Second Primary Lung Cancer after Breast Cancer: A Case Series

doi:10.21203/rs.3.rs-2693053/v1

Background: Breast cancer (BC) accounts for approximately 24.2% of all malignant tumours in women. Due to advances in chemotherapeutic agents and targeted treatment, survival of BC patients is increasing. Second primary cancers (SPC) are becoming more common, among which lung cancer (LC) has a latency of approximately ten years and may be related to risk factors such as exposure to BC radiotherapy. We present a case series of nine patients with SPC of the lung after BC (BC-LC), highlighting the clinical and molecular findings in a tertiary care hospital in Colombia.

Case presentation: This is a retrospective case series report describing demographic, diagnostic, therapeutic and molecular profile data of patients with SPC of the lung diagnosed between 2014 and 2019 with a history of BC in a referred tertiary care hospital.

Nine women with BC-LC were included. The mean age at BC diagnosis was 56.2 ± 10.8 years. All cases were ductal carcinoma, seven were triple negative, one was HER2 positive, and one was estrogen and progesterone positive. Adenocarcinoma was the only histological type of LC. All patients had received radiotherapy for BC, and the mean latency between the two diagnoses was 8.1 years.

Conclusion: Our case series provides preliminary data on patients with BC-LC and contributes to the local epidemiology. Histology (ductal BC, adenocarcinoma of the lung) has a role in BC-LC patients and radiotherapy for BC. Adequate histological diagnosis of lung lesions in patients with BC is essential for appropriate approach and treatment.

Second Primary Neoplasm

Lung Cancer

Breast Cancer

Ductal Carcinoma

Lung Adenocarcinoma

Cancer survival rates have improved in recent years, thanks to advances in chemotherapy drugs and the advent of targeted therapies. According to the latest data reported by Globocan, the global incidence of cancer in 2018 was 18.1 million new cases. In addition, 9.6 million people died from cancer that year, accounting for one in six deaths. Second primary cancers (SPCs) - cancers that occur in a person with a history of another primary cancer - are becoming increasingly common. According to Surveillance, Epidemiology, and End Results, they account for about 16% of cancer cases in high-income countries [1]. Worldwide, breast cancer (BC) is the most common malignancy in women. It accounts for approximately 24.2% of all cancer cases and is the leading cause of death (15.0%), followed by lung cancer (LC) (13.8%) [2]. In Colombia, BC is the second leading cause of death in women after cervical cancer. In 2013, it was reported that approximately 7000 new cases were diagnosed annually in the country, with an associated mortality of 2500 women per year [3–5].

As with other cancers, advances in breast cancer screening and treatment techniques have improved survival rates in recent decades. However, at least 10% of patients who undergo mastectomy and post-mastectomy radiotherapy have been reported to have an increased risk of developing a second primary cancer. A latency of about ten years has been described for second primary LC. Associated risk factors include smoking, early diagnosis, black ethnicity, triple-negative BC and undifferentiated histological grade. Interestingly, LC is more common on the side where the patient received radiotherapy and its primary histological type is non-small cell [6].

The above is based on reports from studies that mainly included Asian and European patients, whose characteristics differ from those of the Colombian and Latin American populations. There are no epidemiological data on the second primary tumours after BC and the associated molecular and histological risk factors that would determine their prevalence in our region. We present a case series of nine patients with SPC of the lung after BC (BC-LC) in a tertiary care hospital in Colombia. Clinical and molecular aspects are described as reported at initial diagnosis and during the follow-up period.

This case series describes demographic, diagnostic, treatment and molecular profile data of patients with lung SPC with a history of BC diagnosed between 2014 and 2019 at a tertiary care referral hospital. The data source was electronic medical records. Qualitative variables were presented as absolute and relative frequencies. For quantitative variables, measures of central tendency and dispersion were used according to the distribution of the analyses data, evaluated by the Shapiro-Wilk test. Mean and standard deviation were used when the distribution was normal, otherwise median, and interquartile range estimates were used.

As this study involved human participants, the ethical principles for research involving human subjects, as stated in the Declaration of Helsinki of 2013 and Resolution 8430 of Colombia of 1993, were followed. The Institutional Ethics Committee evaluated and approved this study.

