Exceptional Locoregional Pathological Response in Metastatic Triple‐Negative Breast Cancer Treated With Palliative Platinum‐Based Chemotherapy

ABSTRACT

Locoregional pathological complete response with concurrent radiologic metabolic remission following palliative gemcitabine–carboplatin chemotherapy in young, low‐grade metastatic triple‐negative breast cancer patient suggests potential chemosensitivity in select advanced cases, warranting further clinical investigation.

1. Introduction

Breast cancer remains the most common and fatal cancer diagnosed in women. It usually originates from the ductal epithelium but can also develop from the lobular epithelium. The incidence of breast cancer is more common in high‐income countries than in low‐income ones, largely attributable to the widespread availability of advanced screening and diagnostic modalities [1].

Recognized risk factors include early puberty, early menarche, late childbirth age, smoking, hormone replacement therapy, and oral contraceptive use. Clinically, most breast cancers present as asymptomatic palpable lumps detected during routine breast examination. Advanced disease may manifest as frank ulceration, peau d'orange, or features of distant metastasis, with bone being the most common metastatic site. Skeletal involvement often presents with various complications like pain, pathologic fractures, spinal cord compression, and hypercalcemia of malignancy [2].

Mammography is the primary modality for screening of breast carcinoma with findings categorized according to the Breast Imaging Reporting and Data System (BI‐RADS). Additional imaging modalities such as computed tomography (CT) and technetium‐99 m bone scintigraphy are valuable for assessing metastatic involvement. Diagnosis is typically confirmed through histopathological examination while molecular classification offers a more precise assessment of prognosis and therapeutic response. Breast cancers are broadly classified into receptor‐positive (Luminal A, Luminal B, and HER2‐enriched) and receptor‐negative subtypes, including Triple‐Negative Breast Cancer (TNBC), which accounts for approximately 15% of all breast cancers [3].

Management of metastatic breast carcinoma is multidisciplinary, incorporating chemotherapy, targeted therapy, immunotherapy, and hormonal therapy. Anthracycline‐ and taxane‐based chemotherapy regimens are widely used in both adjuvant and neoadjuvant settings, with approximately 40%–50% of patients with early‐stage TNBC achieving a pathological complete response (pCR) following neoadjuvant chemotherapy [3]. Despite the therapeutic advances, the prognosis for metastatic breast cancer remains poor, with a five‐year survival rate of less than 30%, even among patients receiving systemic therapy [4].

Against this background, we report a rare case of early‐onset, highly proliferative, invasive Grade 1 TNBC with osseous metastasis that demonstrated a pathological complete response in the breast and axillary nodes, with a radiologic metabolic response of osseous metastases, following palliative gemcitabine‐carboplatin‐based chemotherapy and zoledronate therapy in a young patient.

2. Case Presentation/Examination

A 33‐year‐old multiparous lady presented to the oncology clinic with a four‐month history of a gradually enlarging, painless lump in the left breast. She denied any history of significant weight loss, fever, night sweats, and trauma to the breast. Her personal and family history were unremarkable for any malignancies or co‐morbidities. On local examination, there were multiple firm, mobile, and non‐tender lumps measuring roughly 1 × 2 cm involving the central region and the nipple‐areola complex of the left breast. There was no evidence of nipple discharge, nipple inversion, skin tethering, or overlying skin changes. However, multiple palpable lymph nodes of size 2–3 cm were noted in the ipsilateral axilla. The remainder of the physical examination and a comprehensive review of systems were unremarkable. The findings raised clinical suspicion for an underlying neoplastic process, warranting further diagnostic evaluation.

3. Methods

Initial mammographic evaluation demonstrated increased density of the left breast with increased fibro‐glandular component relative to the contralateral side. No apparent microlesions were visualized within the subareolar region. The overlying skin and nipple appeared normal. However, a few confluent, morphologically suspicious lymph nodes were noted in the left axilla, the largest measuring 3.4 × 1.0 cm. Hematological and biochemical parameters were within the normal limits.

