The Five-years Overall Survival and Recurrence Free Survival of Neoadjuvant Systemic Therapy in Breast Cancer Sudanese Patients: A Retrospective Comparative study

Introduction

Breast cancer (BC) remains one of the most prevalent malignancies affecting women globally, with almost 80% of mortalities recoded in low- and middle-income countries (LMICs). Its prevalence rates in Sub-Saharan Africa are on the increase, determined by lifestyle conversions, urbanization, and reduced birth rates.¹

Breast cancer incidence in Africa has been on the rise, with nearly 169,000 cases reported in 2018. Projections by GLOBOCAN indicate that this number could nearly double by 2040 if current trends continue. This escalating burden highlights a critical public health challenge across the continent.²

In Sudan, there is no national population-BC registry, leading to cancer estimates primarily relying on hospital case series. Data from the Cancer Registry for Khartoum State during 2009-2010 indicated that BC was the most prevalent cancer among Sudanese women.³ According to statistics from the National Cancer Institute—University of Gezira (NCI–UG), BC accounted for 34% of all cancers in female cases in 2017.⁴ Research on the clinicopathologic features of BC in Sudan has shown that Sudanese women are diagnosed at a younger age and at more advanced stages, with higher tumor grades and greater lymph node involvement compared to women in developed countries. This trend mirrors findings from other sub-Saharan African nations, highlighting the urgent need for improved awareness and early detection strategies in Sudan.^5,6

Although locally advanced breast cancer (LABC) is relatively rare among women in the Western world, it is a common occurrence in Sudan, where it tends to affect women at a younger age.⁷ And the high LABC prevalence in Sudan attributed to such factors like seeking traditional healing, fear of stigma, and fear of treatments side effects as reported by one recent study.⁸

Breast cancer remains a significant health challenge, particularly in its LABC, which are characterized by larger tumor sizes and regional lymph node involvement. Traditionally, the treatment approach for LABC has included surgery followed by adjuvant chemotherapy. However, the introduction of neoadjuvant chemotherapy (NAC) has shifted this paradigm. NAC is administered prior to surgery with the dual objectives of reducing tumor size to facilitate breast-conserving surgery and providing early systemic treatment to address potential micrometastatic disease.^9,10

NAC has gained traction due to its potential to improve surgical outcomes and provide prognostic information based on the pathological response. Achieving a pathologic complete response (pCR) after NAC is associated with improved disease-free survival (DFS) and overall survival (OS) rates.^10,11 Studies indicate that patients who achieve pCR exhibit significantly better outcomes compared to those who do not, with 5-year DFS rates reported at 73.17% for pCR patients versus 51.25% for those with residual disease.¹⁰

Despite these advantages, the comparative effectiveness of NAC versus surgery-first strategies remains a topic of investigation. Some studies have shown no statistically significant differences in overall survival between neoadjuvant and adjuvant chemotherapy groups, suggesting that while NAC may enhance surgical options and reduce tumor burden, it does not necessarily confer a survival advantage over traditional adjuvant approaches.^9,12 For illustration, a meta-analysis involving over 4,700 patients revealed that while NAC improved local therapy feasibility and response rates, long-term outcomes such as distant recurrence and breast cancer mortality were comparable to those seen with adjuvant chemotherapy.¹²

Furthermore, the decision-making process regarding treatment strategies for LABC must consider various factors including tumor biology, patient preferences, and the potential for breast-conserving surgery. While NAC can lead to downstaging of tumors and increased rates of breast-conserving surgery, it is crucial to weigh these benefits against the overall survival outcomes observed in clinical practice.⁹

In summary, while NAC offers several advantages in managing locally advanced breast cancer, including improved surgical options and potential prognostic insights, its impact on overall survival compared to surgery-first approaches is debatable requires further investigation through further studies, as no study in Sudan examined this. The ongoing evaluation of long-term outcomes will be essential in refining treatment protocols for this challenging patient population. As, no study in Sudan examined this topic we aim in this work to find out the 5-years overall survival and recurrence free survival of NAC in Sudanese women with LABC.