Breast Cancer

Nine female patients were diagnosed with LC between 2014 and 2019, corresponding to a second primary cancer after BC. The mean age at diagnosis of BC was 56.2 ± 10.8 years (ranging from 35 to 73 years) Table 1. All cases were ductal carcinomas; 67% were located on the right and 33% on the left. Data on the patients' stage at diagnosis are shown in Table 2; these data were not available for two cases because the history did not provide sufficient clinical information to determine the BC stage. With regard to hormonal markers, seven cases were triple-negative ductal carcinoma (PR-, ER-), one case was HER2-enriched BC (hormone receptor negative, HER2 score 3+), and one case was positive for estrogen and progesterone only (PR+, ER+).

Table 1

Demographic characteristics
	Patient 1	Patient 2^*	Patient 3	Patient 4	Patient 5	Patient 6	Patient 7	Patient 8	Patient 9
Tabaco	Yes Until 2002	Yes	Yes	Yes 50 packages year Hypertension, OSA¹, bronchial hyper responsiveness	No	No	Yes	No	No
Medical History	DM2, COPD, dyslipidemia, subclinical hypothyroidism.	DM2, Dyslipidemia and hypothyroidism. Hormone therapy during 5 years before	Hypertension, dyslipidemia		DM2, Hypertension	Obesity (BMI 35)	Hypertension, hypothyroidism.	No	No
Family history of cancer	No	Two sisters with medical history of breast cancer	Hepatocarcinoma (brother), prostate cancer (brother), lung cancer (brother), and breast cancer (niece).	No	No	Lung cancer (grandfather), ovarian cancer (cousin)	No	Colon cancer (mother)	No
* The patient had no clinical follow-up, only the diagnosis was made at our hospital, 1 Obstructive Sleep Apnea.

Six patients received hormonal therapy (anastrozole in two cases and tamoxifen in one). All patients received radiotherapy for BC. Of these, eight had received it before the diagnosis of LC and one had received it concomitantly. The mean latency between the two diagnoses was 8.1 years (SD = 6.2 years; range 0.5 to 17.5).

Secondary Primary Lung Cancer

All patients had lung adenocarcinoma, three of which had EGFR mutations (one of which had ROS-1 rearrangements) and three of which had high PD-L1 expression. No ALK gene rearrangements were identified in this series. The average tumour size was 22 mm. Of all the tumours, six were peripheral lung nodules (< 3 cm). The remainder were masses larger than 3 cm in maximum diameter. The LC stage at the time of diagnosis is shown in Table 3. In one case, data were not available because the patient was lost to follow-up in the outpatient clinic.

Regarding treatment, all patients received radiotherapy, three in combination with chemotherapy, five underwent resection surgery, two received a tyrosine kinase inhibitor (erlotinib) and one received immunotherapy (pembrolizumab). Only one patient (#9) died during the follow-up period, 69 months after the diagnosis of BC, and seven patients were followed up in our hospital. The radiological and histopathological findings are shown in Figs. 1–8.

The incidence of LC as an SPC is on the rise due to the prolongation of survival in breast cancer (BC) as a result of advances in current treatment. Nine patients with primary LC, predominantly adenocarcinoma of the non-small cell lung cancer (NSCLC) subtype, who had previously had ductal carcinoma of the breast, mostly triple negative, were identified over a five-year period. As previously reported in the literature, there appears to be an association between ductal carcinoma in situ and primary lung adenocarcinoma as the most common histological types found in this type of patient [6].

According to some reports, women treated for BC, especially with radiotherapy, have an increased risk of new primary tumours such as sarcomas, contralateral BC and LC compared to the general population [7, 8]. In our study, all patients received radiotherapy for BC, a finding that supports what has been reported previously in these studies. In recent years, there has been a trend towards diagnosis at earlier stages in patients with BC-LC, particularly NSCLC, which may reflect the increased use of radiological imaging in the follow-up of patients with BC undergoing treatment [9, 10]. Interestingly, a significant proportion of patients in this case series were in advanced stages (IIIB and IVB).

The latency period for the development of a second cancer has been calculated to be approximately 10 years after treatment of the first cancer [11–18], which can vary from 1 to 26 years [7]. In our case series, the median time to the development of a second primary LC was 8.1 years. This is consistent with the latency time reported in several studies. Furthermore, it has been suggested that the use of radiotherapy in the treatment of BC may increase the risk of ipsilateral NSCLC. However, this comparison was not possible in our case series as all patients received radiotherapy.

