Abstract
Background
Neoadjuvant chemotherapy (NAC) is an integral component of T4 breast cancer (BCa) treatment. We compared response to NAC for T4 BCa in the U.S. and Nigeria to direct future interventions.
Materials and Methods
Cross‐sectional retrospective analysis included all patients with non‐metastatic T4 BCa treated from 2010 to 2016 at Memorial Sloan Kettering Cancer Center (New York, New York) and Obafemi Awolowo University Teaching Hospitals Complex (Ile Ife, Nigeria). Pathologic complete response (pCR) and survival were compared and factors contributing to disparities evaluated.
Results
Three hundred and eight patients met inclusion criteria: 157 (51%) in the U.S. and 151 (49%) in Nigeria. All U.S. patients received NAC and surgery compared with 93 (62%) Nigerian patients. Fifty‐six out of ninety‐three (60%) Nigerian patients completed their prescribed course of NAC. In Nigeria, older age and higher socioeconomic status were associated with treatment receipt.
Fewer patients in Nigeria had immunohistochemistry performed (100% U.S. vs. 18% Nigeria). Of those with available receptor subtype, 18% (28/157) of U.S. patients were triple negative versus 39% (9/23) of Nigerian patients. Overall pCR was seen in 27% (42/155) of U.S. patients and 5% (4/76) of Nigerian patients. Five‐year survival was significantly shorter in Nigeria versus the U.S. (61% vs. 72%). However, among the subset of patients who received multimodality therapy, including NAC and surgery with curative intent, 5‐year survival (67% vs. 72%) and 5‐year recurrence‐free survival (48% vs. 61%) did not significantly differ between countries.
Conclusion
Addressing health system, socioeconomic, and psychosocial barriers is necessary for administration of complete NAC to improve BCa outcomes in Nigeria.
Implications for Practice
This cross‐sectional retrospective analysis of patients with T4 breast cancer in Nigeria and the U.S. found a significant difference in pathologic complete response to neoadjuvant chemotherapy (5% Nigeria vs. 27% U.S.). Five‐year survival was shorter in Nigeria, but in patients receiving multimodality treatment, including neoadjuvant chemotherapy and surgery with curative intent, 5‐year overall and recurrence‐free survival did not differ between countries. Capacity‐building efforts in Nigeria should focus on access to pathology services to direct systemic therapy and promoting receipt of complete chemotherapy to improve outcomes.
Keywords: Neoadjuvant chemotherapy, T4 breast cancer, Nigeria, Locally advanced breast cancer, Global oncology
Short abstract
In many low‐ and middle‐income countries, T4 breast cancer is common and outcomes are poor. This article compares the results of neoadjuvant chemotherapy for T4 breast cancer in Nigeria and the U.S. to identify modifiable targets for intervention and, in turn, improve outcomes.
Introduction
The age‐standardized mortality rate of breast cancer (BCa) in sub‐Saharan Africa (SSA) is among the highest in the world, due partly to advanced stage at diagnosis [1, 2]. In Nigeria, 85% of patients are diagnosed with locally advanced or metastatic BCa. Five‐year survival for stage III disease is 28% in Nigeria [2], compared with 85% for regional disease in the U.S. [3]. The etiology of these outcome disparities is multifactorial, with differential access to effective treatment playing a major role [2].
T4 BCa is defined as a tumor with direct extension to the chest wall and/or skin. Regardless of country of origin, T4 BCa is locally advanced, carries a poorer prognosis, and requires more resources to treat than early‐stage BCa. Multimodality treatment consists of neoadjuvant chemotherapy (NAC), modified radical mastectomy, postmastectomy radiation (PMRT), and often, targeted systemic therapy depending on molecular subtype. According to resource‐stratified guidelines, at all levels of health care system development, treatment for T4 BCa involves NAC followed by surgery [4].
