen receptor positive patients a randomized trial comparing tamoxifen alone versus tamoxifen plus CMF. Cancer 50:2747–2750 [DOI] [PubMed] [Google Scholar]
- 30.Press DJ, Miller ME, Liederbach E, et al. (2017) De novo metastasis in breast cancer: occurrence and overall survival stratified by molecular subtype. Clin Exp Metastasis 34:457–465 [DOI] [PubMed] [Google Scholar]
- 31.Ogiya R, Sagara Y, Niikura N, Freedman RA (2019) Impact of Subtype on Survival of Young Patients With Stage IV Breast Cancer. Clin Breast Cancer 19:200–207.e1 [DOI] [PubMed] [Google Scholar]
- 32.Harris E, Barry M, Kell MR (2013) Meta-analysis to determine if surgical resection of the primary tumour in the setting of stage IV breast cancer impacts on survival. Ann Surg Oncol 20:2828–2834 [DOI] [PubMed] [Google Scholar]
- 33.Khan SA, Zhao F, Solin LJ, et al. (2020) A randomized phase III trial of systemic therapy plus early local therapy versus systemic therapy alone in women with de novo stage IV breast cancer: A trial of the ECOG-ACRIN Research Group (E2108). J Clin Oncol 38: [Google Scholar]
- 34.Wang R, Zhu Y, Liu X, et al. (2019) The Clinicopathological features and survival outcomes of patients with different metastatic sites in stage IV breast cancer. BMC Cancer 19:1091. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 35.Shiels MS, Pfeiffer RM, Engels EA (2010) Age at Cancer Diagnosis Among Persons With AIDS in the United States. Ann Intern Med 153:452. 10.7326/0003-4819-153-7-201010050-00008 [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Supplementary Fig.1 Overall Survival in HIV-Positive Women with Stage IV Breast Cancer Enrolled in the SABCHO cohort (2015–2019), by baseline HIV characteristics
(A) CD4 count
(B) Length of Time on Antiretroviral Treatment
(C) HIV Viral Load at Breast Cancer Diagnosis
Data Availability Statement
The datasets generated during an/or analyzed during the current study are available from the corresponding author in reasonable request.