Complete Pathological Response to Neoadjuvant Cisplatin, Etoposide, and Pembrolizumab in Small Cell Breast Carcinoma: A Case Report and Review of the Literature.

Introduction
Small cell breast carcinoma (SCBC) is an exceedingly rare and aggressive subtype of breast cancer, comprising less than 1% of all breast malignancies. It has an estimated incidence of 0.14 per 100,000 women annually between 1990 and 2018 [1]. First described in 1983 [2], SCBC was formally classified in the 2019 World Health Organization (WHO) classification of breast tumours as a poorly differentiated neuroendocrine carcinoma [3]. Morphologically and immunohistochemically, it closely resembles small cell lung carcinoma (SCLC), and its histological hallmark features include nuclear moulding, hyperchromatic nuclei, minimal cytoplasm, and high mitotic rates [4–6].
Molecularly, SCBC demonstrates both overlapping and distinct characteristics compared to SCLC. Genomic profiling has revealed frequent TP53 mutations, high TOP2A expression, and PD-L1 expression similar to SCLC, supporting its high proliferative and immunogenic potential [7]. However, approximately one-third of SCBC cases harbour PIK3CA mutations – alterations typically absent in SCLC – suggesting a biologically unique subset amenable to PI3K-pathway targeting. Most tumours exhibit high Ki-67 indices (>80%) and triple-negative receptor status, features consistent with genomic instability and enhanced neoantigen presentation [7].
Because of its rarity, there are no established clinical guidelines for the management of SCBC. Treatment approaches are generally extrapolated from those used in SCLC and triple-negative breast cancer (TNBC), given that most SCBC cases are hormone receptor-negative and HER2-negative [1, 5]. Regimens, such as cisplatin and etoposide, commonly used in SCLC, and anthracycline or taxane-based chemotherapies used in breast cancer, have been applied in published case reports and small series [8–11]. Immunotherapy has emerged as a promising modality in both TNBC and extensive-stage SCLC. The KEYNOTE-522 trial demonstrated that adding pembrolizumab to neoadjuvant chemotherapy in early-stage TNBC significantly improved pathologic complete response rates (64.8% vs. 51.2%) and event-free survival (hazard ratio 0.63, 95% CI 0.48–0.82) [12]. In extensive-stage SCLC, the IMpower133 trial showed overall survival benefit with atezolizumab plus platinum-etoposide (median OS 12.3 vs. 10.3 months, HR 0.70) [13]. Similarly, durvalumab demonstrated survival benefits in the CASPIAN trial [14]. Given SCBC’s shared neuroendocrine features with SCLC and frequent triple-negative status, these data provide strong translational rationale for incorporating immune checkpoint inhibitors (ICIs) into SCBC treatment paradigms. However, to date, the role of ICIs in SCBC has not been clearly defined.
Here, we report the first known case of early-stage SCBC treated with neoadjuvant cisplatin, etoposide, and pembrolizumab, resulting in a complete pathological response (pCR). This case adds to the limited literature on the clinical management of SCBC and raises the possibility that immunotherapy could play a significant role in selected patients with this disease. Her Eastern Cooperative Oncology Group (ECOG) performance status was 0.

