Primary malignant tumor of breast is one of the most common malignant tumors in adult women, but as the breast is rich in fibrous tissue, poor blood circulation, so secondary metastasis of breast is very rare. Metastatic breast tumors are very rare, accounting for only 0.4–1.3% of breast malignancies, and the most common are leukemia, lymphoma, melanoma, rhabdomyosarcoma, and lung cancer6. The ways of breast metastasis in patients with primary lung cancer are as follows: To the ipsilateral breast through intrathoracic lymphatic metastasis; Tumor cells along with the lymph circulation through the thoracic duct into the vein, through systemic circulation to the contralateral breast; Tumor cells enter the blood circulation and metastasize far away7.Mirrielees et al. analyzed through a systematic retrospective analysis of 43 cases of lung cancer breast metastasis reported from 1989 to 2013; Among them, 10 cases were small cell lung cancer, 33 cases were non-small cell carcinoma, including 19 cases of adenocarcinoma, 3 cases of squamous cell carcinoma, 4 cases of large cell carcinoma, 4 cases of neuroendocrine carcinoma, 3 cases of undifferentiated carcinoma or others; The report involved 38 female and 5 male patients, with similar incidence in each age group. Among them, the average age of breast metastasis in NSCLC patients was 55 years old, SCLC patients were 58 years old, and patients were between 28 and 83 years old8. The correlation between the incidence of lung cancer and breast metastasis and pathological types remains to be studied with large samples.
There are big differences between primary breast cancer and secondary breast cancer in clinical features, imaging, pathology and immunohistochemistry. This patient started with pericardial effusion and pleural effusion. Breast masses are clues. Adenocarcinoma cells were found through puncture and drainage of pericardial effusion and exfoliated cytology. Combined with immunohistochemistry, tumorous lesions in the lung were further found. At the time of diagnosis, it was at an advanced stage. It is easy to be considered as primary breast cancer at the first diagnosis, or the coexistence of lung cancer and breast cancer. The role of histopathology as the gold standard in the diagnosis of diseases is beyond doubt. However, the morphological identification of small biopsy specimens with atypical morphology is limited, and immunohistochemical testing is indispensable for diagnosis at this time. At present, the commonly used immune markers in lung adenocarcinoma include NapsinA, TTF-1, CK7 and alveolar surface glycoprotein, etc9. Breast cancer mainly expresses ER/PR, GATA-3 and Mamma-globin, etc. The positive rate of GATA-3 is 47%-100%, which is a specific marker of breast cancer10. Immunohistochemistry of the breast tumor in this patient showed positive TTF-1, NapsinA, and CK7, supporting the diagnosis of lung adenocarcinoma. The patient's immunohistochemical results showed TTF-1 positive and ER negative. Although a small number of breast cancers can also express TTF-1, they need to be distinguished from primary breast cancer11,12. Because of the more specific NapsinA positive and GATA-3 negative, the diagnosis of lung adenocarcinoma and breast metastasis is clear.
Our patient had metastasis to her right breast, which is the same side affected by the malignant pleural effusion, consistent with the hypothesis by Huang et al13. To this end, they considered a stepwise mechanism involving parietal pleural seeding, followed by invasion into chest wall lymphatic vessels draining to ipsilateral axillary lymph nodes and retrograde lymphatic spreading to the breast. This mechanism of breast metastasis could be supported by findings of enlarged homolateral axillary lymph nodes. Moreover, Barber et al14 demonstrated lymphatic communication between the breast and mediastinal lymphatic channels. These hypotheses could be confirmed by the fact that almost 80% of the cases reported from 2000 to date had ipsilateral lesions. Another potential type of spread could be hematogenous. However, if lung cancer spreads through this route, both breasts should have the same probability of being affected. This is not reflected in the reviewed cases, where only 5.4% of patients had bilateral breast involvement. The last possible explanation could be direct tumor invasion through the chest wall to the breast, but chest CT scans did not reveal this alteration in the reported cases. Therefore, lymphatic spreading might be the most reasonable mechanism of lung cancer dissemination to the breast.
Judging from previous research evidence, EGFR TKI and immunotherapy are incompatible. Current research does not support the use of immunotherapy in patients with EGFR mutations, because of low efficacy, high toxicity, and prone to super progress. But a clinical study broke this conventional "consensus"15.The use of PD-1 inhibitor after drug resistance in patients with EGFR mutations is not only safe but also makes patients susceptible to EGFR TKI again.This study retrospectively analyzed the efficacy of EGFR TKI (Afatinib, Erlotinib, or Gefitinib) after progressing.The study included 75 patients with advanced NSCLC with EGFR mutations (19Del or L858R or L851Q) who had previously received EGFR-targeted therapy and had disease progression.The study was divided into two groups according to whether or not to use immunotherapy in the future. The experimental group: received PD-1 treatment (pembrolizumab or nivolizumab), and then challenged EGFR-targeted drugs after progress (n = 13 cases) ; Control group: did not receive PD-1 treatment and was challenged with targeted drugs (n = 62 cases).The results found that after EGFR TKI resistance was interspersed with immunotherapy, EGFR TKI challenged again, with ORR reaching 46.1%; In the group that did not receive immunotherapy after EGFR resistance, the ORR was only 16.1%, and the difference was statistically significant (P = 0.026). In addition, the DCR of the experimental group reached 76.1%, and the PFS and OS were 5 months and 25 months, respectively.
Our case was advanced lung cancer, genetic testing revealed an EGFR mutation, and Almonertinib was treated. Almonertinibis the second third-generation EGFR TKI innovative drug in the world. It is mainly used for disease progression during or after treatment with EGFR TKI. The test confirmed the presence of EGFR T790M mutation-positive adult patients with locally advanced or metastatic non-small cell lung cancer. Almonertinibis easier to cross the blood-brain barrier than other EGFR TKI targeted drugs. We took into account the presence of brain metastases in our patient, so in the case of ineffective immunotherapy, we chose amitinib combined with EGFR TKI. As a result, the patient controlled the brain lesions and achieved stable disease control for 2 months. Treatment is currently underway. We will continue to track and record the patient’s disease.
The above PD-1 inhibitor sequential EGFR TKI treatment model brings new ideas for the treatment of breast cancer lung metastasis. Remind us that the sequential/crossover schemes of immunization and targeted therapy can be flexible and changeable. Breaking the conventional thinking after multi-line resistance may be surprisingly successful. However, the number of clinical studies is currently limited, and it is expected that researchers will release more research data. EGFR TKI re-challenge treatment brings us many medicine inspirations.In summary, switching to another regimen for a period of time after the treatment of drug resistance may change the characteristics of tumor cells, and there may be a chance of being sensitive to the original regimen again.Of course, the beneficiaries of EGFR TKI challenges are also the focus of clinical exploration. It is expected that in the future, EGFR TKIs can be rationally selected and the order of medication can be arranged under precise guidance, so as to maximize the benefits of patients.