Incidence and risk factors of hypothyroidism after treatment for early breast cancer: a population-based cohort study.

PURPOSE: An increased incidence of hypothyroidism among breast cancer survivors has been observed in earlier studies. The impact of the postoperative treatment modalities and their potential interplay on hypothyroidism development needs to be studied. METHODS: We conducted a population- and registry-based study using the Breast Cancer Data Base Sweden (BCBaSe) including females diagnosed with breast cancer between 2006 and 2012. In total, 21,268 female patients diagnosed with early breast cancer between 2006 and 2012, with no previous prescription of thyroid hormones and no malignant diagnosis during the last ten years before breast cancer diagnosis, were included in the final analysis. RESULTS: During the follow-up (median follow-up time 7.9 years), 1212 patients (5.7%) developed hypothyroidism at a median time of 3.45 years from the index date. No association of the systemic oncological treatment in terms of either chemotherapy or endocrine therapy and hypothyroidism development could be identified. A higher risk (HR 1.68;95% CI 1.42-1.99) of hypothyroidism identified among patients treated with radiation treatment of the regional lymph nodes whereas no increased risk in patients treated only with radiation therapy to the breast/chest wall was found (HR 1.01; 95% CI 0.86-1.19). The risk of hypothyroidism in the cohort treated with radiotherapy of the regional lymph nodes was present irrespective of the use of adjuvant chemotherapy treatment. CONCLUSIONS: Based on the results of our study, the implementation of hypothyroidism surveillance among the breast cancer survivors treated with radiotherapy of the regional lymph nodes can be considered as reasonable in the follow-up program.

Association of clinicopathologic variables and patient preference with the choice of surgical treatment for early-stage breast cancer: A registry-based study.

INTRODUCTION: Observational studies suggest that breast conserving surgery (BCS) and radiotherapy (RT) offers superior survival compared to mastectomy. The aim was to compare patient and tumour characteristics in women with invasive breast cancer ≤30 mm treated with either BCS or mastectomy, and to explore the underlying reason for choosing mastectomy. METHODS: Women registered with breast cancer ≤30 mm and ≤4 positive axillary lymph nodes in the Swedish National Breast Cancer Register 2013-2016 were included. Logistic regression analyses were performed to assess the association of tumour and patient characteristics with receiving a mastectomy vs. BCS. RESULTS: Of 1860 breast cancers in 1825 women, 1346 were treated by BCS and 514 by mastectomy. Adjuvant RT was given to 1309 women (97.1 %) after BCS and 146 (27.6 %) after mastectomy. Variables associated with receiving a mastectomy vs. BCS included clinical detection (Odds Ratio (OR) 4.15 (95 % Confidence Interval (CI) 3.35-5.14)) and clinical stage (T2 vs. T1 (OR 3.68 (95 % CI 2.90-4.68)), N1 vs. N0 (OR 2.02 (95 % CI 1.38-2.96)). Women receiving mastectomy more often had oestrogen receptor negative, HER2 positive tumours of higher histological grade. The most common reported reason for mastectomy was large or multifocal tumours (53.5 %), followed by patient preference (34.5 %). CONCLUSION: Choice of surgery is strongly associated with key prognostic factors among women undergoing BCS with RT compared to mastectomy. Failure to control for all relevant confounders may bias results in outcome studies in favour of BCS.

Angiosarcoma in the breast: a population-based cohort from Sweden.

BACKGROUND: Breast angiosarcoma is a rare disease mostly observed in breast cancer (BC) patients who have previously received radiotherapy (RT). Little is known about angiosarcoma aetiology, management, and outcome. The study aim was to estimate risk and to characterize breast angiosarcoma in a Swedish population-based cohort. METHODS: The Swedish Cancer Registry was searched for breast angiosarcoma between 1992 and 2018 in three Swedish healthcare regions (population 5.5 million). Information on previous BC, RT, management, and outcome were retrieved from medical records. RESULTS: Overall, 49 angiosarcomas located in the breast, chest wall, or axilla were identified, 8 primary and 41 secondary to BC treatment. Median age was 51 and 73 years, respectively. The minimum latency period of secondary angiosarcoma after a BC diagnosis was 4 years (range 4-21 years). The cumulative incidence of angiosarcoma after breast RT increased continuously, reaching 1.4‰ after 20 years. Among 44 women with angiosarcoma treated by surgery, 29 developed subsequent local recurrence. Median recurrence-free survival was 3.4 and 1.8 years for primary and secondary angiosarcoma, respectively. The 5-year overall survival probability for the whole cohort was 50 per cent (95 per cent c.i., 21 per cent-100 per cent) for primary breast angiosarcoma and 35 per cent (95 per cent c.i., 23 per cent-54 per cent) for secondary angiosarcoma. CONCLUSION: Breast angiosarcoma is a rare disease strongly associated with a history of previous BC RT. Overall survival is poor with high rates of local recurrences and distant metastasis.