Despite a significant burden of BCa in Africa, there is a paucity of high‐quality data from the region, particularly with regard to chemotherapy administration and response [1]. There is also poor long‐term follow‐up, which limits the ability to draw conclusions regarding recurrence and survival. Pathologic complete response (pCR) to NAC correlates with recurrence‐free survival (RFS) and overall survival (OS) on an individual patient level [5], making pCR a particularly valuable indicator in a region lacking reliable long‐term follow‐up data. pCR rates vary by biologic subtype: 4% for hormone receptor (HR) positive (HR+)/human epidermal growth receptor 2 negative (HER2−) disease, and 25% for triple negative breast cancer (TNBC) [6]. In the U.S., approximately 73% of BCa is HR+/HER2− [7]. Conversely, in SSA, TNBC is generally more common and has been reported to account for up to 82% of BCa in some countries [8], although this difference may be partially attributable to variable pathology and lack of reliable immunohistochemistry (IHC) testing in SSA.
In most high‐income countries (HICs), T4 BCa is relatively rare because of population‐based screening and early detection practices. In addition, outcomes from T4 BCa in HICs are improving, largely because of advances in systemic therapy [9, 10]. In most low‐ and middle‐income countries (LMICs), T4 BCa is common, and outcomes are poor. A unique prospective BCa database at a Nigerian tertiary care institution, and the relatively high volume of T4 BCa treated at a specialized cancer center in the U.S. make comparison of a similar number of patients with T4 BCa in Nigeria and the U.S. possible. The aim of this study was to compare administration of and response to NAC for T4 BCa in Nigeria and the U.S., and subsequent survival, to identify modifiable targets for intervention and, in turn, improve outcomes.
Materials and Methods
Setting
Following Institutional Review Board approval, retrospective review was performed at Memorial Sloan Kettering Cancer Center (MSKCC) in New York, New York, U.S., and Obafemi Awolowo University Teaching Hospitals Complex (OAU) in Ile Ife, Nigeria. MSKCC is a National Cancer Institute–designated comprehensive cancer center that treats approximately 4,500 new patients with BCa annually. OAU is an academic, tertiary care institution that treats approximately 120 patients with BCa annually. Key differences between the two institutions are outlined in supplemental online Table 1.
Table 1.
Patient demographics and disease characteristics in the U.S. and Nigeria.
| Demographics and disease characteristics | U.S. (n = 157) | Nigeria (n = 151) |
|---|---|---|
| Age at diagnosis, median (range), yr | 53 (28–85) | 50 (25–82) |
| BMI | ||
| Median (range) | 28 (16–56) | 27 (15–41) |
| Missing (n) | 10 | 57 |
| Race n (%) | ||
| Black | 18 (11.5) | 151 (100) |
| White | 113 (72) | 0 (0) |
| Asian | 14 (8.9) | 0 (0) |
| Other | 3 (1.9) | 0 (0) |
| Unknown | 9 (5.7) | 0 (0) |
| Clinical tumor size | ||
| Median (range), cm | 7 (2–28) | 12 (2–31) |
| Missing, n | 54 | 24 |
| Histology, n (%) | ||
| Ductal | 139 (88.5) | 117 (77.5) |
| Lobular | 9 (5.7) | 0 (0) |
| Mixed | 7 (4.5) | 0 (0) |
| Other | 2 (1.3) | 6 (4) |
| Unknown | 0 (0) | 28 (18.5) |
| Immunohistochemistry performed, n (%) | ||
| Yes | 157 (100) | 27 (17.9) |
| No | 0 (0) | 124 (82.1) |
| Subtype, n (%) | ||
| HR+/HER2− | 70 (44.6) | 4 (2.6) |
| HR+/HER2+ | 28 (17.8) | 6 (4) |
| HR−/HER2+ | 31 (19.7) | 4 (2.6) |
| HR−/HER2− | 28 (17.8) | 9 (6) |
| Unknown | 0 (0) | 128 (84.8) |
| Clinical tumor stage, n (%) | ||
| T4a | 6 (3.8) | 8 (5.3) |
| T4b | 59 (37.6) | 92 (60.9) |
| T4c | 2 (1.3) | 13 (8.6) |
| T4d | 90 (57.3) | 19 (12.6) |
| Unknown | 0 (0) | 19 (12.6) |
| Clinical lymph node status, n (%) | ||
| N0 | 2 (1.3) | 34 (22.5) |
| N+ | 155 (98.7) | 116 (76.8) |
| Unknown | 0 (0) | 1 (0.7) |
Abbreviations: BMI, body mass index; HER2−, human epidermal growth receptor negative; HER2+, human epidermal growth receptor positive; HR−, hormone receptor negative; HR+, hormone receptor positive.
