Breast cancer remains one of the most common malignancies affecting women and continues to produce a substantial global health burden. International epidemiological data show that breast cancer is the most frequently diagnosed cancer among women in most countries, and its future burden is expected to increase because of population growth, ageing, lifestyle transitions, and inequities in access to early diagnosis and treatment (1). In low- and middle-income countries, delayed presentation remains a major challenge. Many patients present with larger tumors, clinically positive lymph nodes, or locally advanced disease, creating difficulty in performing immediate breast-conserving surgery and increasing the need for multimodality treatment.

Neoadjuvant chemotherapy (NACT) has become an important component of breast cancer management. It was initially used mainly for inoperable or locally advanced disease, but its role has expanded to include selected operable patients in whom preoperative systemic treatment may improve surgical options, assess tumor chemosensitivity, and guide postoperative therapy. Contemporary guidelines support the use of neoadjuvant systemic therapy for selected patients with high-risk HER2-positive disease, triple-negative breast cancer, and locally advanced tumors, provided that decisions are made through multidisciplinary assessment and supported by accurate receptor testing (2,3).

The value of NACT extends beyond tumor shrinkage. Response to treatment offers real-time information about tumor biology. Pathological complete response (pCR), commonly defined as the absence of residual invasive cancer in the breast and sampled regional lymph nodes at surgery, is a widely used endpoint in neoadjuvant studies. Evidence from large pooled analyses and meta-analyses demonstrates that patients who achieve pCR generally have better long-term outcomes than those with residual disease, although the strength of this relationship differs by molecular subtype (4-6). The prognostic value of pCR is particularly strong in triple-negative and HER2-positive breast cancers.

Molecular subtype is one of the most important predictors of response to NACT. HER2-enriched and triple-negative tumors are usually more chemosensitive and achieve higher pCR rates than hormone receptor-positive luminal tumors. Conversely, luminal A tumors often show lower pCR rates after chemotherapy, despite sometimes achieving clinically meaningful downstaging. This distinction is important because a low pCR rate in luminal disease should not be interpreted as complete absence of benefit. In selected patients, NACT may still reduce tumor size, improve operability, or support surgical planning, especially when baseline tumor burden is high (7).

Response to NACT also has surgical implications. Tumor downstaging may increase eligibility for wide local excision and may influence axillary management. In patients who initially present with nodal disease, post-NACT axillary assessment can affect whether axillary lymph node dissection or sentinel lymph node biopsy is selected. However, these decisions require robust documentation of pretreatment nodal status, placement of clips where indicated, post-treatment imaging, and clear pathological reporting (8,9). In real-world settings, incomplete documentation may limit accurate interpretation of clinical outcomes.

Despite the increasing use of NACT in Pakistan, local real-world data regarding response patterns and their association with molecular subtype remain limited. Hospital-based retrospective studies can identify treatment response trends, documentation gaps, and opportunities to strengthen multidisciplinary cancer care. Therefore, the present study was conducted to evaluate clinical and pathological responses to NACT among breast cancer patients treated at Recep Tayyip Erdogan Hospital, Muzaffargarh, Pakistan, and to assess the association of molecular subtype with treatment response and surgical outcomes.

Study Design, Setting, and Sampling Technique

This retrospective observational study was conducted at Recep Tayyip Erdogan Hospital, Muzaffargarh, Pakistan. Data were retrieved from the hospital electronic medical record system. The study included breast cancer patients who received neoadjuvant chemotherapy during the study period from January 2022 to December 2024.

A non-probability consecutive sampling technique was used. All eligible breast cancer patients who received neoadjuvant chemotherapy and had available post-treatment response assessment during the defined study period were included. A total of 252 patient records were initially screened. Thirty-one records were excluded because of incomplete data, leaving 221 patients for final analysis.

Study Population

The final study population consisted of 221 eligible breast cancer patients who received neoadjuvant chemotherapy and had sufficient records for response assessment during the study period.

Inclusion and Exclusion Criteria

Patients were included if they had histologically confirmed breast cancer, received neoadjuvant chemotherapy, had available baseline clinicopathological information, and had post-NACT response assessment recorded in the hospital electronic medical record. Patients were excluded if they had metastatic breast cancer receiving palliative chemotherapy, did not receive neoadjuvant chemotherapy, had incomplete baseline or response data, or had missing records preventing assessment of treatment response. Patient names, medical record numbers, and other direct identifiers were excluded from the analytic dataset and manuscript reporting.