Methods

Results

In total, this study included 28 LABC females receiving NAC as the case group compared to 18 upfront surgery patients as the control group. Most of the patients in the case (n = 16; 57.1%) and control group (n = 14; 77.8%) were aged above 40 years (P value = 0.150). The majority of the patients in the case group (n = 12; 42.9%) had symptoms lasting from 3-6 months and in the control group (n = 10; 55.6%) from 7-12 months (P value = 0.199). Invasive ductal carcinoma (IDC) was the most common histological type in the case group (78.5%) and control group (50%) documented cases and mainly were grade 3 in both groups (case = 35.7%, control = 22.2%). Most of the patients in the case group (n = 14; 50%) and control group (n = 8; 44.4%) underwent modified radical mastectomy (MRM) plus axillary lymph node clearance (ALC) surgeries. Other patients’ details are revealed in Table 1.

As shown in Figure 1, most of the patients in NAC group 13 (46.4%) received six cycles of chemotherapy.

Figure 1. XXX.

Table 2 revealed the prognostic markers, in which ER/PR were +ve/+ve or +ve/-ve in four (14.3%) of the case group and four (22.2%) patients in the control group (P value = 0.469). The HER2 was positive in six (21.4%) of the case group and one (5.6%) patient in the control group (P value = 0.334). The Ki67 below 20% was found in four (14.3%) of the case group and three (16.7%) patients of control groups (P = 0.969). Table 2 revealed the prognostic markers, in which ER/PR were +ve/+ve or +ve/-ve in four (14.3%) of the case group and four (22.2%) patients in the control group (P value = 0.469). The HER2 was positive in six (21.4%) of the case group and one (5.6%) patient in the control group (P value = 0.334). The Ki67 below 20% was found in four (14.3%) of the case group and three (16.7%) patients of control groups (P = 0.969).

Table 3 illustrates that the rate of metastasis was significantly greater in the controls compared to the case group (n = 9; 50% vs n = 6; 21.4%; P value = 0.043), while the recurrence rate was not significantly differed between the groups (P value = 0.353).

Moreover, as revealed in Table 4, the development of metastasis and recurrence was not significantly affected by the types of surgery in the case (P value = 0.655) and control groups (P value = 0.529).

Table 5 demonstrated that the 5-year overall survival rate was 50% (n = 14) in the case group and 55.6% (n = 10) in the control group, but it was not statistically significant (P value = 0.454).

Kaplan-Meier survival analysis illustrated that the estimated mean of survival time was 74.1 (95% CI: 71.5 – 92.5) months in the case group and 82.0 (95% CI: 64.2 – 84.1) months in the control group. Nonetheless, the difference was not statistically significant (log-rank sign value = 0.973), as illustrated in Table 6 and Figure 2.

Figure 2. XXX.

As presented in Table 7 the association between 5-year overall survival was not significantly affected by the duration of symptoms (P value = 0.833), ER/PR expression (P value = 0.915), HER2 expression (P value = 0.364), and levels of Ki67 (P value = 0.548) in the case group. However, the 5-year mortality rate was higher in IDC grade-3 (n = 6; 42.9%) than in IDC grade-2 (n = 2; 14.3%), IDC grade-1 (n = 2; 14.3%) and ILC (n = 1; 7.1%) in the case group, but the differences was statistically insignificant (P value = 0.569).

Discussion

There is a growing trend towards using NAC in breast cancer treatment. This approach confers several advantages, including the facilitation of breast-conserving surgeries, eradication of axillary metastasis, and allowing in vivo assessments of tumor response to systemic therapies. In this study most of the in NAC group 13 (46.4%) received six cycles of chemotherapy.

Since we have studied those patients retrospectively, demographic and clinical data were similarly distributed between NAC and upfront surgery groups. So, the two groups were roughly matched.