Study Population
All female patients with T4 BCa without known metastatic disease treated at each institution from January 2010 to December 2016 were included. Patients were identified from an institutional BCa database at each institution. At MSKCC, the database is prospectively maintained. At OAU, the database has been prospectively maintained since January 2016; prior to 2016 data were collected retrospectively.
Socioeconomic classification in the Nigerian cohort was defined as previously described by Oyedeji et al. in a study conducted in a Nigerian cohort [11]. Patients were categorized into five groups using occupation and level of education as the defining variables. Those in groups 1 and 2 are considered upper socioeconomic status (SES), group 3 represents middle SES, and groups 4 and 5 are lower SES.
T4 was defined as disease in the breast with skin and/or chest wall involvement. Patients with bilateral disease were excluded. Clinicopathologic and treatment data were collected from the patient's medical record. Clinical tumor size was determined by the largest tumor diameter by clinical examination or imaging at MSKCC, and the largest tumor diameter by clinical examination at OAU. HR positivity was defined as >1% of cells staining for the estrogen receptor (ER) or progesterone receptor. HER2 was considered positive with staining of 3+ staining on IHC or when amplified on fluorescence in situ hybridization. Central pathology review was not undertaken because of resource limitations. Metastatic work‐up in the U.S. is a computed tomography (CT) scan of the chest/abdomen/pelvis with a bone scan or a positron emission tomography (PET) scan. Metastatic work‐up in Nigeria consists of a chest x‐ray and abdominal ultrasound, as advanced imaging is largely unavailable.
Systemic therapy was administered at the discretion of the treating medical oncologist at MSKCC and the surgeon at OAU as per institutional norms. Surgery with curative intent was defined as patients undergoing either breast conserving surgery or mastectomy, with axillary lymph node dissection. pCR to NAC was defined as no residual invasive disease in the breast and lymph nodes, in situ disease allowed. Following completion of treatment, patients at both institutions are recommended to return for follow‐up, including a detailed review of systems, targeted physical examination, and laboratory evaluation or imaging as needed, every 3–6 months. In Nigeria, telephone calls are also made to every patient every 3 months to evaluate their status and encourage in‐person follow‐up as recommended.
Statistical Analysis
Clinicopathologic and treatment characteristics were described for each cohort, but no formal statistical comparison was performed for these variables because of the significant differences in institutional settings. Univariable logistic regression was used to assess the association between patient characteristics with receipt of surgery and receipt of NAC in the Nigerian cohort. Age was analyzed as a continuous variable in which the unit of measurement was 1 year. For U.S. patients, clinical outcomes were calculated from date of diagnosis. For Nigerian patients, clinical outcomes were calculated from the date of presentation, because the date of diagnosis was often unknown. In all patients, OS was calculated until death; patients alive at last follow‐up were censored. In patients who received NAC and surgery with curative intent, RFS was calculated until recurrence or death; patients alive and disease free at last follow‐up were censored. Kaplan‐Meier methods were used to estimate OS and RFS, and cohorts were compared with the log‐rank test. Two‐sided, unadjusted p values < .05 were considered statistically significant. All analyses were performed with SAS 9.4 TS1M5 (SAS Institute, Cary, NC).
Results
Study Population
Three hundred and eight patients met inclusion criteria: 157 (51%) in the U.S. and 151 (49%) in Nigeria. Figure 1 presents the clinical stage of patients with BCa overall at each institution during the study period. Median age was 53 years (range, 28–85) in the U.S. versus 50 years (range 25–82) in Nigeria. Eleven percent of the U.S. cohort was Black, compared with 100% of the Nigerian cohort (Table 1).
Figure 1.
Breast cancer clinical stage at Memorial Sloan Kettering Cancer Center versus Obafemi Awolowo University Teaching Hospitals Complex during the study period. Abbreviations: MSKCC, Memorial Sloan Kettering Cancer Center, OAU, Obafemi Awolowo University Teaching Hospitals Complex.
Work‐Up and Disease Characteristics
Median clinical tumor size was larger in the Nigerian cohort (12 cm vs. 7 cm) in those with available data (n = 230). Mammography was used in 148 (94%) U.S. patients and 18 (12%) Nigerian patients. Breast ultrasound was used in 151 (96%) U.S. patients and 33 (22%) Nigerian patients. Evaluation for metastatic disease was performed in 151 (96%) and 146 (97%) patients in the U.S. and Nigeria, respectively.
