Introduction. Metaplastic breast carcinoma is a rare aggressive subtype of invasive breast carcinoma, with an incidence of less than 1%, being characterized by rapid growth, a relatively large tumor size and a tendency to metastasize to distant organs, particularly the lungs, although the axillary lymph nodes are less frequently affected and poorly responsive to neoadjuvant systemic therapy (NAST) in retrospective studies. The rates of complete pathologic response (pCR) after standard chemotherapy are low in patients with metaplastic breast cancer. Those with smaller tumors are more likely to achieve pCR. Patients with metaplastic breast cancer (MpBC) should be closely monitored during the NAST treatment for progressive disease (PD). Germline genetic testing should be performed. Adjuvant radiotherapy should be carried out according to standard practice. The surgical treatment depends on the size of the tumor. Mastectomy is not indicated if the size of the tumor allows the conservative operative treatment. Objective. To increase awareness, outline strategies, and offer guidance on the recommended treatment management of patients with metaplastic breast cancer. This article represents the current standard of treatment in Germany and a case study of two patients with resistance to current chemotherapy. Materials and method. This article used the medical data of patients treated in Clinic Essen Mitte and the guideline of therapy performed by Clinic Essen Mitte.
Metaplastic breast cancer. German guidelines for triple-negative breast carcinoma
Carcinomul mamar metaplastic. Ghidul german pentru carcinomul mamar triplu-negativ
First published: 31 mai 2024
Editorial Group: MEDICHUB MEDIA
DOI: 10.26416/OnHe.67.2.2024.9695
Abstract
Rezumat
Introducere. Carcinomul mamar metaplastic este un subtip agresiv de carcinom mamar invaziv, rar, cu o incidenţă mai mică de 1%, caracterizat printr-o creştere rapidă, o dimensiune tumorală relativ mare şi o tendinţă de metastazare la distanţă, în special la plămâni, deşi ganglionii limfatici axilari sunt mai puţin frecvent afectaţi şi răspund slab la terapia neoadjuvantă sistemică (NAST) în studiile retrospective. Ratele de răspuns patologic complet (pCR) după chimioterapia standard sunt scăzute la pacientele cu cancer mamar metaplastic. Pacientele cu tumori mai mici au mai multe şanse de a obţine pCR. Pacientele cu cancer de sân metaplastic (MpBC) trebuie monitorizate îndeaproape în timpul tratamentului NAST pentru boală progresivă (PD). Este necesară efectuarea de teste genetice germinale. Radioterapia adjuvantă ar trebui efectuată în conformitate cu practica standard. Tratamentul chirurgical depinde de dimensiunea tumorii, mastectomia nefiind indicată dacă dimensiunea tumorii permite un tratament operatoriu conservator. Obiectiv. Creşterea nivelului de conştientizare, conturarea de strategii şi oferirea unor îndrumări privind managementul recomandat al tratamentului pacientelor cu cancer mamar metaplazic. Acest articol reprezintă standardul actual de tratament în Germania şi un studiu de caz a doi pacienţi cu rezistenţă la chimioterapia actuală. Materiale şi metodă. Acest articol utilizează datele medicale ale pacienţilor trataţi în Clinic Essen Mitte şi ghidul terapiei efectuate în această clinică.
Introduction
Metaplastic breast carcinoma (MpBC) is a rare and aggressive subtype of invasive breast carcinoma characterized by rapid growth, a relatively large tumor size and a tendency to metastasize to distant organs, particularly the lungs, although the axillary lymph nodes are less frequently affected.
This article represents the current standard of treatment in Germany and a case study of two patients with resistance to current chemotherapy. The article used the medical data of patients treated in Clinic Essen Mitte and the guideline of therapy performed by Clinic Essen Mitte. Our objective was to increase awareness, outline strategies, and offer guidance on the recommended treatment management of patients with metaplastic breast cancer.
Histology. These types of cancers are often triple-negative carcinomas. The tumor shows a high degree of cellularity and heterologous differentiation, including chondroid, osseous, pleomorphic/sarcomatous, spindle-shaped and squamous elements.
Molecular changes
Typically, mesenchymal subtype PT53 is the most common mutation, occurring in about 60% of cases. Mutations in PI3K kinase occur in one third of cases. MYC is the most frequently amplified gene, followed by EGFR. The most common gene loss is the CDKN2A/CDKN2B locus, followed by PTEN germline. Genetic testing should be performed.