Data Collection

Data were extracted using a structured data collection format. Variables included age, gender, menopausal status, parity, comorbidities, family history, baseline TNM stage, imaging modality, histopathological type, tumor grade, estrogen receptor (ER) status, progesterone receptor (PR) status, HER2/neu status, Ki-67 index where available, molecular subtype, number of NACT cycles, clipping status, post-NACT assessment, type of breast surgery, type of axillary surgery, lymphovascular invasion, margin status, and treatment response. Records were checked for duplicate entries and obvious spelling variations in categorical variables were standardized before analysis.

Molecular Subtype Classification

Molecular subtype was assigned from documented ER, PR, and HER2/neu status. Tumors were categorized as luminal A, luminal B, HER2-enriched, triple-negative breast cancer, or not recorded. Cases with unavailable receptor information were not forced into any molecular category and were reported separately as not recorded. This approach was used to avoid misclassification and to preserve transparency in the analysis.

Outcome Assessment

The primary outcome was response to NACT as documented in clinical and pathological records. Response was categorized as complete clinical/pathological response, partial response, no response, or progressive disease. For additional summary interpretation, complete and partial responses were grouped as favorable response, while no response and progressive disease were grouped as non-favorable response. Surgical outcomes were analyzed among patients with available surgical records. Cases with missing, unrecorded, or lost surgical follow-up were retained in the overall response analysis only if post-NACT response assessment was available.

Statistical Analysis

Data were analyzed using SPSS version 25. Continuous variables were summarized as mean with standard deviation or median with interquartile range, as appropriate. Categorical variables were presented as frequencies and percentages. The chi-square test was used to assess the association between molecular subtype and response to NACT. Cases with unrecorded molecular subtype were excluded from subtype-specific inferential testing. For inferential testing, complete response was compared with non-complete response where appropriate. A p-value of <0.05 was considered statistically significant.

Ethical Considerations

The study was based on retrospective review of hospital records. Direct patient identifiers were removed before analysis and reporting. Data were handled confidentially and used only for academic and research purposes. Institutional ethical approval details are provided in the Declarations section.

A total of 252 records were initially reviewed. Thirty-one records were excluded because of incomplete data, resulting in a final cohort of 221 patients. The mean age was 48.8 ± 10.0 years and the median age was 48 years. Most patients were between 40 and 59 years of age, with 75 patients (33.9%) in the 40-49-year group and 70 patients (31.7%) in the 50-59-year group. Forty-four patients (19.9%) were younger than 40 years and 32 patients (14.5%) were 60 years or older. Premenopausal patients constituted 55.7% of the cohort, while 44.3% were postmenopausal. Comorbidities were documented in 37 patients (16.7%). Family history was poorly documented, with 209 cases (94.6%) having no recorded family history status. Baseline tumor staging showed that T2 disease was the most frequently recorded tumor stage, while T4 categories together represented 21.7% of the cohort. Initial nodal status showed N1/N1a disease in 44.3% of patients and N0 disease in 34.8%. Baseline demographic and clinical characteristics are summarized in Table 1.

Table 1. Baseline demographic and clinical characteristics of the included cohort (N=221)

Tumor biology and pathological characteristics are presented in Table 2. Invasive ductal carcinoma was the predominant histological type, reported in 212 patients (95.9%). Invasive lobular carcinoma and metaplastic carcinoma were less frequent. ER positivity was recorded in 89 patients (40.3%), while PR positivity was recorded in 70 patients (31.7%). HER2/neu positivity was found in 75 patients (33.9%), while HER2/neu negativity was recorded in 135 patients (61.1%).

The most frequent molecular subtype was triple-negative breast cancer, observed in 77 patients (34.8%), followed by luminal A breast cancer in 60 (27.1%), HER2-enriched breast cancer in 53 (24.0%), and luminal B breast cancer in 22 (10.0%). Molecular subtype was not recorded in 9 patients (4.1%). Lymphovascular invasion was present in 78 patients (35.3%), and surgical margins were negative in 217 patients (98.2%).

