Incidental discovery of second primary lung tumors in breast cancer patients: an institutional case series.

Introduction
Breast cancer is the second leading cause of cancer death in U.S. women1, with mortality driven by metastatic disease.2,3 Metastatic breast cancer (MBC) is considered incurable, with treatments aimed at disease control. National guidelines recommend a biopsy at the first suspected recurrence of breast cancer.4 Despite this, clinicians frequently rely on imaging alone to diagnose MBC: our group has published data revealing that only half of patients in Washington state diagnosed with MBC between 2008 and 2017 underwent metastatic biopsy.5
Lung cancer is the leading cause of cancer deaths worldwide, despite efforts to screen high-risk individuals.6,7 Lung cancers are sometimes identified incidentally. While most incidental pulmonary nodules (IPNs) are benign, the importance of early detection for lung cancer survival has prompted the development of algorithms for IPN management, most notably the Fleischner Society and the British Thoracic Society guidelines.8,9 Several risk models also exist to guide clinicians in estimating risk of malignancy for a given IPN.10 Despite this, IPNs are frequently not followed up.10
Lung findings identified in patients with a breast cancer history are thus subject to two potential errors—misdiagnosis as MBC or failure to follow up. Cases of falsely presuming MBC are difficult to identify, as progression of an undiagnosed lung cancer could be attributed to resistant MBC. We can, however, characterize examples of breast cancer patients who were subsequently diagnosed with lung cancer.

Methods
We surveyed breast oncologists to obtain records of patients treated at our institution from 2018 to 2022, in whom a lung malignancy was uncovered in tandem with or following a breast cancer diagnosis. We reviewed patient charts, recording how the pulmonary malignancy was identified, what treatments were offered for both cancers, and what outcomes were observed.

Results
We identified eight cases of lung malignancies diagnosed during breast cancer workup and treatment (see Table 1). Approximately 1500 breast cancer patients were under treatment by the providers surveyed during the period in question.
Cases 1–5 represent patients in whom a staging or radiation-planning CT revealed an IPN during workup and treatment for early-stage, estrogen-receptor positive (ER+) breast cancer. In cases 1 and 2, patients were referred to the UW lung nodule clinic, which managed the workup and resection of the suspicious nodule. Patients 1–3 had screen-detected early-stage breast cancers requiring only adjuvant radiation and endocrine therapy and small pulmonary malignancies needing no further treatment after resection. Patients 4 and 5 presented with higher-risk breast cancer and underwent chemotherapy for several months before undergoing resections of their IPNs. All patients were treated curatively for both malignancies and remain disease free.
Case 6 represents a patient who was treated in 1997 and 2017 for two early-stage ER+ breast cancers. In 2021 she presented to the emergency department with diverticulitis; a diagnostic CT scan incidentally demonstrated a left pleural effusion. This led to the identification of a left upper lobe lung mass with mediastinal lymphadenopathy. Biopsy revealed non-small cell lung cancer (NSCLC) harboring an EGFR exon 19 deletion. She remains breast-cancer free, and her lung cancer is stable on EGFR-targeted therapy.
Case 7 describes a patient diagnosed in 2017 with recurrent, biopsy-proven ER+ breast cancer metastatic to her pleura. She initiated letrozole, with resolution of her pleural disease and associated effusion. She had no further evidence of disease until 2019, when restaging showed a left upper lobe nodule that grew on interval imaging and not amenable to biopsy. She underwent a left thoracotomy followed by radiation; pathology showed pT2apN0 invasive lung adenocarcinoma. She has no evidence of lung cancer recurrence to date. Her breast cancer ultimately progressed, but she currently has stable disease on second-line endocrine therapy.
Case 8 represents a 60-year-old woman with a history of early-stage HER2-positive breast cancer treated curatively in 2015 who presented in 2020 with chest pain and cough. CT torso demonstrated multiple bone and visceral lesions. Liver biopsy confirmed metastatic carcinoma consistent with her prior breast primary. Weeks later she re-presented with hypoxemic respiratory failure owing to pleural and pericardial effusions. Fluid showed malignant cells consistent with lung primary (CK7+, TTF1+, NapsinA+, GATA3−, ER−, HER2−). She was treated with paclitaxel, and her condition stabilized. She began endocrine therapy plus CDK4/6 inhibitor for breast cancer, and her lung cancer was treated with entrectanib. She died a year later on hospice.

Discussion
Our cases range from early- to late-stage breast and lung cancer. In cases 1-4, clinicians were alerted to the presence of a nodule in the radiology reports of scans obtained for other purposes; they then initiated the evaluation and management that led to cure of both cancers. Referral to a lung nodule clinic accomplished this in two of four cases; barriers may arise in community practice settings where similar resources are not available. Clinicians may also rely on a risk stratification tool such as the Mayo Clinic Model to estimate the need for further workup; this model, unlike some others, incorporates a prior history of extrapulmonary malignancy into its calculations.11 In all of these cases, however, the most important curative step was taken when an attentive physician noted and took responsibility for following an IPN.
Cases 5 and 6, where lung masses arose in the setting of a history of high-risk early-stage breast cancer, illustrate the importance of guideline-driven tissue biopsy of any suspected metastatic recurrence of breast cancer. Had either of these findings been assumed to be a metastatic recurrence of breast cancer, patients could have died from complications of lung cancer without receiving the correct diagnosis or treatment. As above, clinicians must first think to consider non-MBC diagnoses, then rely on clinical judgment and the expertise of radiology colleagues to identify features not consistent with an overall MBC picture.
A more difficult situation is presented by case 7, where metastatic breast cancer was already present. Biopsy is rarely possible at every instance of suspected progression. Currently, the judgment of the oncologist and radiologist regarding lesion appearance and/or behavior must guide pursuit of tissue diagnosis. Newer technologies such as FES-PET may help discriminate between MBC lesions vs those of a different tissue origin.
Case 8 represents a situation in which an advanced lung cancer was diagnosed during treatment for MBC, which allowed joint treatment of both cancers with one cytotoxic drug, followed by targeted therapy for each malignancy. The patient died a year later, but treatment of both conditions likely led to prolongation of her life.
This study is limited by small numbers and recall bias; we plan a formal quantitative investigation next. We also identified other malignancies, for example, colon cancer, diagnosed incidentally during breast cancer treatment, which warrants further study. Our initial efforts were complicated by challenges encountered when using our electronic medical record (EMR), which relies on billing codes to assign diagnoses, to perform retrospective studies for research and/or quality assurance purposes. We are developing search functions using natural language processing technologies that will facilitate quantitative approaches for this and similar studies, but we also hope that affordable off-the-shelf technologies will become available in the near future to better integrate research into existing EMRs.

Conclusions
While imaging can raise suspicion for MBC, assuming that a new lesion represents metastasis of the known primary breast cancer risks treating both the primary tumor and the newly detected neoplasm inappropriately. Patients with MBC live for extended periods on cancer-directed therapy and should undergo diagnosis and treatment when suspicion arises for a non-breast malignancy.