Background : Breast and lung cancer are two of the most commonly diagnosed cancers in North America. While patients are living longer with advances in treatment and supportive care, some patients are being diagnosed with a second malignancy. The primary objective in this study was to assess the correlation between the development of an ipsilateral lung cancer or breast cancer, and prior radiation therapy. In addition, we sought to report the survival outcomes of patients in these clinical scenarios. Methods : We conducted a single institution (the Ottawa Hospital Cancer Centre) retrospective review of patients with the diagnoses of both breast and lung cancer treated between 1995 and 2013. Patients were included if they received radiation for a breast primary, and subsequently developed an ipsilateral lung primary, or vice-versa. Data included patient demographics, lifestyle factors, tumor location and subtype, cancer stages, treatment modalities, and survival outcomes. Results : Of 252 patients included in the study, 217 patients developed a breast primary first, with 35 patients developing a lung primary first. Median disease-free survival from the second primary diagnosis was 36 months in breast primary first patients, and 59 months in the lung primary first cohort. There was no significant correlation between the laterality of radiation treatment and side of second primary based on Fisher’s exact test. Conclusions : Our data reveal no association between side of radiation treatment and subsequent cancer development. The benefits of radiotherapy outweigh the risk of radiation-induced primaries. Longer term studies with matched patient cohorts are required to further assess treatment and lifestyle factors that may contribute towards the development of second malignancies.
Lung cancer and breast cancer are two of the most commonly diagnosed malignancies in North America and rank first and second among cancer-related deaths respectively. Given the high incidence of these cancers, some patients may have the risk of developing multiple primaries in their lifetime.
There have been several studies that reported an increased risk of second primary cancers in patients with an initial diagnosis of breast cancer [
Historically, individuals with cancer have rarely survived past the latency periods inherent to the development of treatment-induced malignancies, but improvements in systemic and radiation therapy have increased the time for these second primaries to emerge [
There is a paucity of data regarding the risk of secondary cancer attributable to modern radiation therapy. In this retrospective cohort study, our primary objective was to assess the risk of breast cancer patients developing an ipsilateral lung cancer and the risk of lung cancer patients developing an ipsilateral breast cancer. We also sought to determine the predominant tumor subtypes and survival outcomes of patients in both clinical scenarios.
We conducted a single institution retrospective review of patients treated at the Ottawa Hospital Cancer Centre between 1995 and 2013. Patients included in the study were diagnosed with both breast cancer and lung cancer primaries within this period. Subjects were included irrespective of order in which primaries were diagnosed and length of time between diagnoses. Patients with distant metastatic disease were excluded. Ethics approval for the project was obtained through the Ottawa Hospital Research Ethics Board.
The chart review identified a total of 261 patients, of whom 252 were deemed eligible for study inclusion. Six patients were excluded due to secondary metastases and three patients were excluded who had mediastinal masses rather than lung primaries. Data from the medical chart of each patient were extracted. Information was recorded pertaining to patient demographics, cancer location and subtype, tumor stage, surgery, radiotherapy, systemic treatment, dates of diagnoses, lifestyle factors, past medical history, cancer recurrence and patient outcome. The same data was obtained for the subsequent primary.
Data were analyzed to produce basic descriptive information, bivariate and survival outcomes. Fisher’s Exact test was used to evaluate correlation between laterality of the second cancer primary and radiation treatment site. Survival data were assessed with Kaplan-Meier analyses.
All patients (252) were women with most individuals developing a breast primary first (BPF) and fewer diagnosed with a lung primary first (LPF) (
The median survival of the BPF group was further broken down by stage of the secondary lung primary (
Breast Primary First | Lung Primary First | |
---|---|---|
Patient Number | 217 | 35 |
Median age at first cancer diagnosis | 65.5 (Range 37 - 92) | 67.2 (Range 47 - 84) |
Median age at second cancer diagnosis | 71.1 (Range 41 - 97) | 71.3 (Range 52 - 88) |
Median follow-up (months) | 82 (Range 0 - 238) | 58 (Range 2 - 191) |
Breast Primary | Lung Primary | |||
---|---|---|---|---|
Tumor staging | Stage 0 | 22 (10%) | Stage I | 62 (29%) |
Stage I | 106 (49%) | Stage II | 29 (13%) | |
Stage II | 75 (35%) | Stage III | 44 (20%) | |
Stage III | 8 (4%) | Stage IV | 82 (38%) | |
Stage IV | 6 (2%) | |||
Tumor subtypesa | IDC | 176 (81%) | Adenocarcinoma | 88 (41%) |
ILC | 15 (7%) | NSCLC NOS | 51 (24%) | |
DCIS | 21 (10%) | Squamous cell carcinoma | 34 (15%) | |
IDC/ILC (mammary) | 3 (1%) | Small cell lung cancer | 30 (14%) | |
Spindle Cell | 1 (0.5%) | Large cell lung cancer | 11 (5%) | |
Phyllodes | 1 (0.5%) | Carcinoid | 3 (1%) |
ainvasive ductal carcinoma (IDC), invasive lobular carcinoma (ILC), ductal carcinoma in situ (DCIS), non-small cell lung cancer not otherwise specified (NSCLC NOS).
