KEYNOTE—522 and male spindle cell carcinoma of the breast: A case report

Abstract

Metaplastic Breast Cancer (MBC) is a rare group of tumors often presenting as triple-negative. MBC accounts for less than 1% of all breast cancers with the spindle cell variant comprising less than 0.5%. While rare, spindle cell carcinoma is the commonest subtype in the western world. It has a more aggressive biological behavior with increased risk of recurrence and death due to disease compared to triple negative breast cancers. There is no treatment guideline for management of MBC due to the rarity of the disease. Instead, treatment is theorized based off success with other types of aggressive breast and metaplastic cancers of different tissue. We present the first known case report of male spindle cell carcinoma of the breast treated with KEYNOTE-522 regimen. Therapy included a first phase with pembrolizumab (dose of 200 mg) every 3 weeks plus paclitaxel and carboplatin and second phase, with four cycles of pembrolizumab with doxorubicin-cyclophosphamide.

Introduction

Metaplastic Breast Cancer (MBC) is a rare group of tumors with an array of morphologies that is composed of mesenchymal cells or non-glandular epithelium accounting for less than 1% of all breast cancers.^1,2 The vast majority are triple negative but have shown to contain various immunoprofiles.^3,4 MBC spreads hematogenously with low incidence of lymph node involvement and typically presents with a higher tumor stage with increased risk of recurrence and death due to disease compared to triple negative breast cancer and invasive ductal carcinoma.^1-3,5 According to the 2019 World Health Organization (WHO), six subtypes of MBCs are recognized: low-grade adenosquamous carcinoma, fibromatosis-like metaplastic carcinoma, squamous cell carcinoma, spindle cell carcinoma, metaplastic carcinoma with heterologous mesenchymal differentiation, and mixed metaplastic carcinoma. ⁶ The spindle cell variant comprises less than 0.5% of all breast cancers but is the most common MBC subtype in the western world (34%) and is biologically more aggressive.^7,8

Case Presentation

A 72-year-old male with history of hypertension and hyperlipidemia presented to his primary care physician with right breast tenderness and swelling after accidentally hitting it against a wall. The patient experienced rapid breast swelling that progressed over five weeks after injury and new purulent nipple discharge, which prompted him to seek medical attention (Figure 1).

Figure 1.

Initial clinical presentation.

Mammogram (Figure 2) showed a large central mass with a group of suspicious microcalcifications within the mass. There was evidence of breast parenchymal edema and skin thickening without nipple retraction. Ultrasound showed a large mass with mixed echogenicity measuring 7.8 × 6.7 × 6.5 cm and suggestion of a central scar. Color Doppler showed internal blood flow and multiple dilated ducts. An ultrasound guided core needle biopsy was performed, and immunohistochemical analysis showed focally positive PanKeratin, keratin 5 and GATA-3. There was diffuse positivity for p63 in a nuclear pattern. Staining for SOX-10 was negative. Based on the morphology and immunophenotype, the findings were most compatible with a high-grade metaplastic breast carcinoma—spindle cell subtype, ER -, PR -, HER2 -, and Ki67 83%. Genomic testing was negative for BRCA^1,2 with PIK3CA: Alpelisib + Fulvestarnt.

Figure 2.

Mammogram of right breast demostrating large central mass with microcalcifications.

Staging PET/CT scan (Figure 3) was negative for avid regional or distant metastatic disease and the patient was determined to have clinical stage IV disease due to its inflammatory presentation.

Figure 3.

PET-CT demonstrating avid regional uptake in the right breast.

The patient was placed on neoadjuvant chemotherapy based off the KEYNOTE-522 trial that has shown success against triple negative breast cancer. ⁹ Phase one was comprised of four cycles of pembrolizumab (at a dose of 200 mg) every 3 weeks plus paclitaxel and carboplatin. The second phase consisted of four cycles of pembrolizumab administered every three weeks plus doxorubicin, cyclophosphamide and Neulasta.

Phase one was tolerated well and without issue, however the patient demonstrated poor tolerance to phase two of treatment. He was hospitalized twice for neutropenic fever and sepsis despite Neulasta administration and decreasing Adriamycin dosage. He was unable to tolerate a fourth cycle due to significant ongoing side-effects of Adriamycin. On physical exam, there was an interval worsening but overall significant improvement in the size and texture of the right breast. His erythema and induration worsened after the first cycle of phase one but began to improve by the end of the second cycle. His mass became more freely mobile and has clinically shrunk in size from 12.5 × 11.5 cm to 5 × 5.5 cm. After completion of neoadjuvant treatment, restaging CT was preformed and showed significant shrinkage of the tumor from 6.4 × 5.5 cm to 3.2 × 3.9 cm with areas of hypoattenuation suggestive of central necrosis. There was no evidence of metastatic disease within the axilla, chest, or abdomen. A mastectomy with sentinel node biopsy was completed with an R0 resection of the tumor, however 5/5 lymph nodes were positive with evidence of extra-nodal extension.