All patients in both cohorts had a biopsy of the primary tumor to obtain a pathologic diagnosis. In the U.S. 100% of breast biopsies were core needle biopsies compared with 55% in Nigeria, where fine needle aspiration, incisional biopsy, and excisional biopsy were also performed. The majority of patients had ductal histology. IHC was performed in 100% of U.S. patients (n = 157), compared with 18% of Nigerian patients (n = 23). Of those with receptor subtype, 62% (98/157) of U.S. patients were HR+, compared with 43% (10/23) of Nigerian patients, and 18% (28/157) of patients in the U.S. had TNBC, compared with 39% (9/23) in Nigeria.
Systemic Therapy
A flowchart of breast cancer treatment received in the U.S. and Nigeria is depicted in Figure 2. All patients in the U.S. received chemotherapy, compared with 89% (134/151) of those in Nigeria (Table 2). In the U.S., all patients received chemotherapy in the neoadjuvant setting compared with 93/151 (62%) in Nigeria. Of those who received NAC in Nigeria, 56/93 (60%) completed their intended course of chemotherapy without interruption. The most commonly used NAC regimen in the U.S. was doxorubicin, cyclophosphamide, and paclitaxel (AC‐T), and the most commonly used NAC regimen in Nigeria was 5‐fluorouracil, epirubicin, and cyclophosphamide (FEC) (Fig. 3).
Figure 2.
Flowchart of breast cancer treatment received in the U.S. and Nigeria. *, Eighty‐five of these patients had surgery with curative intent.
Table 2.
Treatment modalities used
| Treatment modality | U.S. (n = 157), n (%) | Nigeria (n = 151), n (%) |
|---|---|---|
| Systemic therapy | ||
| Any chemotherapy administered | 157 (100) | 134 (88.7) |
| Neoadjuvant chemotherapy | 157 (100) | 93 (61.6) |
| Surgery performed | 157 (100) | 99 (65.6) |
| Breast surgery | ||
| Mastectomy | 145 (92.4) | 98 (64.9) |
| Breast conserving surgery | 12 (7.6) | 1 (0.7) |
| None | 0 (0) | 52 (34.4) |
| Axillary surgery | ||
| Axillary dissection | 139 (88.5) | 89 (58.9) |
| SLNB converted to ALND | 18 (11.5) | 0 (0) |
| None | 0 (0) | 62 (41.1) |
| Reconstruction | ||
| None | 109 (69.4) | 151 (100) |
| Breast reconstruction | 44 (28) | 0 (0) |
| Defect closure | 3 (1.9) | 0 (0) |
| Radiation | 152 (96.8) | 16 (10.6) |
Abbreviations: ALND, axillary lymph node dissection; SLNB, sentinel lymph node biopsy.
Figure 3.
Neoadjuvant chemotherapy regimens administered. Abbreviations: A, doxorubicin; C, cyclophosphamide; F, 5‐fluorouracil; E, epirubicin; M, methotrexate; T, docetaxel.
In Nigeria, the odds of receiving NAC increased with age (odds ratio [OR], 1.04; 95% confidence interval [CI], 1.01–1.08; p = .008), and each year increase in age resulted in a 4% increase in odds of receiving NAC. Middle SES compared with low SES patients (OR, 2.41; 95% CI, 1.22–4.75; p = .011) had higher odds of receiving NAC (there were no upper SES patients in the cohort). No other significant associations were found between receipt of NAC and education level, religion, body mass index (BMI), year of diagnosis, or tumor size (p = .12–.94).
All patients in the U.S. cohort with HR+ tumors were offered endocrine therapy, in the form of either tamoxifen or an aromatase inhibitor. In Nigeria, 10 patients were known to be HR+; 13 received tamoxifen, and 1 received letrozole. All patients in the U.S. with HER2‐positive (HER2+) tumors received anti‐HER2 therapy in the neoadjuvant setting, to be continued for 1 year. In Nigeria, 10 patients were known to be HER2+; none received targeted treatment.