Lung Primary | Breast Primary | |||
---|---|---|---|---|
Tumor staging | Stage I | 18 (51%) | Stage 0 | 2 (6%) |
Stage II | 6 (17%) | Stage I | 15 (43%) | |
Stage III | 6 (17%) | Stage II | 13 (37%) | |
Stage IV | 5 (14%) | Stage III | 4 (11%) | |
Stage IV | 1 (3%) | |||
Tumor subtypesb | Adenocarcinoma | 19 (54%) | IDC | 24 (69%) |
NSCLC NOS | 6 (17%) | ILC | 7 (20%) | |
Squamous cell carcinoma | 3 (9%) | DCIS | 2 (6%) | |
Large cell lung cancer | 4 (11%) | Carcinoma NOS | 2 (6%) | |
Small cell lung cancer | 2 (6%) | |||
Carcinoma NOS | 1 (3%) |
bnon-small cell lung cancer not otherwise specified (NSCLC NOS), carcinoma not otherwise specified (carcinoma NOS), invasive ductal carcinoma (IDC), invasive lobular carcinoma (ILC), ductal carcinoma in situ (DCIS)
In the BPF cohort, 65% of the patients received breast-conserving surgery while 29% had a mastectomy. The BPF group had a higher proportion of patients who received radiation treatment in comparison to the LPF patients (67% [BPF] vs. 51% [LPF];
Breast Primary First | Lung Primary First | |
---|---|---|
Smoking history n | 198 (91%) | 31 (89%) |
Radiation treatment n | 145 (67% = 145/217) | 18 (51% = 18/35) |
Ipsilateral radiation n | 75 (52% = 75/145) | 7 (39% = 7/18) |
Cancer-related mortality (%) | 77 | 61 |
Median survival from second diagnosis (months) | 17 | 40 |
Median survival for stage I and II from second diagnosis (months) | 42 | 40 |
Median survival for stage III and IV from second diagnosis (months) | 8 | 42 |
was no correlation between the location of the second cancer and the side that received treatment based on Fisher’s exact test (P = 0.7382 [BPF], P = 0.1141 [LPF]). In other words, having localized radiation to the chest for either primary did not appear to influence the emergence of a second primary on the ipsilateral side.
The BPF cohort was broken down into patients who developed the second lung primary on the ipsilateral side and contralateral side in reference to the location of radiation treatment (
Kaplan-Meier survival data for both cohorts can be seen in
Ipsilateral Lung Cancer | Contralateral Lung Cancer | |||
---|---|---|---|---|
Number | 111 | 106 | ||
Median age at breast diagnosis | 64.5 | 66.2 | ||
Median age at lung diagnosis | 70.1 | 71.5 | ||
Smoking history n (%) | 97 (87) | 100 (94) | ||
Breast radiation (%) | 60 | 62 | ||
Breast cancer treatment modalities (%) | Surgery Hormonal Therapy Chemotherapy | 94 64 26 | Surgery Hormonal Therapy Chemotherapy | 95 63 29 |
Cancer-related mortality (%) | 49 | 42 | ||
Median survival from lung diagnosis (months) | 24 | 18 | ||
Ipsilateral Lung Cancer | Contralateral Lung Cancer | |||
---|---|---|---|---|
Lung cancer stage | Stage I | 37 (33%) | Stage I | 34 (32%) |
Stage II | 12 (11%) | Stage II | 16 (15%) | |
Stage III | 25 (23%) | Stage III | 16 (15%) | |
Stage IV | 37 (33%) | Stage IV | 40 (38%) | |
Lung cancer tumor subtypes (%) | Adenocarcinoma | 47 (42%) | Adenocarcinoma | 38 (36%) |
NSCLC NOSc | 28 (25%) | NSCLC NOS | 27 (25%) | |
Squamous cell carcinoma | 18 (16%) | Small cell carcinoma | 17 (16%) | |
Small cell carcinoma | 14 (13%) | Squamous cell carcinoma | 16 (15%) | |
Large cell carcinoma | 2 (2%) | Large cell l carcinoma | 7 (7%) | |
Carcinoid | 2 (2%) | Carcinoid | 1 (1%) |
cnon-small cell lung cancer not otherwise specified (NSCLC NOS).