On further evaluation, a core needle biopsy of the lesion was performed. Histopathological examination revealed proliferating tumor cells with intraductal extension exhibiting pleomorphic nuclei, prominent nucleoli, and scanty cytoplasm along with atypical myoepithelial cells. These findings were consistent with Grade 1 Invasive Carcinoma of no special subtype based on the Nottingham grading system. Furthermore, immunohistochemical analysis of the lesion demonstrated negative expression of estrogen receptor (ER), progesterone receptor (PR), and HER2, confirming a triple negative phenotype. The Ki‐67 proliferative index was 40%, indicating a high proliferative index (Table 1). In order to assess the locoregional spread and distant metastasis, a comprehensive review of the anatomy with Contrast Enhanced Computed Tomography (CECT) of the neck, thorax, abdomen, and pelvis was done. The imaging demonstrated an enlarged left breast with increased fibroglandular component and thickened overlying subcutaneous tissue and skin associated with few discrete‐confluent lymph nodes noted in the left axilla, with the largest node measuring 1.4 × 1.0 cm in the axial plane. It also showcased lytic lesions in the third, sixth, and twelfth dorsal vertebrae; the first and fourth lumbar vertebrae; the first sacral vertebra; as well as the bilateral iliac bones and left acetabulum, all suggestive of osseous metastases from the carcinoma. Skeletal metastasis was further consolidated by the findings of ^99MTC‐MDP whole body bone scan—which revealed increased tracer uptake in multiple dorsal and lumbar vertebrae, sacrum, both ilium and acetabulum, right pubic bone, and both femurs. Based on the triple assessment, a diagnosis of highly proliferative triple negative invasive carcinoma of the left breast with osseous metastases was formulated. Given the advanced stage of the disease (Stage IV), the patient was started on palliative chemotherapy consisting of intravenous gemcitabine (1600 mg) and intravenous carboplatin (450 mg) given 2 weeks apart for six cycles. Additionally, intravenous zoledronate 4 mg was administered for a total of six doses to manage osseous metastases. Adjuvant therapy included filgrastim, ranitidine, ondansetron, olanzapine, dexamethasone, and pyridoxine supplements aimed at mitigating chemotherapy‐induced side effects and maintaining treatment tolerance.

TABLE 1.

The immunohistochemical profile of the tumor.

Marker	Result	Interpretation
Estrogen receptor (ER)	Negative	Triple negative phenotype
Progesterone receptor (PR)	Negative	Triple negative phenotype
HER2	Negative	Triple negative phenotype
Ki‐67	40%	High proliferative index

4. Conclusions and Results

The patient tolerated chemotherapy without any major hematological or systemic complication. After completing four cycles of chemotherapy, a repeat scan demonstrated an ill‐defined, hypodense enhancing lesion with asymmetric fibroglandular tissue in the sub‐areolar region of the left breast with diffuse cutaneous thickening and nipple retraction without significant axillary lymphadenopathy. Lytic bony lesions were converted to sclerotic ones. Similarly, following six cycles, a whole‐body F‐18‐Fluoro‐2‐deoxy‐D‐glucose Positron Emission Tomography (F‐18 FDG PET) scan showcased mildly active fibroglandular thickening in the central left breast, suggesting residual disease. Axillary nodes and bone lesions were metabolically inactive, with no evidence of active disease elsewhere (Figure 1). The patient then underwent Modified Radical Mastectomy (MRM) of the left breast for locoregional disease control and prevention of complications, rather than curation. Postoperative histopathology of the lesion revealed a complete pathological response in the breast and axillary nodes (ypT0N0). This was followed by adjuvant radiation therapy aimed at pain management. The patient continues to be monitored and at 12 months follow‐up remains in good clinical condition, without evidence of disease recurrence.

FIGURE 1.

Post‐treatment 18F‐FDG PET/CT and CT findings after six cycles of chemotherapy. (A) Axial fused PET/CT image showing the thoracic region with no definite abnormal hypermetabolic focus. (B) Corresponding axial PET/CT image demonstrating mildly active fibroglandular thickening in the central left breast, with metabolically inactive axillary and osseous lesions (large white arrow). (C) Sagittal CT image demonstrating multiple sclerotic osseous lesions involving the spine and pelvis, corresponding to previously identified metastatic sites (small black arrows).

