Ipsilateral Breast Metastasis from Lung Adenocarcinoma Harboring Anaplastic Lymphoma Kinase or ROS1 Rearrangement and Significant Response After Targeted Therapy: Report of Two Cases
Breast metastasis from extra-mammary malignancies is a rare occurrence, accounting for approximately 2% of all malignant mammary neoplasms. This report presents two cases of ipsilateral breast metastasis from lung adenocarcinoma harboring anaplastic lymphoma kinase (ALK) or c-ros oncogene 1 (ROS1) rearrangement, both of which showed significant response to targeted therapy.
Case 1: ALK-Rearranged Lung Adenocarcinoma with Breast Metastasis
A 43-year-old female patient was admitted to the Department of Respiratory Disease at The First Affiliated Hospital, College of Medicine, Zhejiang University, in July 2013. She had a 6-month history of paroxysmal cough and was previously diagnosed with right lower lung adenocarcinoma (cT2aN3M1b, stage IV, ALK-positive) with bone metastasis at another hospital. She was referred to participate in a phase III trial of crizotinib (ClinicalTrials.gov Identifier: NCT01639001).
Computed tomography (CT) scan revealed a mass in the right lower lung and two masses in the right breast, located in the lower and outer quadrant and the upper and inner quadrant, respectively. A needle biopsy of the breast masses was performed to determine their nature. Immunohistochemistry (IHC) results showed that the breast cancer tissues were positive for ALK, thyroid transcription factor-1 (TTF-1), NapsinA, P53, CK5, E-cadherin, and Ki-67, while they were negative for P63, estrogen receptor (ER), progesterone receptor (PR), C-erbB-2, MMG, and G-15. Fluorescence in situ hybridization (FISH) confirmed the presence of ALK rearrangement in the breast cancer tissues.
The patient was enrolled in the clinical trial and assigned to the chemotherapy group on August 1, 2013. After 12 weeks of chemotherapy, the disease showed progression. She received whole brain radiotherapy in December 2013 and was crossed over to the crizotinib group on January 22, 2014. The patient achieved a partial response (PR) with significant shrinkage of the tumor lesions in the lung and brain, and the disappearance of the tumor lesions in the breast. The efficacy of crizotinib persisted until August 9, 2017, when enlargement of the lung lesion and new brain lesions were observed. She then participated in another clinical trial (ClinicalTrials.gov Identifier: NCT03215693) and received treatment with Ensartinib (X-396) starting on December 19, 2017. The brain metastases significantly shrank, and the lung lesion remained stable. The patient died in August 2019 due to meningeal metastasis, while the lung and breast lesions were still stable at the time of death.
Case 2: ROS1-Rearranged Lung Adenocarcinoma with Breast Metastasis
A 44-year-old woman was admitted to the same department in March 2014 with a 6-month history of progressive cough. CT scan revealed a mass in the right lower lung, enlarged lymph nodes in the mediastinum and retroperitoneum, and a mass in the right breast. A supraclavicular lymph node biopsy and a breast nodule needle biopsy were performed. IHC results showed that the cancer tissues from both the right breast and the right supraclavicular lymph node were positive for ROS1, TTF-1, NapsinA, P53, CK5, E-cadherin, and Ki-67, while they were negative for ALK, G-15, P63, ER, PR, C-erbB-2, and MMG. FISH using a probe specific to the ROS1 locus confirmed the presence of ROS1 translocation.
The patient was diagnosed with lung adenocarcinoma with multiple metastases, including breast, bone, and brain (T4N3M1b, stage IV), harboring ROS1 rearrangement. She was enrolled in a Phase II study of crizotinib (ClinicalTrials.gov Identifier: NCT01945021) and began treatment on April 15, 2014. The patient achieved a PR with significant shrinkage of the tumor lesions in the lung and the disappearance of the tumor lesions in the breast. However, there was no obvious improvement in the central nervous system lesions, and she died 8 months later.
Discussion
Breast metastasis from extra-mammary malignancies is rare, and distinguishing it from primary breast cancer is crucial for appropriate treatment. In both cases presented here, the primary lung lesions and breast metastases were immunohistochemically positive for ALK or ROS1 rearrangement, which were further confirmed by FISH. These findings highlight the importance of detecting EGFR, ALK, and ROS1 gene mutations in patients with both lung and breast lesions to identify the primary lesion and guide treatment decisions.
Crizotinib, a targeted tyrosine kinase inhibitor, has been approved by the FDA for the treatment of non-small cell lung cancer patients with ALK or ROS1 rearrangement. It has shown a response rate of nearly 60% and a median progression-free survival (PFS) of 7.7 to 8.1 months in ALK-positive patients, and a 72% objective response rate and a median PFS of 19.2 months in ROS1-positive patients. In both cases, crizotinib demonstrated significant efficacy in reducing tumor burden in the lung and breast metastases, although the response in the central nervous system was limited.
The identification of driver gene mutations, such as EGFR, ALK, and ROS1, is essential for distinguishing primary breast cancer from lung cancer breast metastases. Targeted therapy based on these mutations can lead to significant clinical responses and improved outcomes for patients with advanced lung adenocarcinoma and breast metastasis.
Conclusion
These two cases illustrate the importance of molecular profiling in patients with both lung and breast lesions to identify the primary cancer and guide targeted therapy. The significant response to crizotinib in both cases underscores the potential of targeted therapy in managing advanced lung adenocarcinoma with breast metastasis harboring ALK or ROS1 rearrangement. Further research and clinical trials are needed to explore the efficacy of targeted therapies in similar cases and to improve the overall survival and quality of life for these patients.
doi.org/10.1097/CM9.0000000000000890
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