In this study, the rate of metastasis in the upfront surgery group was significantly greater compared to the NAC group (P = 0.043). This finding indicating that neo-adjuvant therapy may effectively reduce the risk of metastasis by downstaging tumors before surgery. Conversely, our study found no significant difference in recurrence rates between the two groups (P = 0.353), which is consistent with findings from the meta-analysis of Mauri D et al who evaluated nine randomized studies, including a total of 3946 patients with breast cancer, that compared neoadjuvant therapy with adjuvant therapy, and reported similar recurrence rates regardless of treatment strategy.¹⁴ However, the study of Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) reported that NAC was associated with more frequent local recurrence than was adjuvant chemotherapy.¹²

A big body of evidence has grown over the last decade proving that the development of metastasis and local recurrence does not influenced by the type of surgery performed, as breast conservative surgery and mastectomy both has no difference in terms of metastasis and recurrence rate.^14–16 Similarly, this study demonstrated that, the development of metastasis and recurrence was not significantly affected by the types of surgery in the NAC (P value = 0.655) and upfront surgery groups (P value = 0.529).

Regarding the survival rate, it was 50% in cases and 44.4% in controls. It is slightly lower than what has been reported by the first Sudanese study on survival outcome in breast cancer done by Muddather H et al,¹⁷ which showed 58% overall survival for all breast cancer cases treated in the center. This difference would probably be due to the fact that they have included all disease stages including the early stages which has good survival rates. Nevertheless, our data is not far-away from the data reported by other developing countries in Africa such as Uganda (51.8%), and Ghana (47.9%).¹⁸ In contrary higher rate of survival was reported in Indian (83%) by Akhtar M et al.¹⁹

Furthermore, in this study, the 5-year overall survival rates were similar between groups (50% for NAC and 55.6% for upfront surgery; P = 0.454), indicating that both approaches may offer comparable long-term survival benefits. Kaplan-Meier survival analysis further supports these findings, revealing mean survival times of 74.1 (95% CI: 71.5 – 92.5) months for the NAC group and 82.0 (95% CI: 64.2 – 84.1) for the upfront surgery group, with no statistically significant difference (log-rank P = 0.973). These results are consistent with other studies those reported the survival benefits for patients with LABC who received either NAC or upfront surgeries were comparable.^9,12,20–24

The analysis also examined several biological markers and clinical factors, such as duration of symptoms, hormone receptor expression (ER/PR), HER2 status, and Ki67 levels. None of these factors significantly impacted the 5-year overall survival (P value > 0.05). Also, the 5-year mortality rate was higher in IDC grade-3 (n = 6; 42.9%) than in IDC grade-2 (n = 2; 14.3%), IDC grade-1 (n = 2; 14.3%) and ILC (n = 1; 7.1%) in the NAC group, but the differences was statistically insignificant (P value= 0.569). This finding suggests that tumor grade may play a role in patient outcomes but requires further investigation to establish definitive correlations.

Several limitations must be acknowledged. Firstly, the sample size appears relatively small, which may limit the generalizability of the findings and reduce the power to detect significant differences in outcomes. Secondly, the retrospective nature of the study could introduce biases related to patient selection and treatment allocation. Future studies with larger cohorts and prospective designs are needed to validate these findings and better elucidate the role of neo-adjuvant therapy in breast cancer treatment.

Conclusion

In conclusion, while NAC appears to reduce metastasis rates compared to upfront surgery, both treatment strategies yield similar overall survival outcomes and recurrence rates in LABC. The lack of significant differences across various biological markers indicates that additional factors may influence patient prognosis and highlights the need for personalized treatment approaches based on individual patient characteristics and tumor biology. Future studies should aim to explore these relationships further and assess long-term outcomes in larger patient cohorts to refine treatment protocols effectively.

Ethics statement

Ethical approval was obtained from the General Surgery Institutional Review Board (IRB) at the Sudan Medical Specialization Board (SMSB) (02/2020), and performed following the ethical standards of the 1964 Declaration of Helsinki.¹³

Consent to participate

Both verbal and written consents to publish this information were gained from the patients.

Transparency statement

Tamador Elhadi Osman, the lead author, declares that this manuscript is an honest, accurate, and transparent. He also clarifies that significant aspects of this study were not excluded and any discrepancies from the planned study have been explicitly explained.

Consent to publish

All authors gave their approval for publication.