Aromatase inhibitors use and risk for cardiovascular disease in breast cancer patients: A population-based cohort study.

BACKGROUND: Prior studies regarding use of Aromatase inhibitors (AIs) and risk for cardiovascular disease (CVD) have shown conflicting results. This retrospective cohort study aimed to investigate whether AIs use affects risk for CVD events in postmenopausal breast cancer survivors. METHODS: Using a retrospective cohort study design, four CVD outcomes; heart failure or cardiomyopathy, arrhythmia, acute ischemic heart disease and ischemic stroke or Transient Ischemic Attack were compared with uni- and multivariate Cox regression analyses according to exposure to endocrine therapy (use of AI, tamoxifen or AI/tamoxifen sequentially) or no endocrine therapy. RESULTS: In total 15815 postmenopausal women, surgically treated to early breast cancer during 2006-2012, were included. No significantly increased risk for CVD events was observed in patients with AI use in the whole cohort. However, two subgroup analyses showed increased risk for CVD events in the AI/tamoxifen sequential group; heart failure in patients older than 75 years (Hazard Ratio (HR) 2.44; 95% Confidence Interval (CI): 1.32-4.54) and arrhythmia in patients without prior CVD (HR 1.45; 95% CI: 1.01-2.10). An increased risk for arrhythmia and acute ischemic heart disease in patients with at least four years of AI treatment compared with no or short-time exposure was observed (HR 2.12; 95% CI: 1.40-3.25 for arrhythmia; HR 2.03; 95% CI: 1.15-3.58 for ischemic heart disease). CONCLUSION: Our results indicate an increased risk for ischemic heart disease and arrhythmia in patients treated for more than four years with AIs. This should be considered in the risk-benefit assessment concerning endocrine therapy.

Risk of primary lung cancer after adjuvant radiotherapy in breast cancer-a large population-based study.

Adjuvant radiotherapy (RT) for breast cancer (BC) has been associated with an increased risk of later radiation-induced lung cancer (LC). We examined the risk of primary LC in a population-based cohort of 52300 women treated for BC during 1992 to 2012, and 253796 age-matched women without BC. Cumulative incidence of LC was calculated by the Kaplan-Meier method, and the risk of LC after BC treatment was estimated by Cox proportional hazards regression analyses. Women with BC receiving RT had a higher cumulative incidence of LC compared to women with BC not receiving RT and women without BC. This became apparent 5 years after RT and increased with longer follow-up. Women with BC receiving RT had a Hazard ratio of 1.59 (95% confidence interval 1.37-1.84) for LC compared to women without BC. RT techniques that lower the incidental lung doses, e.g breathing adaption techniques, may lower this risk.

Treatment patterns, risk for hospitalization and mortality in older patients with triple negative breast cancer.

OBJECTIVES: To study the treatment patterns, potential risk factors for hospitalization within one year from diagnosis, and causes of death in older patients with triple negative breast cancer (TNBC). MATERIALS AND METHODS: We performed a registry-based cohort study using the BCBaSe database which links cases of breast cancer from three Swedish healthcare regions with socioeconomic factors, hospitalizations and causes of death. Women ≥70 years old with non-metastatic TNBC, between 1/12007 and 31/122012 were included (n = 413). RESULTS: In total, 168 patients (40.7%) received chemotherapy after surgery and 123 patients (30.0%) in the whole cohort had at least one hospitalization within one year from diagnosis. The risk of hospitalization overall was increased in the group receiving chemotherapy (Odds Ratio 2.35, 95% Confidence Intervall: 1.30-4.26) mainly due to toxicities. Cumulative incidence of breast cancer mortality was comparable among different age groups (70-74 vs. 75-79 vs. ≥ 80 years old) whereas non-breast cancer mortality was higher in patients ≥80 years old. Stage at diagnosis and comorbidities were independently associated with both breast cancer-specific- and overall mortality whereas age was only associated with overall mortality. CONCLUSIONS: The use of chemotherapy in older patients with TNBC was associated with age, tumor stage, and comorbidities. Chemotherapy use was also associated with increased risk for hospitalization within one year from diagnosis. Although the impact of chemotherapy on mortality was analyzed in a multivariate manner showing neither increased or decreased mortality, no firm conclusion can be drawn due to unmeasured confounders.