Locoregional Therapy
All U.S. patients underwent surgery, compared with 99 (66%) patients in Nigeria. The most commonly performed operation in both cohorts was a modified radical mastectomy (Table 2). In the Nigerian cohort, there were six patients who underwent primary surgery without first receiving NAC. In Nigeria, older compared with younger patients (OR, 1.04; 95% CI, 1.01–1.08; p = .008) and middle SES compared with low SES patients (OR, 2.27; 95% CI, 1.13–4.54; p = .021) had higher odds of receiving surgery. There was no significant association found between receipt of surgery and education level, religion, diagnosis year, BMI, or tumor size (p = .14 to >.95). Postoperative radiation was administered in 152 (97%) U.S. patients versus 16 (11%) Nigerian patients.
Pathologic Response to Treatment
Response to treatment was evaluated for individuals who received NAC, underwent surgery, and had available pathologic response data. Overall pCR (i.e., breast and regional lymph nodes) was seen in 27% (95% CI, 20%–35%; 42/155) of U.S. patients and 5% (95% CI, 2%–13%; 4/76) of Nigerian patients (p < .001). Within the breast, pCR was seen in 29% (95% CI, 22%–36%; 45/157) and 5% (95% CI, 2%–13%; 4/76) of U.S. and Nigerian patients, respectively (p < .001). Within the regional lymph nodes, pCR was seen in 43% (95% CI, 35%–51%; 66/155) and 32% (95% CI, 21%–43%; 24/76) of U.S. and Nigerian patients, respectively (p = .12; Table 3).
Table 3.
Surgical pathology in patients who received neoadjuvant chemotherapy and surgery, with available pathology data (n = 250)
| Surgical pathology | U.S. (n = 157), n (%) | Nigeria (n = 93), n (%) | p value |
|---|---|---|---|
| Breast pCRa | <.001 | ||
| Yes | 45 (28.7) | 4 (4.3) | |
| No | 112 (71.3) | 72 (77.4) | |
| Unknown | 0 (0) | 17 (18.3) | |
| Nodal pCR | .12 | ||
| Yes | 66 (42) | 24 (25.8) | |
| No | 89 (56.7) | 52 (55.9) | |
| Unknown | 2 (1.3) | 17 (18.3) | |
| Overall pCR | <.001 | ||
| Yes | 42 (26.8) | 4 (4.3) | |
| No | 113 (72) | 72 (77.4) | |
| Unknown | 2 (1.3) | 17 (18.3) | |
| Pathologic tumor stage | <.001 | ||
| T0 | 36 (22.9) | 4 (4.3) | |
| Tis | 8 (5.1) | 0 (0) | |
| T1 | 57 (36.3) | 2 (2.2) | |
| T2 | 28 (17.8) | 13 (14) | |
| T3 | 7 (4.5) | 26 (28) | |
| T4 | 21 (13.4) | 31 (33.3) | |
| Unknown | 0 (0) | 17 (18.3) | |
| Pathologic nodal stage | .004 | ||
| N0 | 68 (43.3) | 24 (25.8) | |
| N1 | 41 (26.1) | 20 (21.5) | |
| N2 | 31 (19.7) | 30 (32.3) | |
| N3 | 17 (10.8) | 2 (2.2) | |
| Unknown | 0 (0) | 17 (18.3) |
In situ disease allowed.
Abbreviation: pCR, pathologic complete response.
Outcomes
In the U.S. cohort (n = 157), 33 patients died prior to the end of follow‐up. In the Nigerian sample with sufficient data (n = 150), 38 patients died by the end of follow‐up. Median follow‐up for survivors in the U.S. was 42.9 months (range, 11.1–90.6) versus 24.6 months (range, 2.5–9.67) in Nigeria. Five‐year OS was 71.8% (95% CI, 61.6–79.7) in the U.S. compared with 60.5% (95% CI, 48.3–70.7) in Nigeria (p = .005; Fig. 4A).
Figure 4.
Survival in Nigeria versus the U.S. (A): Overall survival in the total cohort. (B): Overall survival in patients who received multimodality therapy, including neoadjuvant chemotherapy and surgery with curative intent. (C): Recurrence‐free survival in patients who received multimodality therapy, including neoadjuvant chemotherapy and surgery with curative intent with available recurrence data.Abbreviations: CI, confidence interval; E, event; RFS, recurrence‐free survival.