Table 2. Tumor biology and pathological characteristics (N=221)

Treatment and surgical characteristics are summarized in Table 3. The mean number of NACT cycles was 7.6 ± 1.1 and the median number was 8 cycles. Most patients received 7-8 cycles of NACT. Forty-eight patients (21.7%) received 6 or fewer cycles, while 11 patients (5.0%) received 9 or more cycles. The exact chemotherapy regimen was recorded in only 23 patients (10.4%), indicating a major documentation limitation. Tumor clipping was documented as performed in 60 patients (27.1%) and not performed in 89 patients (40.3%), while clipping status was not recorded in 72 patients (32.6%). Regarding breast surgery, total mastectomy was performed in 121 patients (54.8%), while wide local excision was performed in 96 patients (43.4%). Axillary lymph node dissection was performed in 119 patients (53.8%), and sentinel lymph node biopsy was performed in 98 patients (44.3%).

Table 3. Neoadjuvant chemotherapy and surgical characteristics (N=221)

The overall response after NACT is shown in Table 4. Complete clinical/pathological response was recorded in 58 patients (26.2%). Partial response was recorded in 82 patients (37.1%), no response in 73 patients (33.0%), and progressive disease in 8 patients (3.6%). When complete and partial responses were combined, 140 patients (63.3%) achieved a favorable response. In contrast, 81 patients (36.7%) had a non-favorable response, including no response or progressive disease.

Table 4. Overall clinical/pathological response after NACT (N=221)

Response to NACT differed substantially across molecular subtypes, as shown in Table 5. Among patients with triple-negative breast cancer, 24 of 77 patients (31.2%) achieved complete clinical/pathological response, 24 (31.2%) achieved partial response, 27 (35.1%) showed no response, and 2 (2.6%) developed progressive disease. Among patients with HER2-enriched breast cancer, 23 of 53 patients (43.4%) achieved complete clinical/pathological response, representing the highest complete response rate among recorded subtypes. Partial response was observed in 17 patients (32.1%), no response in 10 (18.9%), and progressive disease in 3 (5.7%).  Among patients with luminal A breast cancer, only 3 of 60 patients (5.0%) achieved complete clinical/pathological response, while no response was observed in 31 (51.7%). Among luminal B cases, 5 of 22 patients (22.7%) achieved complete clinical/pathological response, 15 (68.2%) achieved partial response, 2 (9.1%) showed no response, and no patient developed progressive disease. After excluding cases with unrecorded molecular subtype, molecular subtype was significantly associated with complete versus non-complete response (chi-square test, p<0.001). Molecular subtype was also significantly associated with the four-category response pattern (p<0.001).

Table 5. Response to NACT according to molecular subtype

Statistical note: Molecular subtype was significantly associated with complete versus non-complete response after excluding cases with unrecorded subtype (chi-square test, p<0.001).

This retrospective study evaluated clinicopathologic response to neoadjuvant chemotherapy among breast cancer patients treated at a tertiary care hospital in Pakistan. The principal finding was that nearly two-thirds of patients achieved a favorable response to NACT, including 26.2% with complete clinical/pathological response and 37.1% with partial response. Molecular subtype was significantly associated with response. HER2-enriched and triple-negative breast cancers showed higher complete response rates, whereas luminal A tumors showed the lowest complete response rate.

The overall complete response rate of 26.2% is clinically meaningful and broadly consistent with the established heterogeneity of response to NACT across breast cancer subtypes. Pathological complete response is widely used as a short-term endpoint in neoadjuvant research because it reflects tumor chemosensitivity and residual disease burden after systemic therapy. Large pooled analyses and meta-analyses have shown that achieving pCR is associated with improved event-free survival and overall survival, particularly in triple-negative and HER2-positive breast cancers (4-6).

HER2-enriched tumors showed the highest complete response rate in this study, with 43.4% achieving complete clinical/pathological response. This finding is compatible with the known responsiveness of HER2-positive disease to neoadjuvant systemic therapy, particularly when chemotherapy is combined with HER2-targeted treatment (10). Current guidelines support neoadjuvant therapy for selected HER2-positive patients, especially when tumor size or nodal status makes preoperative systemic therapy useful for surgical planning or subsequent treatment decisions (2,3). However, regimen and targeted therapy details were not consistently documented in this dataset; therefore, the contribution of anti-HER2 therapy could not be assessed reliably.

Triple-negative breast cancer was the most frequent molecular subtype in the cohort and showed a complete response rate of 31.2%. TNBC is generally more chemosensitive than hormone receptor-positive disease, but it is also biologically aggressive and associated with higher recurrence risk when residual disease remains after NACT. The strong prognostic value of pCR in TNBC has been repeatedly demonstrated (4-6), and residual disease after preoperative chemotherapy may have therapeutic implications for adjuvant treatment decisions (11).