5. Discussion

In females, breast carcinoma is the most commonly diagnosed and one of the most lethal cancers worldwide [5]. Similarly, the prevalence of breast cancer in Nepal is 4.93% with an ever‐increasing trend, most commonly affecting women between the ages of 40 and 60 years. Our case presents an uncommon instance of breast cancer occurring in a significantly younger age group, highlighting the need for greater awareness and consideration of early‐onset disease. The invasive carcinoma of no special subtype is the most prevalent breast cancer in Nepal whereas the prevalence of TNBC is around 20.59%, according to a study conducted in a university hospital of Nepal [6, 7, 8]. Breast carcinomas most commonly metastasize to bone, liver, and lungs and less frequently to the brain and skin. Patients with metastatic breast malignancy typically present with a new breast lump, bone or back pain, weight loss, shortness of breath, and generalized fatigue indicating systemic involvement. Visceral metastases are not clinically apparent but palpable axillary lymphadenopathy and bony tenderness are consistent findings associated with advanced disease, particularly with osseous spread [9]. In a similar context, our patient presented with a gradually progressive, painless left breast lump and palpable ipsilateral axillary lymphadenopathy. However, features suggestive of systemic involvement were remarkably absent, thereby confounding the consideration of a metastatic disease.

A cross‐sectional study conducted in India showed patients in late‐stage breast cancer with deranged biochemical and hematological parameters, notably in the form of elevated random blood sugar, alkaline phosphatase, and urea levels and depleted hemoglobin levels [10]. In contrast, all the laboratory parameters were within the normal range in our case.

The definitive diagnosis of breast carcinoma is established through histopathological examination and immunohistochemical analysis, while radiological imaging plays a supportive role in disease staging, assessment of local and distant spread, evaluation of lymph node involvement, and treatment planning. Positron Emission Tomography—Computed Tomography (PET‐CT) is a recent advancement in oncological imaging which helps in staging, restaging, and assessing treatment response in breast cancer. It utilizes radiotracers to evaluate various metabolic processes—providing insights into metabolic activity, blood flow, and chemical composition. Areas of higher metabolic activity—often indicative of malignancy—appear as bright spots or hypermetabolic foci in imaging [11]. In ER‐positive breast cancers, newer tracers like 18F‐fluoroestradiol (18F‐ FES) allow non‐invasive assessment of estrogen receptor expression, predicting endocrine responsiveness and tumor heterogeneity with high sensitivity (81%–94%) and specificity (78%–95%). However, in TNBC, as the tumor lacks ER, PR, and HER2 expression, F‐18 FDG PET scan remains the appropriate choice despite having low sensitivity [12, 13]. The bone scan confirmed widespread skeletal involvement in our case, but PET scan provided greater accuracy in detecting metabolically active lesions—diagnosing the residual disease and guiding the further treatment. This was in line with the evidence of PET scan being better than bone scan [14].

The eighth edition of American Joint Committee on Cancer (AJCC) staging manual integrates both traditional tumor, lymph node, metastasis (TNM) systems and selected molecular and biological factors to better predict prognosis and guide personalized treatment—indicating a shift towards precision oncology. According to the AJCC eighth edition staging manual, our case corresponds to Stage IV breast cancer owing to osseous spread thereby warranting a systemic treatment approach focused on palliation, disease control and quality of life rather than curative intent [15].