In the subset of patients who were treated with NAC and surgery with curative intent (n = 157 in U.S. and n = 85 in Nigeria), OS and RFS did not significantly differ between countries. In this cohort, 5‐year OS was 71.8% (95% CI, 61.6%–79.7%) in the U.S. compared with 66.5% (95% CI, 50.3%–78.6%) in Nigeria (p = .20; Fig. 4B). Five‐year RFS was 60.9% (95% CI, 50.0%–70.1%) in the U.S. compared with 48.4% (95% CI, 33.0%–62.2%) in Nigeria (p = .23; Fig. 4C). Median RFS was 72.4 months (95% CI, 62.7–84.9) in the U.S. versus 58.7 months (95% CI, 38.0–not reached) in Nigeria (p = .23).
Discussion
Even with the best evidence‐based, multimodality treatment available, patients with T4 BCa have significantly worse survival than those with early‐stage disease [12, 13]. BCa detected at an earlier stage can also be treated effectively with fewer resources [14]. Nine percent of patients with BCa seen at MSKCC during the study period had stage III disease, compared with 58% of patients at OAU (Fig. 1). BCa control efforts in Nigeria should promote early diagnosis, beginning with early detection of clinically apparent disease, including awareness education, technical training, and access to accurate pathology services [15].
Immunohistochemistry
Receptor subtype was not available for the majority of Nigerian patients (82%) in this cohort. In the subset of Nigerian patients with available biologic subtype, 39% had TNBC compared with 18% in the U.S. This difference could be explained by the known preponderance of TNBC in African populations [16, 17, 18, 19]. However, unreliable pathologic testing for ER, PR, and HER2 may render specimens falsely negative for these receptors.
High‐quality histopathology is an integral component of an effective cancer care system and is essential to maximize the benefits of systemic therapy. As biologic subtype distribution is not uniform, receptor testing to tailor systemic therapy is of fundamental importance. Making IHC broadly available in Nigeria would allow for better selection of patients to receive targeted systemic therapy, including endocrine therapy, thus improving outcomes and conserving resources by only administering targeted treatment to those who have the potential to benefit from it.
Metastatic Work‐Up
Nearly all patients in both cohorts underwent a context‐appropriate metastatic work‐up based on available resources. However, as cross‐sectional imaging for staging is largely unavailable Nigeria, there are patients with metastatic disease who go undiagnosed until they are symptomatic. Therefore, there are likely patients with undiagnosed stage IV disease in the Nigerian cohort, which would falsely elevate “recurrence” rates and negatively impact survival. Infrastructural investment in equipment and trained personnel for more thorough evaluation of metastatic disease would allow for more appropriate stratification of patients for treatment. More accurate staging would spare patients with metastatic disease unnecessary exposure to toxic chemotherapy that is unlikely to achieve curative outcomes.
Treatment Receipt
All U.S. patients received NAC and underwent surgical intervention compared with 62% of Nigerian patients. There are a multitude of patient‐, provider‐ and health system–level barriers that contribute to this disparity. In Nigeria, younger patients had lower odds of receiving NAC and surgery. This may be related to aggressive pathology in younger women resulting in disease progression and inability to receive curative surgery. Additionally, young women experience unique psychosocial stress surrounding mastectomy, which is exacerbated by a lack of routine breast reconstructive services in this setting and may contribute to decreased treatment receipt. Young women make up a significant proportion of patients with BCa in Nigeria, and interventions directed toward improving treatment in this population are necessary [20].
The association of SES with receipt of treatment is not surprising as many Nigerian patients are responsible for the cost of treatment [21, 22, 23]. Increasing coverage of the National Health Insurance Scheme to include systemic therapy may help lessen this disparity. Similarly, insurance coverage in the U.S. also influences access to care and outcomes [24, 25, 26, 27, 28]. Although not specifically evaluated in this study, distance from the health care facility is another factor influencing access to care and receipt of treatment in Nigeria [29, 30].
Differences in chemotherapeutic regimens between countries can be explained by the cost and availability of chemotherapy as well as medication necessary to mitigate side effects. The most commonly administered chemotherapy in both countries (AC‐T in the U.S. and FEC in Nigeria) was guideline‐concordant [31]. Six Nigerian patients underwent primary surgery without first receiving NAC. Although reasons for this are not captured within the scope of this study, it is possible that the treating physician determined they would be better served by mastectomy upfront, because of either symptomatic clinical presentation or limited access to chemotherapy.