Regarding the relationship with hormone receptors, a higher incidence of lung adenocarcinoma has been observed in patients with estrogen receptor-negative (ER-) BC compared to ER + tumours, suggesting that there may be common aetiological factors between the two types of cancer [19]. In contrast, cases of lung adenocarcinoma reported in other studies show high EGFR expression associated with triple-negative BC, which may also suggest a common pathway [6, 19]. No previous studies were found that described an association between the development of a typical lung carcinoid tumour and any histological type of BC. As the typical carcinoid tumour is a less common neuroendocrine tumour within the NSCLC type, it is usually reported as "another NSCLC", and it is not possible to determine a clear relationship or frequency for this type of tumour in the literature reviewed.

The development of lung lesions in a patient with BC often leads to a misdiagnosis, almost always confused with metastasis. Therefore, obtaining biopsies and molecular testing such as EGFR, ALK, PD-L1 and ROS-1 is essential to reduce empirical diagnosis, which can lead to inappropriate treatment. This is particularly important in patients with triple-negative BC, as described in this case series. A higher incidence of second primary LC has been observed, possibly due to common oncogenic pathways [6, 20]. Therefore, all patients, especially those diagnosed with triple-negative BC, need to be followed closely and a multidisciplinary approach should be adopted.

In conclusion, this case series describes patients with second primary LC after BC. Histological types seem to play a role in this association (ductal BC, lung adenocarcinoma). It is also worth mentioning that all patients identified with BC-LC SPC had a history of radiotherapy. Although our limitation is the use of medical records and retrospective analysis, this case series contributes to local epidemiology. It is important to continue to perform studies in larger samples that can help to establish an association between different histological types of both pathologies and to determine the incidence of second primary LC in the total population of patients with BC, as well as other types of cancer not included in this report.

BC	Breast cancer
SPC	Secondary primary cancers
LC	Lung cancer
CT	Computerized tomography
VATS	Video-assisted thoracoscopy
PD-L1	Programmed death-ligand 1
PET-CT	Positron emission tomography – CT
EBUS-TBNA	Endobronchial ultrasound-guided transbronchial needle aspiration
TPS	Tumor proportion score
MRI	Magnetic resonance imaging
CNS	Central nervous system
X-ray	Radiography
NSCLC	Non-small cell cancer
ER-	Estrogen receptor-negative
ER+ OSA NYHA	Estrogen receptor-positive Obstruction sleep apnea New York Heart Association

Ethics approval and consent to participate

This manuscript was written in compliance with the ethical standards of the institutional ethics committee and with the 1964 Helsinki Declaration. We have the approval of the Ethics Committee in Biomedical Research from Fundación Valle del Lili. This is supported in letter No. 331 of 2019, which is available with the Corresponding Author if needed.

Consent for publication

Written informed consent was obtained from the patients to publish this case series and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.

Availability of data and materials

Datasets used and analyzed during the current study are available from the corresponding author upon reasonable request.

Competing interests

The authors declare that they have no competing interests. This manuscript has not been published and is not under consideration for publication elsewhere. Additionally, all authors have approved this paper's contents and agreed to the journal's submission policies.

Funding

No funding sources were used.

Authors' contributions

All authors have read and approved the manuscript, and significantly contributed to this paper. LFS: Conception and design, literature review, manuscript writing and correction, final approval of the manuscript. AO: Conception and design, final approval of the manuscript., VZR: Literature review, manuscript writing and correction, final approval of the manuscript. AIC: Literature review, manuscript writing and correction, final approval of the manuscript. CI: Data collection, literature review, final approval of the manuscript. NQ: Data collection, literature review, final approval of the manuscript. LFT: Conception and design, literature review, manuscript writing and correction, final approval of the manuscript.

Acknowledgment

Not applicable

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Tables 2-3 is available in the Supplementary Files section.

No competing interests reported.

Second Primary Lung Cancer after Breast Cancer: A Case Series

Status:

Version 1

Abstract

Figures

Introduction

Case Series Presentation

Breast Cancer

Secondary Primary Lung Cancer

Discussion And Conclusions

Abbreviations

Declarations

References

Tables

Additional Declarations

Supplementary Files

Status:

Version 1