Case Report
A 65-year-old postmenopausal woman presented in September 2024 with a self-detected lump in her right breast. The lump was painless, with no associated nipple discharge, skin changes, or systemic symptoms. Her most recent prior mammogram, completed in March 2024, had been unremarkable. Her past medical history included repaired tetralogy of Fallot, bronchiectasis, migraines, and depression. She had undergone bilateral breast augmentation in 2015 and had no history of prior breast pathology. Her medications included venlafaxine, furosemide, melatonin, and sumatriptan. She reported allergies to mirtazapine and penicillin. She was a lifelong non-smoker, consumed approximately four standard drinks of alcohol per week, and remained physically active. Family history was significant for kidney cancer in her brother and lung cancer in her father.
On her initial clinical examination, there was a firm, mobile 25-mm mass in the upper outer quadrant of the right breast. No axillary or supraclavicular lymphadenopathy was palpable. A repeat mammogram and targeted ultrasound were performed on 18 September 2024, confirming a suspicious mass at the 2 o’clock position, measuring 20 × 14 mm and located 3 cm from the nipple. Ultrasound-guided core biopsy was performed on 20 September. Histological examination revealed a poorly differentiated carcinoma with small cells, hyperchromatic nuclei, scant cytoplasm, frequent mitoses, and evidence of nuclear moulding and crush artefact. Immunohistochemistry showed strong positivity for synaptophysin and CK7 but was negative for chromogranin, ER, PR, HER2, and TTF-1. The Ki-67 index was over 90%, consistent with a highly proliferative tumour. PD-L1 expression was not assessed on the diagnostic biopsy specimen as there is no guideline for PD-L1 testing in small cell cancers in Australia. The features were diagnostic of small cell neuroendocrine carcinoma of the breast. TTF-1 negativity (seen in most lung tumours) and absence of pulmonary lesions on imaging supported a primary breast origin.
A staging CT scan of the chest, abdomen, and pelvis on 25 September revealed a 2.0 × 1.2 cm lesion in the medial aspect of the right breast with no axillary or mediastinal lymphadenopathy and no visceral metastases. Several small hypoattenuating liver lesions were noted, interpreted as benign hepatic cysts. MRI of the breasts on 25 October demonstrated an irregular lobulated mass located at the 3 o’clock position, abutting the implant capsule but without evidence of capsular invasion or skin involvement (Fig. 1). No additional suspicious lesions were identified in either breast. Subsequent PET-CT imaging was also conducted to ensure no evidence of distant metastatic disease (Fig. 2).
Given the rapid interval growth of the tumour and the aggressive histopathological features, her case was discussed at a multidisciplinary tumour board. A consensus was reached to proceed with neoadjuvant chemoimmunotherapy as per the TNBC protocol. However, the chemotherapy backbone used was cisplatin and etoposide extrapolating from data in the SCLC space. The rationale for the addition of pembrolizumab was based on its demonstrated benefit in early TNBC and in SCLC when used with platinum-based regimens. Chemoimmunotherapy was followed by breast-conserving surgery and adjuvant immunotherapy and radiotherapy.
Neoadjuvant treatment was initiated in early October 2024. The patient received four 21-day cycles of cisplatin (75 mg/m2 IV on day 1) and etoposide (100 mg/m2 IV on days 1–3), with concurrent pembrolizumab 200 mg IV every 3 weeks administered on day 1 of each chemotherapy cycle. Treatment was well tolerated overall, with only grade 1 fatigue and mild nausea. No immune-related adverse events were reported. By the end of the second cycle, she reported a noticeable reduction in the size of the breast lump. Interim ultrasound confirmed a radiologic partial response. Following completion of four cycles, she underwent wide local excision and sentinel lymph node biopsy on 12 February 2025. Gross examination of the surgical specimen showed a fibrotic tumour bed. Histopathological analysis revealed a pCR with no residual invasive carcinoma. A 6-mm focus of intermediate-to-high-grade ductal carcinoma in situ, ER/PR-negative, was identified within the resected area. All surgical margins were clear, and none of the seven sentinel lymph nodes demonstrated metastatic disease. No lymphovascular invasion was present.
Postoperatively, the patient received adjuvant radiotherapy to the right breast (40 Gy in 15 fractions). Prophylactic cranial irradiation (PCI), which is sometimes considered in SCLC, was not offered due to a lack of supporting evidence in extrapulmonary small cell carcinomas. She resumed pembrolizumab monotherapy and completed an additional 13 cycles, completing a total treatment duration of approximately 1 year, consistent with the schedule used in the KEYNOTE-522 trial for early-stage TNBC [12]. Follow-up imaging in May 2025 showed no evidence of recurrence or residual disease. The patient remains in clinical and radiological remission at the time of this report.