Influenza vaccination in breast cancer patients during subcutaneous trastuzumab in adjuvant setting.

BACKGROUND: Despite the current recommendation for influenza vaccination in cancer patients with active oncological therapy, limited data are available on the efficacy of vaccination in cancer patients receiving targeted therapies. We aimed to investigate the immunogenicity and tolerability of influenza vaccination in breast cancer patients treated with trastuzumab in adjuvant setting. METHODS: A prospective open-label multicenter study was performed including patients with breast cancer during trastuzumab treatment in adjuvant setting and healthy controls. Blood samples were taken before, 4 weeks after, and 12 weeks after a single dose of trivalent influenza vaccine containing inactivated A/California/7/2009 (H1N1) pdm09, A/Hongkong4801/2014 (H3N2), and B/Brisbane/60/2008. Levels of serum antibody titers to hemagglutinin for H1N1 and influenza B strains were measured. RESULTS: Twenty breast cancer patients and 37 controls were included in the study. No difference in seroprotection rate between trastuzumab-treated patients and controls was observed for either H1N1 (100% in both groups) or B strain (78.9% vs. 89.2%, p value = 0.423). A statistically significant increase in geometric mean titers from baseline was seen in both groups and was evident both 4 weeks and 12 weeks after vaccination. Adverse events in the trastuzumab-treated group were uncommon and mild with only one serious adverse event not related to vaccination. CONCLUSION: Breast cancer patients treated with trastuzumab in adjuvant setting seem to benefit from influenza vaccination in terms of immunogenicity without increasing the risk for adverse events. The current data support the recommendation to offer influenza vaccination in breast cancer patients treated with this type of targeted therapy.

Impact of chemotherapy, radiotherapy, and endocrine therapy on sick leave in women with early-stage breast cancer during a 5-year period: a population-based cohort study.

PURPOSE: To examine the influence of type of oncological treatment on sick leave in women of working age with early-stage breast cancer. METHODS: We identified 8870 women aged 30-64 diagnosed with stage I-II breast cancer between 2005 and 2012 in the Breast Cancer Data Base Sweden. Associations between type of oncological treatment (radiotherapy, endocrine therapy, and chemotherapy) and sick leave were estimated by hazard ratios, probabilities, and length of sick leave using multi-state survival analysis. RESULTS: During the first 5 years after diagnosis, women aged 50-54 years at diagnosis receiving chemotherapy spent on average 182 (95% CI 151-218) additional days on sick leave compared with women not receiving chemotherapy, but with otherwise similar characteristics. Correspondingly, women initiating endocrine therapy spent 30 (95% CI 18-44) additional days on sick leave and women receiving post-mastectomy radiotherapy 53 (95% CI 37-69) additional days. At year five, the rate of sick leave was increased in women who had received chemotherapy (HR 1.19, 95% CI 1.11-1.28) or endocrine therapy (HR 1.15, 95% CI 1.05-1.26). Chemotherapy and endocrine therapy were associated with increased rates of sick leave due to depression or anxiety. CONCLUSION: Our findings of increased long-term risks of sick leave after oncological treatment for breast cancer warrant attention from caregivers taking part in cancer rehabilitation. In light of the ongoing debate about overtreatment of early-stage breast cancer, our findings point to the importance of properly selecting patients for chemotherapy not only for the medical toxicity but also the possible impact on their livelihood.

Long-term risk of ischemic heart disease after adjuvant radiotherapy in breast cancer: results from a large population-based cohort.

