Metastasis of breast cancer to the lungs is relatively common in clinical practice19. Therefore, in breast cancer patients who exhibit pulmonary nodules, lung metastasis is often the first diagnosis considered. However, a certain number of patients with breast cancer and primary lung cancer experience complications of solitary pulmonary nodules20. Therefore, it is necessary to understand the frequency of primary lung cancer in breast cancer patients.
To address the deficiency of information regarding the development of a second primary cancer following breast cancer, we retrospectively reviewed data from the Jiangsu Province Hospital to analyze all patients with breast cancer and second primary lung cancer, as well as those with breast cancer diagnosed as a second primary cancer after lung cancer, between 2008 and 2018. Our research provides further evidence demonstrating that the occurrence of lung cancer is closely related to the development of breast cancer, especially lung adenocarcinoma with EGFR mutation. As breast cancer patients live longer, there is an increased possibility of developing subsequent primary lung cancer owing to underlying genetic or other factors21. An interesting phenomenon in our study was the higher frequency of second lung cancer in patients with low-grade malignancies, which differed from our expectations. Breast cancer patients who were older, had ER-negative cancer, had a low Ki67 index, and displayed no lymph node metastasis exhibited a significantly higher rate of development of a second primary lung cancer. The characteristics of second lung cancer were strikingly similar: 100% were ER-negative, 95% had wild-type ALK, and 85% exhibited low Ki67 (< 30%). Further, most patients had stable nodules at the first follow-up. We speculate that low malignancy contributes to longer survival times in cancer patients, and, given that the mean interval of diagnosis of double primary cancers was 35 ± 13.0 months, this was sufficient to permit the development of a second primary lung cancer.
Many previous studies have reported that second primary lung cancer rates are significantly higher in breast cancer patients than in patients with other primary cancers8,16,21, which is consistent with the results of our study. The incidence of secondary primary lung cancer in breast cancer patients may have previously been higher, as there was no pathological diagnosis in the remaining 345 patients with stable GGOs. Chest CT at regular intervals could result in increased detection of pulmonary nodules. Further, the occurrence of stable GGO may be related to common risk factors, including genetics, heredity, hormones, and environmental factors. Previous studies have reported that breast cancer patients who undergo radiotherapy15,22, smokers23, and those treated with chemotherapy11 have a higher possibility of developing secondary lung cancer.
Nevertheless, the higher risk for developing lung cancer in patients with primary breast cancer cannot be explained merely by regular follow-up. An interesting finding of our study was that the rate of EGFR mutation was as high as 75.6%, which is almost twice that in patients with non-small cell lung cancer without another primary cancer24. This phenomenon has not been reported in previous studies. These observations suggest that EGFR signaling may play a crucial role in the development of concurrent lung and breast cancers. Several studies have reported that overexpression of EGFR is common in breast cancer patients and is associated with decreased survival25–28. Moreover, previous reports have indicated that ER signaling plays an important role in primary lung cancer following breast cancer, and that activation of ER signaling occurs through EGFR/HER-1, thus confirming a correlation between ER expression and EGFR mutation29–34. Patients with an acquired resistance to EGFR antagonists may, therefore, benefit from antiestrogen therapy12. Moreover, EGFR and HER2 are members of the human epidermal growth factor receptor family, which are type I transmembrane growth factor receptors that activate intracellular signaling pathways and are major determinants of human cancer35. According to previous studies, overexpression of EGFR is associated with apoptosis, angiogenesis, and formation of tumor vessels. Therefore, EGFR mutation may provide clues of a common etiological pathway between primary lung adenocarcinoma and breast cancer36,37.
Patients with a second primary lung cancer were less likely to have pGGOs and more likely to have sGGOs, and those with EGFR mutations exhibited a similar trend (P = 0.05). Analysis of the correlation between CT image patterns and gene mutations demonstrated no statistical significance. Similarly, most of the GGOs had not changed in size at the first follow-up. Unexpectedly, the lesion in one of the patients who underwent endocrine therapy shrunk, consistent with a previous report that breast cancer patients with second primary lung cancers who are treated with antiestrogen therapy exhibit longer cancer-specific survival12,33.
There were several limitations to the present study, the first of which was its retrospective, as opposed to prospective, design. Second, random variation and low statistical power resulted from the limited number of patients. Finally, the lack of long-term follow-up prevented us from observing more cancer-related events and assessing cancer-specific survival. The next step is to further follow up the patient, collect more clinical samples, and conduct basic research to explore its underlying mechanisms.
In conclusion, we observed that women diagnosed with breast cancer demonstrated an increased risk of second primary lung cancer. The present study is the first to report a higher rate of EGFR mutations in second primary lung cancer, which may play an important role in the development of double primary breast and lung cancer. This is an interesting clinical finding that can further the exploration of the mechanism behind elevated EGFR expression in patients with primary breast cancer and the mechanism of EGFR expression in lung cancer and breast cancer, paving the way for development of new drugs. Based on the results of the current research, we recommend that breast cancer patients who exhibit high-risk factors be closely followed. EGFR-targeted treatment represents an alternative option for these patients.