Common mutations are TP53, EGFR, PIK3CA, and PTEN.
Aggressiveness
The subtype with heterologous (mesenchymal), squamous or high-grade spindle cell differentiation is highly malignant.
The subtype with adenosquamous or fibromatosis-like differentiation has uncertain malignant potential (low-grade).
Surgical treatment
The operative treatment depends on the size of the tumor, mastectomy not being indicated if the size of the tumor allows the conservative operative treatment.
Radiotherapy is performed in case of conservative treatment with or without axilla or in case of T3 tumors of the chest wall.
Neoadjuvant treatment for metaplastic breast cancer
The rate of complete pathologic response (pCR) after standard chemotherapy is low in patients with metaplastic breast cancer. PCR rate is less than 10%. Patients who achieve pCR have a similarly favorable prognosis to other triple-negative breast cancers (TNBCs).
The five-year overall survival (OS) is 93% for pCR compared to 63% without pCR. Patients with smaller tumors are more likely to achieve pCR. There are no data on the use of neoadjuvant specific immunotherapy for metaplastic carcinoma (Haque et al., Clin Breast Cancer. 2022).
Immunotherapy
Metaplastic breast cancer is more likely to have PDL-positive tumor cells than other TNBC subtypes. Also, 30% to 70% of cases express PD-L1 in tumor cells.
No difference in PD-L1 expression has been observed in immune cells between MpBC and other TNBC subtypes. Also, 42% to 80% MpBC expresses PD-L1 in immune cells (Tray et al., Breast. 2019; Gonzalez-Martinez et al., Int J Mol Sci. 2021).
Current neoadjuvant cancer treatment guidelines according to AGO and treatment guidelines of Klinikum Essen Mitte
The current neoadjuvant oncological therapy according to the gynecological oncology guidelines in Germany is represented by four cycles of epirubicin/cyclophosphamide every two weeks combined with pembrolizumab every three weeks followed by 12x paclitaxel/carboplatin weekly and pembrolizumab every three weeks.
Postoperatively, continue immunotherapy with nine cycles of pembrolizumab at three weeks intervals (in case of metaplastic triple-negative breast cancer).
Clinical trial
A prospective clinical study (NCT02276443) with a total of 211 patients with TNBC, with 39 patients with MpBC, received doxorubicin-cyclophosphamide-based neoadjuvant therapy.
Results. Patients with MpBCs were less likely to experience a pCR(23%versus 40%; p=0.07) and had shorter event-free survival (29.4 versus 34.3 months; p=0.02).
Conclusions. The 23% pCR rate in this study suggests that patients with MpBC should be considered for NAT.
Patients with MpBC should be closely monitored for progressive disease (PD) during neoadjuvant systemic therapy (NAST).
To improve this rate, a pathway analysis predicted enrichment of histone deacetylase (HDAC) and RTK/MAPK pathways in MpBC, wich may serve as new targetable vulnerabilities (American Association for Cancer Research, 2022).
Metastatic MpBC systemic
treatment
mTOR inhibition with chemotherapy and antiangiogenic therapy for metastatic metaplastic BC.
Treatment with liposomal doxorubicin, bevacizumab and mTOR inhibition with everolimus or temsirolimus.
The median progression-free survival (PFS) is 4.8 months for MpBC versus 2.5 months for TNBC without MpBC (p=0.087).
The median overall survival is 10 months for MpBC versus 3.7 months for non-MpBC TNBC (p<0001).
Case reports
Case 1
The patient B.M., 55 years old. Family history: the father had cholangiocarcinoma.
06.01.23: sonography. Right breast biopsy at 9:00 + Clip.
Histology: triple-negative metaplastic NST cT2 (26 mm), cN0, G2, M0.
ER 0%, PR 0%, Her2neu 0, KI67 – 35%.
January 2003: neoadjuvant chemotherapy with 4x epirubicin (90), cyclophosphamide (600) at an interval of two weeks plus pembrolizumab (200 mg) at an interval of three week, followed by 12x paclitaxel (80) + carboplatin AUC two weeks + pembrolizumab at three weeks interval.
13.07.23: surgical treatment. Conservative surgery – lumpectomy + removal of right sentinel lymph node.
Histology: ypT2 (24 mm), ypN0 (0/3sn), G2, L0, V0, R0, M0.