Discussion

MBC with spindle cell variant is exceedingly rare with incidence of less than 0.5%. ² MBC has an overall worse survival compared to poorly differentiated ductal carcinoma and triple negative breast cancer with higher incidence of developing locoregional recurrence, metastatic disease, and death from progression of disease.^1,2 Excluding the low-grade adenosquamous and fibromatosis-like variants, MBCs are often aggressive and chemoresistant.^2,3

Per literature review, there are only a handful of reported cases of male MBC ^10-15 and to our knowledge, there is no recorded evidence of a male spindle cell breast cancer subtype. Male breast cancer is very rare, accounting for less than 1% of all cancers in men and less than 1% of all breast cancers. ¹⁶ It is often found in older men with family history of breast cancer, Klinefelter syndrome, radiation exposure, and breast cancer susceptibility gene 2 (BRCA2).^16,17 Male breast cancer patients typically have a worse prognosis compared to females because of older age and more advanced disease at presentation. ¹⁸ Our patient had no family history of breast cancer or common risk factors associated with male breast cancer. Given the scarcity of literature regarding MBC and male MBC, our treatment plan focused on prior success using immunotherapy as an adjunct to standard breast cancer chemotherapy regimens against triple-negative, non-MBC breast cancer. ⁹

There are currently no standard treatment guidelines for MBC. Surgery (+/−) radiation has been a common historical approach given its sarcomatous histology. Despite suggestion for its chemoresistant nature, neoadjuvant or adjuvant chemotherapy is commonly administered to metaplastic cancer patients (53.4–73.1%).^4,19 Success with chemotherapy on MBC varies and is dependent on cancer stage. ⁸ A single case report of high-grade spindle cell breast cancer was treated using doxorubicin, ifosfamide, mesna (AIM), a common chemotherapy regimen used for sarcoma. They appreciated >99% necrosis of the tumor and negative margins on resection. At the time of publication, the patient remained disease-free after two additional adjuvant cycles of AIM and radiation therapy for at least 2 years. ²⁰ In one prospective study, 29 MBCs underwent neoadjuvant chemotherapy with an overall pathological complete response rate of 17.2%. Standard breast cancer agents such as doxorubicin, cyclophosphamide, and taxane were used. Only one of these patients with a complete pathological response was classified as having a pure spindle cell type carcinoma. Despite their findings of highest complete pathologic response rate to date, this did not correlate to increased overall survival. ⁴

Newer evidence indicates an increased benefit using a multimodal approach against MBC. Among retrospective review of 2500 MBC patients, chemotherapy and adjuvant radiotherapy were associated with improved survival. ³ We based our chemotherapeutic regimen off the randomized phase three KEYNOTE 522 trial, which indicates an increased complete pathological response rate for early-stage triple negative breast cancer using pembrolizumab plus neoadjuvant chemotherapy compared to chemotherapy alone. Early stage was defined as stage II or stage III disease. Therapy included a first phase with pembrolizumab (at a dose of 200 mg) every 3 weeks plus paclitaxel and carboplatin and second phase, with an additional four cycles of pembrolizumab with doxorubicin-cyclophosphamide or epidrubicin-cyclophosphamide. ⁹

Our patient presented with node negative disease, consistent with the typical phenotypic presentation of MBC. ³ His clinical diagnosis was upstaged to stage IV given his inflammatory presentation. He completed neoadjuvant immunotherapy and chemotherapy followed by mastectomy with sentinel node biopsy. Despite shrinkage of the tumor on final surgical pathology, all five lymph nodes sampled were positive for disease. It should be noted that no preoperative imaging suggested nodal involvement, before or after neoadjuvant treatment. Therefore, the exact effects of chemoimmunotherapy in the axilla are unknown. We now plan to proceed with radiation therapy to the chest wall and axilla. This will be followed by capecitabine and likely continuance of Keytruda for an additional six months.

Conclusion

The spindle cell subtype of MBC is extremely rare with minimal data on its management. Our patient presented with a rapidly growing clinical stage IV inflammatory tumor and was initiated on neoadjuvant immunotherapy with chemotherapy based off the KEYNOTE 522 trial. This is the first known report on male spindle cell carcinoma and MBC treated as such. While we appreciated clinical improvement in the size and texture of the mass, there was still evidence of extra-nodal extension on final surgical pathology. It is uncertain if nodal disease was present at the time of initial diagnosis, as this was not seen on preoperative imaging. The tumor was noted to significantly shrink in size from 6.4 × 5.5 cm to 3.2 × 3.9 cm. We are unable to assess the true efficacy of KEYNOTE 522 from this single study, however with more data, it could prove to be a plausible approach to future triple negative MBC cases.

Data availability statement

The original data for this study is available. Please contact [e-mail] to request access to the data.