The median survival for the LPF cohort was particularly lower than previously reported numbers (
BPF patients who developed an ipsilateral lung cancer had a longer median survival compared to contralateral development (
Previous clinical trials reported the median survival for lung cancer patients as approximately 120 months for stage I disease, 36 - 60 months for stage II (observation vs. chemo), 15 - 23 months for stage III, and 10 - 12 months for stage IV [
cancers and its underlying effect on survival. This is apparent in a study by Schaapveld et al. that found that second primaries in breast cancer patients increased the risk of death, even if the malignancy was considered prognostically favorable [
Early diagnosis and improved radiotherapy treatment options have been vital to lengthening the survival of cancer patients. However, the increased use of radiation has raised concerns regarding second primary development as long-term sequelae of cancer treatment [
There have been several population-based studies that support the link between radiotherapy for a primary breast tumor and the risk of a second cancer, either inside or outside the treatment field. In particular, the risk of lung cancer development following breast irradiation has been a topic of interest due the increased incidence of radiation-induced pulmonary malignancies, as well as the anatomical proximity to the breast’s treatment field [
Conversely, there have been studies showing no substantial risk in developing treatment-related malignancies after breast cancer radiotherapy. In a systematic evaluation of patients in the SEER cancer registries, Berrington de Gonzalez et al. reported that the majority of second cancers in breast cancer survivors were related to genetics and lifestyle factors rather than radiotherapy exposure [
This study showed no significant association between laterality of radiation treatment and subsequent lung cancer or breast cancer development, as well as no appreciable differences in age, stage, lung tumor subtypes, smoking history, treatment modalities, or cancer-related mortality based on side of irradiation. The findings suggest that while radiotherapy may play a role in development of treatment-related secondary cancer, the effect associated with radiation is overall small compared to other well-established risk factors. The majority of second primaries can be attributed to lifestyle factors such as smoking, gene-environment interactions, genetic mutations, and susceptibility.
Radiation therapy has evolved rapidly over the past two decades with advances in technology that improve treatment conformity while reducing toxicity to surrounding tissues. The use of intensity-modulated radiation therapy (IMRT) has greatly increased in recent years allowing complex dose distributions suitable for avoiding vital structures near the target [
This study included patients with cancer diagnoses between 1995 and 2013. IMRT at the Ottawa Hospital Cancer Centre did not come into clinical practice until 2005 with the first few years being strictly trial participants. Due to this later technological emergence and majority of patients being treated for their primary cancer earlier in the timeframe, IMRT would not have a strong influence on the patient cohort and their radiotherapy-induced cancer risk within the study period. As patients are continued to be monitored following treatment using these modalities, the threat of more modern therapy-induced malignancies can be better assessed.
The current study had several limitations. First, considering the generally low numbers of radiotherapy-induced primaries per patient treated, the sample size was small to analyze this risk. In addition, the patient population was strictly comprised of patients who developed both a primary cancer and a subsequent second primary. This design restricted the level of statistical analyses that could be performed on the data and a matched cohort of patients who did not develop a second malignancy would be needed to further assess the risk factors. Another limitation is the particularly small LPF group. The low incidence of patients who developed a breast primary following an initial lung primary limited the analysis of this data and a study on a larger LPF population would be required to further assess this group.
One important limitation in this study is the length of follow up. Most current data show the latent period for the development of radiotherapy-induced cancer to be over 10 years. However, for a portion of the study patients this threshold was not reached. Many of the patients who were irradiated may have the potential to develop second primaries outside of the study period and would need to be observed over a longer time interval to further characterize the risk of developing therapy-induced cancers.
In this retrospective analysis, we evaluated the possible association between oncologic treatment, and the development of secondary malignancies. The current study showed no significant association between laterality of radiation treatment and subsequent lung or breast cancer development, as well as no appreciable differences in age, stage, tumor subtypes, smoking history, treatment modality, or cancer-related mortality based on the side of the second lung cancer.
Radiotherapy has become a standard adjuvant option in the treatment of breast and lung cancer, contributing to longer survival times in patients with one or both malignancies. Previous literature shows a small but significant risk in developing second primary cancers many years after radiation administration, but our centre’s data failed to confirm this association keeping in mind the nuances of this unique cancer population. Recent advances in radiotherapy modalities show promise in improved imaging and dose conformity, but the overall threat to proximal structures is still unknown at this point. With IMRT playing a prominent role in standard treatment and the patient population reaching latency periods that correspond to the development of radiation-induced malignancies, the risk attributable to newer technologies can be better described.
Given all the lifestyle, environmental and genetic factors which play a role in cancer risk, radiotherapy is simply one of the many contributing factors to second primary development. Larger scale observational studies with longer follow up time are required to further assess the risk of radiation-induced malignancies, especially in younger patient populations. With the current data, the benefits of radiation therapy in appropriate selected patients still outweigh the risks and side effects of treatment. While an effort should be taken to reduce the amount of radiation a patient is subjected to, cancer treatment and prevention with appropriate therapy should always take priority with an appreciation of patient risk factors and latency periods.
Funding support provided by the Ottawa Hospital Research Institute (OHRI).
We declare that we have no conflict of interest.
Nguyen, E.K., Nicholas, G.A. and Song, X.N. (2018) Role of Radiotherapy-Induced Malignancies in Patients with Both Breast and Lung Cancer Diagnoses. Advances in Breast Cancer Research, 7, 231-242. https://doi.org/10.4236/abcr.2018.73014