Discussion
SCBC is an extremely uncommon form of breast cancer with an aggressive clinical course. It shares many biological and morphological features with SCLC and is thought to represent a high-grade variant of neuroendocrine breast carcinoma [3, 4]. Because of its rarity, the disease is underrepresented in clinical trials, and most treatment data are derived from case reports and small retrospective series. In Zhu et al.’s [1] population-based analysis of 323 cases, the median age at diagnosis was 65 years, and the majority of tumours were triple-negative, with a median tumour size of 3.5 cm. Stage II disease was the most common presentation. Five-year disease-specific survival was 61.6%, and overall survival was 53.1%, both significantly lower than those for invasive ductal carcinoma not otherwise specified [1].
Histologically, SCBC is characterised by sheets of small round cells with nuclear moulding, high mitotic activity, and sparse cytoplasm [2, 4, 5]. Immunohistochemical staining often reveals positivity for synaptophysin, chromogranin, CD56, and CK7 [8]. In contrast to SCLC, TTF-1 is often negative, which can assist in confirming a breast origin when metastatic SCLC is in the differential diagnosis [8]. High Ki-67 indices, often exceeding 80–90%, are common, underscoring the aggressive nature of the disease [4, 9]. Molecularly, SCBC has overlapping features with both breast cancer and SCLC. A genomic study by McCullar et al. [7] showed frequent TP53 mutations, PD-1 expression, and high TOP2A in SCBC, similar to SCLC. Approximately one-third of SCBC cases harboured PIK3CA mutations, which were not found in SCLC, suggesting a unique molecular subset with potential for targeted therapy [7].
Given the absence of prospective data, treatment regimens are typically modelled after SCLC or TNBC protocols. Reviews by Boutrid et al. [8] and Mentesidou et al. [9] summarised the heterogeneity of treatment, including platinum-based doublets and anthracycline-taxane combinations. Neoadjuvant chemotherapy has been less commonly reported than adjuvant therapy. Radiation therapy is often included, though the role of PCI remains unclear [6, 10]. Despite intensive multimodal treatment, outcomes remain suboptimal [1, 10].
The optimal chemotherapy regimen for SCBC remains undefined given the absence of randomized trials. While anthracycline-taxane combinations demonstrate efficacy in TNBC and were employed in KEYNOTE-522 [2], platinum-etoposide remains the standard in SCLC based on decades of evidence. Reviews by Boutrid et al. [8] and Mentesidou et al. [9] have documented heterogeneous treatment approaches in published SCBC cases. Our decision to employ cisplatin-etoposide was guided by: (1) the neuroendocrine histology with small cell morphology identical to SCLC, (2) theoretical enhanced synergy between platinum-based therapy and immunotherapy through immunogenic cell death mechanisms, and (3) avoidance of anthracycline-related cardiotoxicity in a patient with congenital heart disease (repaired tetralogy of Fallot). The excellent tolerability and dramatic pathologic response support the feasibility of this approach, though comparative effectiveness studies are needed.
The role of immunotherapy in SCBC is not well defined. However, recent success of ICIs in other aggressive cancers, particularly TNBC and SCLC, suggests a potential role. The KEYNOTE-522 trial demonstrated significantly improved event-free survival and pathological complete response rates in early TNBC when pembrolizumab was added to neoadjuvant chemotherapy [12]. In SCLC, the addition of atezolizumab or durvalumab to platinum-etoposide chemotherapy improved overall survival in the IMpower133 and CASPIAN trials, respectively [13, 14]. These findings provided a rationale for integrating pembrolizumab into our patient’s neoadjuvant regimen, especially given her tumour’s triple-negative status and high proliferation index [4, 12].
Few case reports have explored immunotherapy in SCBC. Stimes et al. [15] described a patient who had a partial response to atezolizumab and nab-paclitaxel in the metastatic setting after intolerance to cisplatin. Fitzsimmons et al. [16] recently reported a patient who experienced a complete response to sacituzumab govitecan, a TROP-2-targeting antibody-drug conjugate, following transformation from hormone-positive IDC to small cell histology. These reports underscore the potential role of novel immunologic and targeted therapies in select patients with SCBC [15–17].
The decision to perform breast-conserving surgery rather than mastectomy was made through multidisciplinary consensus, guided by the patient’s marked radiologic response and small residual imaging footprint following neoadjuvant therapy. Breast conservation was considered oncologically safe and aligned with the patient’s preference. Recent evidence supports this approach: a large population-based study demonstrated superior overall survival for breast-conserving surgery compared with mastectomy following neoadjuvant chemotherapy [17]. These findings reinforce that breast conservation, when technically feasible and clinically appropriate, remains a preferred surgical option even in aggressive tumour subtypes achieving excellent response to systemic therapy.
The remarkable pCR observed in this case raises important questions regarding patient selection for chemoimmunotherapy in SCBC. While KEYNOTE-522 [12] demonstrated benefit from pembrolizumab in early TNBC regardless of PD-L1 status, emerging data suggest that both PD-L1 expression and tumour mutational burden (TMB) may serve as independent predictive biomarkers for ICI response. Across multiple tumour types, TMB >10 mutations/Mb correlates with improved response to immune checkpoint blockade. Similarly, PD-L1 expression – particularly using the Combined Positive Score (CPS) ≥10 – predicts benefit from pembrolizumab in metastatic TNBC. Our patient’s extraordinarily high Ki-67 index (>90%) and triple-negative receptor status likely contributed to treatment sensitivity. High proliferative rates generate increased neoantigen burden, potentially enhancing immune recognition. Additionally, the one-third of SCBC cases harbouring PIK3CA mutations identified by McCullar et al. [7] may represent a molecularly distinct subset. Future prospective studies should incorporate comprehensive molecular profiling including PD-L1 expression (22C3 pharmDx assay), TMB assessment via next-generation sequencing, tumour-infiltrating lymphocyte quantification, and PIK3CA mutational analysis to identify predictive biomarkers for chemoimmunotherapy response in SCBC.
Our case is the first to demonstrate a pCR following neoadjuvant chemoimmunotherapy in SCBC. Importantly, pembrolizumab was well tolerated in both the neoadjuvant and adjuvant settings. The decision to avoid PCI was guided by lack of data in extrapulmonary small cell tumours, though this remains an open question [6]. Long-term follow-up will be necessary to confirm the durability of the response. Further, this case provides compelling rationale for systematic investigation of chemoimmunotherapy in SCBC through several research avenues. Firstly, given the extreme rarity of SCBC (0.14 per 100,000 women annually), international collaborative registries are needed to pool outcomes data and identify prognostic factors. The National Cancer Institute's Rare Tumor Patient Engagement Network or similar platforms could facilitate such efforts. Secondly, basket trials enrolling rare neuroendocrine breast carcinomas to prospectively evaluate standardized chemoimmunotherapy protocols would provide level II evidence. Such trials should incorporate mandatory biomarker collection including PD-L1 expression, TMB, tumour-infiltrating lymphocytes, and comprehensive genomic profiling to enable correlative science. Thirdly, mechanistic studies examining the tumour immune microenvironment before and after treatment could elucidate immunologic determinants of response versus resistance. Fourth, investigation of novel combinations – such as PI3K inhibitors in the PIK3CA-mutant subset or TROP-2-directed antibody-drug conjugates based on the complete response reported by Fitzsimmons et al. [16] – may expand therapeutic options. Finally, quality of life and patient-reported outcome assessments should be integrated into future studies to comprehensively evaluate the risk-benefit profile of intensive multimodal therapy in this aggressive disease.