The relatively high proportion of TNBC in this dataset may reflect referral patterns, biological variation, or presentation of more aggressive disease at a tertiary care center. Luminal A tumors showed the lowest complete response rate, with only 5.0% achieving complete clinical/pathological response. This result is consistent with previous evidence that hormone receptor-positive, HER2-negative tumors generally have lower pCR rates after chemotherapy compared with HER2-positive and triple-negative tumors (7). However, this finding should not be interpreted as evidence that NACT should be categorically avoided in all hormone receptor-positive patients. In luminal disease, the aims of neoadjuvant treatment may include tumor downstaging, improved operability, or surgical planning rather than pCR alone.

Surgical outcomes showed that 43.4% of patients underwent wide local excision after NACT, while 54.8% underwent total mastectomy. This suggests that breast-conserving surgery was feasible in a substantial proportion of patients. Nevertheless, because baseline breast-conservation eligibility was not consistently documented, it is not possible to determine how many patients were converted from mastectomy candidacy to breast conservation by NACT.

This distinction is important for future prospective work, because one of the practical advantages of NACT is its potential to improve breast conservation rates while maintaining oncologic safety in selected patients (8,9). Axillary management after NACT remains an evolving area of breast cancer care. In this cohort, axillary lymph node dissection was performed in 53.8% of patients, while sentinel lymph node biopsy was performed in 44.3%. Interpretation of these findings is limited because documentation of baseline nodal biopsy, nodal clipping, post-NACT nodal imaging, and final nodal response was incomplete. High-quality axillary decision-making after NACT requires clear baseline nodal staging and standardized documentation of nodal response, particularly in patients who initially present with node-positive disease.

A major practical finding of this study is the extent of documentation gaps. NACT regimen details were missing in 89.6% of cases, family history was not recorded in 94.6%, and clipping status was not recorded in 32.6%. These missing data elements restrict the ability to perform deeper analysis and limit comparability with international studies. For Q1-level journal submission, it is important to transparently report these gaps as limitations rather than overstate findings. Future hospital records should include structured fields for receptor status, molecular subtype, chemotherapy regimen, anti-HER2 therapy use, endocrine therapy, radiological response, surgical planning before and after NACT, and pathological response according to a standardized definition.

The strength of this study is that it represents real-world experience from a tertiary care hospital in Pakistan. Such data are valuable because treatment access, disease stage at presentation, documentation practices, and multidisciplinary pathways can differ substantially from clinical trial settings. The study also includes a reasonable sample size and evaluates clinically meaningful variables, including receptor status, molecular subtype, treatment response, breast surgery, axillary surgery, lymphovascular invasion, and margin status.

Several limitations should be acknowledged. First, the retrospective design limits causal inference and depends on the completeness of medical records. Second, treatment regimen and targeted therapy information were poorly documented, preventing assessment of response by chemotherapy protocol or anti-HER2 therapy exposure. Third, some receptor and subtype information was unavailable.

Fourth, Ki-67 and tumor grade were not consistently available for robust modeling. Fifth, complete response was based on recorded hospital data rather than centralized pathology review. Sixth, survival outcomes, recurrence, disease-free survival, and overall survival were not available; therefore, long-term prognostic conclusions cannot be drawn.

Despite these limitations, the study provides useful real-world evidence that NACT achieved favorable response in a substantial proportion of patients and that response varied significantly by molecular subtype. The findings support the use of NACT in selected patients with locally advanced, HER2-enriched, and triple-negative breast cancer, while emphasizing careful patient selection for luminal tumors. Standardization of documentation and response reporting will improve future clinical audits, research quality, and multidisciplinary decision-making.

This retrospective analysis demonstrated that NACT produced a favorable response in 63.3% of breast cancer patients, including a complete clinical/pathological response rate of 26.2%. Response varied significantly according to molecular subtype. HER2-enriched and triple-negative breast cancers showed higher complete response rates, while luminal A tumors showed a comparatively lower complete response rate.

These findings support the role of NACT in selected patients, particularly those with biologically aggressive subtypes and locally advanced disease. Careful patient selection, standardized receptor testing, complete documentation of chemotherapy and targeted therapy, and uniform pathological response reporting are essential to improve treatment planning and research quality.

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