Pathologic Response to Treatment
In prior studies, no difference in survival existed when chemotherapy was given in the neoadjuvant versus the adjuvant setting [32]. However, administering systemic therapy preoperatively confers several advantages: it can downstage disease in the breast and/or axilla facilitating surgery, it allows for real‐time evaluation of clinical response to treatment, and pCR correlates with outcomes [5, 33]. pCR correlates with improved event‐free survival and OS in patients with BCa, with the strongest association in aggressive tumor subtypes [5]. Whereas RFS and OS are difficult to accurately measure in LMICs as a result of poor follow‐up and incomplete data collection, pCR provides a quantifiable measure of response to NAC that correlates with outcomes.
Overall pCR was seen in 27% of U.S. patients compared with only 5% of Nigerian patients. This difference is significant and merits further investigation. pCR varies by biologic subtype, with overall response rates in the U.S. ranging from 4% in HR+/HER2− BCa, to 25% in TNBC, to 57% in HR negative/HER2+ disease with the administration of targeted therapy [6]. Because a minority of Nigerian patients had IHC performed, we are unable to draw conclusions regarding expected pCR rates based on biologic subtype. The low pCR rate in Nigeria may be due, in part, to more advanced disease at diagnosis. Although all patients in this study had T4 disease, Nigerian patients with available data had larger tumors than U.S. patients, which may have rendered them less likely to achieve pCR.
Of Nigerian patients who initiated NAC, only 60% completed treatment, which likely had significant impact on response to therapy. Promoting completion of systemic therapy is a modifiable factor that should be the target of future intervention. Programs aimed at following patients throughout treatment and ensuring access to and utilization of supportive medications to mitigate side effects must be a priority for stakeholders and policy makers aiming to improve BCa outcomes in SSA.
Outcomes
OS was significantly shorter in Nigeria compared with the U.S. This may be explained, in part, by the previously discussed in‐stage migration, potential under‐staging, and incomplete systemic therapy administration. In addition, only 11% of Nigerian patients received PMRT, which is known to convey a survival benefit in patients with positive lymph nodes [34]. In a 2013 analysis, the International Atomic Energy Agency reported that Nigeria had seven radiotherapy machines and would need 145 to treat all patients who require radiation [35]. Investment in capacity for radiotherapy is important for a variety of cancer types and could save lives in this context.
In the subset of patients who received multimodality therapy, including NAC and surgery with curative intent, OS and 5‐year RFS did not differ between countries. This result is promising, as it allows for the possibility that with equal access to effective treatment, outcomes in Nigeria could approximate the U.S.
Strengths and Limitations
T4 BCa is common in SSA, but uncommon in the U.S., where the majority of BCa is diagnosed at an early stage. MSKCC is one of few centers in the U.S. with enough cases of T4 BCa to provide this type of comprehensive comparison. There is a paucity of high‐quality BCa data from Africa, and the institutional database from OAU affords a unique opportunity for comparison of patients with T4 disease [36].
This is an observational study in which selection biases and confounding cannot be ruled out. Data collection at MSKCC is prospective and entered systematically into a departmental database. Data collection at OAU was partially retrospective, and complete data were not available on all patients. Prospective data collection at OAU began in 2016 and will allow for more comprehensive and longitudinal research in the future. Cancer registries and prospective databases play a critical role in clinical research and quality improvement and should be incentivized across Nigeria and other LMICs.
There are also fundamental differences between Nigeria and the U.S. regarding patient population, disease characteristics, and health care systems. We attempted to mitigate these differences by including only patients with T4 disease from both countries, thus comparing as similar a patient subgroup as possible. Another limitation in interpreting these data is lack of central pathology review. Pathologic evaluation at MSKCC is performed by breast pathologists with specialized training and extensive resources. Pathologic evaluation at OAU is performed by general pathologists with limited availability of necessary reagents for IHC. Although we acknowledge that central pathology review would enhance our methodology, it is not possible within the constraints of this research. Capacity‐building efforts at OAU are underway and the number of patients who have IHC performed is increasing. In addition, although chemotherapy administration at both institutions is driven by the National Comprehensive Cancer Network guidelines appropriate for each context, we do not have available patient‐level data to compare doses or timing between institutions.