Conclusion
Here, we report the first known case of early-stage SCBC treated with neoadjuvant cisplatin, etoposide, and pembrolizumab, resulting in a pCR. This case not only adds to the limited literature on SCBC clinical management but provides the first evidence that combining SCLC-derived chemotherapy backbones with TNBC-validated immunotherapy can achieve optimal pathologic outcomes in appropriately selected SCBC patients. Given the rarity of this disease and absence of consensus guidelines, further studies – including molecular profiling and inclusion in basket trials – are essential to define optimal management. This case underscores the importance of early multidisciplinary planning, individualised care, and innovation in malignancies.

Statement of Ethics
This retrospective review of patient data did not require ethical approval in accordance with local or national guidelines. Written informed consent was obtained from the patient for publication of the details of their medical case and any accompanying images. The CARE Checklist has been completed by the authors for this case report, attached as online supplementary material (for all online suppl. material, see https://doi.org/10.1159/000550080).

Conflict of Interest Statement
The authors have no conflicts of interest to declare.

Funding Sources
This study was not supported by any sponsor or funder.

Author Contributions
H.T.S.: write up of case report and submission of manuscript. S.S.: reviewing the article critically for content. F.H.: contribution to the interpretation of the case discussion. K.M. and W.C.: final approval of the version to be published. U.N.: substantial contribution of data and final approval of version to be published.