Systemic therapy remains the primary treatment modality in metastatic TNBC. First line therapy typically includes anthracycline or taxane‐based regimens, along with sequential monotherapy such as eribulin, nab‐paclitaxel, capecitabine, vinorelbine, cyclophosphamide, gemcitabine or liposomal doxorubicin. In resistant cases, specific combination therapy (e.g., paclitaxel and gemcitabine, carboplatin and gemcitabine) are employed. Radiotherapy plays a crucial role in palliation—alleviating pain, preventing fracture, safeguarding neurological function with a dose regimen ranging from 8 to 30 Gy in 1–10 sessions, or radical SBRT (30–45 Gy in 3 sessions, BED ≥ 75 Gy) for oligometastatic tumors, often scheduled between cycles of systemic therapy. Bone‐targeted agents such as bisphosphonates or denosumab are used to reduce skeletal incidents, while radiopharmaceuticals (Sr‐89, Re‐186, Ra‐223) are utilized for painful multifocal bony lesions. Bone loss in advanced breast cancer is common due to metastases, treatment effects, and osteoporosis, often leading to skeletal‐related events (SREs). Zoledronic acid, a potent third‐generation bisphosphonate, reduces osteoclast activity, delays SREs, and alleviates bone pain. Given intravenously, it is more effective than earlier agents and is generally well tolerated with appropriate renal monitoring. In selected cases, surgery is indicated for solitary metastases or impending pathological fractures, and interventional radiology techniques are often used for pain control [16, 17]. In our case, following six cycles of palliative gemcitabine–carboplatin chemotherapy, the patient demonstrated a marked metabolic response of osseous lesions on PET–CT imaging. Evidence from meta‐analyses indicates that adding platinum to standard neoadjuvant anthracycline‐ and taxane‐based chemotherapy in TNBC significantly increases pathological complete response (pCR) and event‐free survival (EFS), particularly in younger patients with aggressive disease [18]. These evidences in addition to lack of PD‐L1 testing provided a strong rationale for using platinum‐based combination therapy over standard taxane‐based regimens or immunotherapy in our case. Subsequent modified radical mastectomy revealed a pathological complete response confined to the breast and axillary lymph nodes (ypT0N0). Importantly, this pathological response pertains solely to locoregional disease, as systemic metastases cannot be pathologically assessed; therefore, the observed response of metastatic lesions represents a radiologic metabolic response rather than disease eradication. Surgical intervention was undertaken for local disease control and prevention of locoregional progression aimed at improving quality of life, and not with curative intent. Adjuvant radiotherapy was administered for palliation of bone pain, in accordance with standard clinical practice.

A study done in Croatia with a retrospective cohort of 152 early TNBC patients, age, tumor size, and the count of positive lymph nodes at diagnosis were identified as the key prognostic factors for 5‐year survival. Younger patients, bigger tumors, and greater nodal involvement were linked to poorer outcomes, indicating the aggressive characteristics of TNBC and its tendency for early lymphatic dissemination. Additionally, elevated Ki67 proliferation index and high tumor grade indicate more aggressive biology—correlating with increased risks of recurrence and mortality—despite having a higher pathological complete response rate [19, 20]. In this case, the tumor demonstrated an unusually favorable response to platinum‐based chemotherapy. Platinum‐based chemotherapy demonstrates enhanced efficacy in TNBC patients with BRCA mutations or homologous recombination deficiency (HRD), likely due to impaired DNA repair mechanisms. Clinical studies report higher rates of pathological complete response in these patients compared with those lacking such mutations [21, 22]. However, germline genetic testing for BRCA1/2 or PALB2 mutations was not performed due to resource limitations, representing a significant limitation. Although HRD status was unknown, the profound response suggests potential underlying HRD, consistent with published evidence of enhanced platinum sensitivity in such tumors. Additionally, the tumor was reported as Grade 1 TNBC according to the Nottingham grading system, which is quite unusual and may partly account for the observed exceptional response.

In summary, this case highlights the biological heterogeneity of metastatic TNBC and demonstrates that profound local pathological response with systemic radiologic response may occur following palliative platinum‐based chemotherapy in selected patients. While not curative, such responses emphasize the importance of individualized treatment strategies and the need for further research into predictive biomarkers guiding therapy selection in advanced TNBC.

Author Contributions

Shristi Gupta: resources, writing – original draft. Abhisek Jha: supervision, writing – original draft, writing – review and editing. Asmita Rayamajhi: conceptualization, data curation, supervision. Aron Neupane: writing – original draft. Kshitiz Parajuli: writing – original draft. Manash Jha: writing – original draft.

Funding

The authors have nothing to report.

Consent

Written informed consent from the patient was obtained for publication according to journal guidelines.

Data Availability Statement

Data is available on request.