BACKGROUND: Adjuvant radiotherapy (RT) for breast cancer (BC) has been associated with an increased risk of ischemic heart disease (IHD). We examined the incidence of IHD in a large population-based cohort of women with BC. METHODS: The Breast Cancer DataBase Sweden (BCBaSe) includes all women diagnosed with BC from 1992 to 2012 (n = 60,217) and age-matched women without a history of BC (n = 300,791) in three Swedish health care regions. Information on comorbidity, educational level, and incidence of IHD was obtained through linkage with population-based registries. The risk of IHD was estimated by Cox proportional hazard regression analyses and cumulative incidence by the Kaplan-Meier method. RESULTS: Women with BC had a lower risk of IHD compared to women without BC with a hazard ratio (HR) of 0.91 (95% CI 0.88-0.95). When women with left-sided BC were compared to right-sided BC, an increased HR for IHD of 1.09 (95% CI 1.01-1.17) was seen. In women receiving RT, a HR of 1.18 (95% CI 1.06-1.31) was seen in left-sided compared to right-sided BC, and the HRs increased with more extensive lymph node involvement and with the addition of systemic therapy. The cumulative IHD incidence was increased in women receiving left-sided RT compared to right-sided RT, starting from the first years after RT and sustained with longer follow-up. CONCLUSIONS: Women given RT for left-sided BC during 1992 to 2012 had an increased risk of IHD compared to women treated for right-sided BC. These women were treated in the era of three-dimensional conformal RT (3DCRT), and the results emphasize the importance of further developing and implementing RT techniques that lower the cardiac doses, without compromising the beneficial effects of RT.

The relationship between radiation doses to coronary arteries and location of coronary stenosis requiring intervention in breast cancer survivors.

BACKGROUND: To assess the relationship between radiation doses to the coronary arteries (CAs) and location of a coronary stenosis that required intervention after three-dimensional conformal radiotherapy (3DCRT) for breast cancer (BC). METHODS: The study population consisted of 182 women treated for BC in Sweden between 1992 and 2012. All women received 3DCRT and subsequently underwent coronary angiography due to a suspected coronary event. CA segments were delineated in the patient's original planning-CT and radiation doses were recalculated based on the dose distribution of the original radiotherapy (RT) plan. The location of the CA stenosis that required intervention was identified from the Swedish Coronary Angiography and Angioplasty Registry (SCAAR). Logistic regression analysis was used to assess the relationship between CA radiation doses and risk of a later coronary intervention at this specific location. RESULTS: The odds ratio (OR) varied by radiation dose to the mid left anterior descending artery (LAD) (p = 0.005). Women receiving mean doses of 1-5 Gray (Gy) to the mid LAD had an adjusted OR of 0.90 (95% CI 0.47-1.74) for a later coronary intervention compared to women receiving mean doses of 0-1 Gy to the mid LAD. In women receiving mean doses of 5-20 Gy to the mid LAD, an adjusted OR of 1.24 (95% CI 0.52-2.95) was observed, which increased to an OR of 5.23 (95% CI 2.01-13.6) for mean doses over 20 Gy, when compared to women receiving mean doses of 0-1 Gy to the mid LAD. CONCLUSIONS: In women receiving conventional 3DCRT for BC between 1992 and 2012, radiation doses to the LAD remained high and were associated with an increased requirement of coronary intervention in mid LAD. The results support that the LAD radiation dose should be considered in RT treatment planning and that the dose should be kept as low as possible. Minimising the dose to LAD is expected to diminish the risk of later radiation-induced stenosis.

Inter-observer variation in delineating the coronary arteries as organs at risk.

PURPOSE: To determine the inter-observer variation in delineating the coronary arteries as organs at risk (OAR) in breast cancer (BC) radiotherapy (RT) and how this variation affects the estimated coronary artery radiation dose. METHOD: Delineation of the left main and the left anterior descending coronary artery (LMCA and LAD), and the right coronary artery (RCA), by using the heart atlas by Feng et al., was performed by three radiation oncologists in 32 women who had received adjuvant RT for BC. Centres of the arteries were calculated and distances between artery centres were measured and the artery radiation doses were estimated. The intraclass correlation coefficient (ICC) was used to quantify the variability in doses. RESULTS: Along the extent of RCA, the median distance between centres of arteries varied from 2 to 9mm with similar patterns over pairs of oncologists. For the LMCA-LAD the median distance varied from 1 to 4mm. The estimated maximum radiation doses showed an ICC variation from 0.82 to 0.97. CONCLUSION: The coronary arteries can be reliably identified and delineated as OARs in BC RT. The spatial variance is limited and the total variation in radiation dose is almost completely determined by the between patient variation.