Length of follow‐up in Nigeria was shorter than that in the U.S., and because of differences in available data, intervals were measured from different time points (date of presentation in Nigeria vs. date of diagnosis in the U.S.). In addition, there are no available disease‐specific survival data. Although we provide a comparison of outcomes between the two cohorts, these data have significant limitations, illustrating the importance of pCR as a surrogate outcome marker.
Next Steps
Addressing multilevel barriers to the care of patients with T4 BCa in Nigeria is necessary to improve treatment receipt. Through the African Research Group for Oncology, a collaboration between MSKCC and 26 institutions in Nigeria, our group is working together to address these barriers. For example, pathology capacity‐building efforts are underway, particularly related to improving completion of reliable IHC. A curriculum is under development for the safe administration of chemotherapy to improve its delivery. A prospective study is evaluating the psychosocial experience of patients with BCa who undergo mastectomy in order to develop targeted interventions to improve receipt of surgery. These initiatives, along with others promoting early detection, rapid diagnosis, and evidence‐based treatment, aim to use a phased implementation approach [37] to reduce disparities and improve outcomes for patients with BCa in Nigeria.
Conclusion
In a setting where the majority of BCa is advanced at diagnosis, administration of targeted and complete NAC is likely to allow for more effective surgical intervention and improved outcomes. Pathology capacity building to improve access to IHC evaluation and ability to target treatment, and addressing health system, socioeconomic, and psychosocial barriers to systemic therapy receipt are necessary to allow for routine administration of NAC for BCa in Nigeria.
Author Contributions
Conception/design: Anya Romanoff, Olalekan Olasehinde, Olusegun I. Alatise, Benjamin O. Anderson, Mary L. Gemignani, T. Peter Kingham
Provision of study material or patients: Anya Romanoff, Olalekan Olasehinde, Olusegun I. Alatise, Oluwole Odujoko, Emmanuella Onabanjo, Adewale O. Adisa, Adeolu O. Arowolo, Adeleye D. Omisore, Olusola C. Famurewa, Mary L. Gemignani, T. Peter Kingham
Collection and/or assembly of data: Anya Romanoff, Olalekan Olasehinde, Debra A. Goldman, Olusegun I. Alatise, Jeremy Constable, Ngozi Monu, Oluwole Odujoko, Emmanuella Onabanjo, Adewale O. Adisa, Adeolu O. Arowolo, Adeleye D. Omisore, Olusola C. Famurewa, T. Peter Kingham
Data analysis and interpretation: Anya Romanoff, Olalekan Olasehinde, Debra A. Goldman, Olusegun I. Alatise, Gregory C. Knapp, Benjamin O. Anderson, T. Peter Kingham
Manuscript writing: Anya Romanoff, Olalekan Olasehinde, Debra A. Goldman, Olusegun I. Alatise, Jeremy Constable, Ngozi Monu, Gregory C. Knapp, Oluwole Odujoko, Emmanuella Onabanjo, Adewale O. Adisa, Adeolu O. Arowolo, Adeleye D. Omisore, Olusola C. Famurewa, Benjamin O. Anderson, Mary L. Gemignani, T. Peter Kingham
Final approval of manuscript: Anya Romanoff, Olalekan Olasehinde, Debra A. Goldman, Olusegun I. Alatise, Jeremy Constable, Ngozi Monu, Gregory C. Knapp, Oluwole Odujoko, Emmanuella Onabanjo, Adewale O. Adisa, Adeolu O. Arowolo, Adeleye D. Omisore, Olusola C. Famurewa, Benjamin O. Anderson, Mary L. Gemignani, T. Peter Kingham
Disclosures
The authors indicated no financial relationships.
Supporting information
See http://www.TheOncologist.com for supplemental material available online.
Appendix S1: Supporting Information
Acknowledgments
The authors acknowledge the dedicated surgical research team at Obafemi Awolowo University Teaching Hospitals Complex in Ile Ife, Nigeria. The Global Cancer Disparities Initiative is funded by Memorial Sloan Kettering Cancer Center, with support from the Thompson Family Foundation. This research was funded in part through the National Institutes of Health/National Cancer Institute Cancer Center Support Grant P30 CA008748.
Disclosures of potential conflicts of interest may be found at the end of this article.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
See http://www.TheOncologist.com for supplemental material available online.
Appendix S1: Supporting Information