ER 5%, PR 0%, Her2neu 0, KI67 – 30%.
Recommendations: pembrolizumab at 3 weeks interval, another nine cycles postoperative plus capecitabine p.o., 1000 mg/m2 (days 1-14 at three weeks interval) for eight cycles.
Screening Study “Sascia”.
Local radiotherapy.
Case 2
The patient C.S., 53 years old. Family history: cousin with breast cancer at 40 years old.
Patient’s genetic testing: negative.
January 2019 – sonography. Right breast biopsy + Clip + biopsy.
Histology: triple-negative metaplastic NST cT2(23 mm), cN0, G3, M0.
ER 0%, PR 0%, Her2neu 0, KI67 – 90%.
02.04.2019: neoadjuvant chemotherapy after three cycles of epirubicin (90), cyclophosphamide (600) at two weeks interval discontinued and replaced with paclitaxel (80), also discontinued after two cycles due to progress.
May 2019: Surgical treatment. Conservative surgery – lumpectomy + removal of right sentinel lymph node.
Histology: ypT1c (20 mm), ypN0 (0/4sn), G3, L0, V0, R1, M0.
ER 5%, PR 0%, Her2neu 0, KI67 – 30%.
27.05.2019: surgical reintervention with re-lumpectomy (histology: R1).
September 2019 – February 2020: adjuvant capecitabine chemotherapy with seven cycles, discontinued due to hand-foot syndrome.
June 2023: local recurrence of NST in the right breast, triple-negative.
rcT2m (35 mm), rcN0, G2, cM1 (SKI).
ER 0%, PR 0%, Her2neu 0, KI67 – 80%.
IC score: 1
CPS: 2.9.
Recommendations: nab-paclitaxel 100 mg/m2, days 1, 8 and 15, plus atezolizumab 840 mg i.v., days 1 and 15, at an interval of four weeks.
Intensive sonographic control.
Surgical treatment after chemotherapy with mastectomy and second-look of axilla.
Conclusions
Metaplastic breast cancer is a rare and aggressive form of breast cancer, with limited data to guide the treatment.
The rates of complete pathologic response (pCR) after standard chemotherapy are low in patients with metaplastic breast cancer. Those with smaller tumors are more likely to achieve pCR.
Patients with metaplastic breast cancer should be closely monitored during neoadjuvant systemic therapy for progressive disease during the treatment.
Germline genetic testing should be performed. Adjuvant radiotherapy should be carried out according to standard practice.
Corresponding author: Alexandra Fischer E-mail: al.fischer@kem-med.com
Conflict of interest: none declared.
Financial support: none declared.
This work is permanently accessible online free of charge and published under the CC-BY licence.
Bibliografie
1.Ditsch N, Wöcke A, Untch M, et al. AGO Recommendations for the Diagnosis and Treatment of Patients with Early Breast Cancer: Update 2022. Breast Care (Basel). 2022;17(4):403-420
2. Burstein HJ, Curigliano G, Thürlimann B, et al. Customizing local and systemic therapies for women with early breast cancer: the St. Gallen International Consensus Guidelines for treatment of early breast cancer 2021. Ann Oncol.
2021;32(10):1216-1235.
3. Giaquinto AN, Sung H, Miller KD, et al. Breast Cancer Statistics, 2022. CA Cancer J Clin. 2022;72(6):524-541.
4. WHO. Breast Tumours: WHO Classification of Tumours. Fofth Edition. Lyon: International Agency for Research on Cancer, 2019.
5. McCart Reed AE, Kalaw E, Nones K, et al. Phenotypic and molecular dissection of metaplastic breast cancer and the prognostic implication. J Pathol.2019;247(2):214-227.
6. Schmied B, Reitsamer R, Gschwandtner E, Farmini A, Fischer T, Kronberger C, Peintinger F. Metaplastisches Mammakarzinom – ein Fallbericht und Review der aktuellen Literatur. Tumorboard. 2014;3(1):16-18.
7. Tray N, Taff J, Singh B, et al. Metaplastic breast cancers: Genomic profiling, mutational burden and tumor-infiltrating lymphocytes. Breast. 2019;44:29-32.
8. González-Martínez S, Pérez-Mies B, Pizarro D, Caniego-Casas T, Cortés J, Palacios J. Epithelial Mesenchymal Transition and Immune Response in Metaplastic Breast Carcinoma. Int J Mol Sci. 2021;22(14):7398.