The impact of breast cancer treatment concordance on survival in relation to comorbidity burden

Background

Patients with breast cancer (BC) and concomitant comorbidity have poorer disease prognosis, which may be related to a reduction in the receipt of curative cancer treatment. This study sought to determine the survival impact of BC treatment concordance in relation to comorbidity burden.

Methods

Incident cases of unilateral stage I-III BC diagnosed between 2000 and 2015 were identified from a prospectively collected New Zealand BC register. Comorbidity severity was measured by C3 index score; derived via linkage with national hospitalization data. Treatment concordance (for breast and axillary surgery, adjuvant radiotherapy, adjuvant chemotherapy and endocrine therapy) was assigned in relation to minimum treatment indications as per national tumor standards and St Gallen Consensus Statements from relevant years. Multiple imputation of missing data was performed. Propensity scores for the conditional probability of receiving each treatment modality were modelled and used to create inverse probability of treatment- (IPTW) and standardized mortality ratio-weighted (SMRW) samples which were balanced with respect to baseline confounding variables between treated and untreated groups. For each treatment modality, weighted Cox proportional hazards (for all-cause mortality) and competing risks regression models (for BC-specific mortality) were produced, giving hazard ratio’s (HR’s) and sub-distribution hazard ratio’s (SHR’s) respectively as estimates of the average treatment effect (ATE) in IPTW samples and the average treatment effect on the treated in SMRW samples. Treatment effect heterogeneity by comorbidity severity was evaluated through the use of interaction tests and confirmatory subgroup analysis.

Results

A total of 12,834 patients were included, with 21.5% possessing one or more pre-existing comorbidities. Patients with comorbidity were less likely to receive all four modalities of breast cancer treatment. Comorbidity burden was associated with poorer age and stage-adjusted survival, with greater impact on all-cause than BC-specific mortality. Overall, and for patients without comorbidity, those who received guideline-concordant treatments experienced significant reductions in all-cause and BC mortality risk (Tables 1 and 2; ATE’s from IPTW samples shown only). Heterogeneity in ATE’s by comorbidity severity was noted for surgery (BC mortality, p=.03) and endocrine therapy (all-cause mortality, p=.003), with lesser benefit at higher levels of comorbidity. Amongst patients with the greatest comorbidity severity (C3 score >2.00), surgery to the breast and axilla reduced the risk of all-cause but not BC mortality, with no mortality benefits obtained from the addition of adjuvant therapies.

Conclusions

Patients with BC and concurrent comorbidity do not obtain the same survival benefits from guideline-concordant treatment as their non-comorbid counterparts. The inferior survival of such patients is therefore likely to be mediated through mechanisms other than reduced receipt of curative treatment.

 

Improvements in long-term outcome for women with estrogen receptor positive (ER+) early stage breast cancer

Pan H et al.

Background

For women with ER+ early stage breast cancer who are disease-free after 5 years of scheduled endocrine therapy, recurrences occur at a steady rate to at least year 20 from diagnosis, and are strongly correlated with tumor and nodal status (TN). For women diagnosed in 1976-2011, 20-year distant recurrence (DR) risk was 13%, 20%, and 34% for T1N0, T1N1-3, and T1N4-9 disease, respectively (Pan et al NEJM 2017). Using updated data, we investigated whether DR risk is lower for women diagnosed more recently.

Methods

Kaplan-Meier and Cox regression analyses, stratified by trial, TN status and treatment, included 82,598 women with ER+ breast cancer from 108 trials who were alive and disease free after 5 years of scheduled endocrine therapy, 19,675 more than in the previously published dataset, of whom 11,391 were diagnosed since 2005.

Results

Estimates of DR during the period from 5 to 20 years were 1% to 2% lower in the updated dataset than reported in 2017. Compared to earlier years (before 1995), the hazard ratio (HR) for DR in years 5-9 was 0.83 (95%CI 0.77 – 0.90) in women diagnosed in 1995-99, decreasing to 0.64 (0.59 – 0.70) in 2000-04, and to 0.58 (0.52 – 0.65) in 2005-12. Those diagnosed after 2000 (median follow-up after year 5 = 2.7, IQR 1.1-4.3 years) had a 30% lower risk of DR (HR = 0.70 (95% CI 0.66 – 0.75) compared with women diagnosed before 2000 (median follow-up after year 5 = 6.1, IQR 4.4-9.9 years). The recurrence risk in years 5-10 after diagnosis in women diagnosed after 2000 was 3% for T1N0 and 5% for T2N0, with few events recorded after year 10. If these recurrence rates continue at the same rate, 20-year risk of DR for women diagnosed after 2000 is projected to be 8% and 14% for T1N0 and T2N0 stages, respectively, compared with 13% and 19% for those diagnosed before 2000. More detailed analyses and investigation of factors influencing the improvements in outcome will be presented.

Conclusion

The risk of DR at 20 years after diagnosis for women with node-negative ER+ early stage breast cancer, who discontinue endocrine therapy at 5 years is likely to be about a third lower now than in our previous report. However, long-term follow-up of patients diagnosed more recently is required to accurately characterize long-term recurrence risks.

 

Use of anastrozole for breast cancer prevention (IBIS-II): long-term results of a randomised controlled trial

Jack Cuzick Prof, Ivana Sestak PhD, John F Forbes Prof, Mitch Dowsett Prof, Simon Cawthron MD, Robert E Mansel MD, Sibylle Loibi Prof, Bernardo Bonanni MD, D Gareth Evans Prof and Anthony Howell Prof

Purpose
Two large clinical trials have shown a reduced rate of breast cancer development in high-risk women in the initial 5 years of follow-up after use of aromatase inhibitors (MAP.3 and International Breast Cancer Intervention Study II [IBIS-II]). Here, we report blinded long-term follow-up results for the IBIS-II trial, which compared anastrozole with placebo, with the objective of determining the efficacy of anastrozole for preventing breast cancer (both invasive and ductal carcinoma in situ) in the post-treatment period.

Methods
IBIS-II is an international, randomised, double-blind, placebo-controlled trial. Postmenopausal women at increased risk of developing breast cancer were recruited and were randomly assigned (1:1) to either anastrozole (1 mg per day, oral) or matching placebo daily for 5 years. After treatment completion, women were followed on a yearly basis to collect data on breast cancer incidence, death, other cancers, and major adverse events (cardiovascular events and fractures). The primary outcome was all breast cancer.

Findings
3864 women were recruited between Feb 2, 2003, and Jan 31, 2012. 1920 women were randomly assigned to 5 years anastrozole and 1944 to placebo. After a median follow-up of 131 months (IQR 105–156), a 49% reduction in breast cancer was observed for anastrozole (85 vs 165 cases, hazard ratio [HR] 0·51, 95% CI 0·39–0·66, p<0·0001). The reduction was larger in the first 5 years (35 vs 89, 0·39, 0·27–0·58, p<0·0001), but still significant after 5 years (50 vs 76 new cases, 0·64, 0·45–0·91, p=0·014), and not significantly different from the first 5 years (p=0·087). Invasive oestrogen receptor-positive breast cancer was reduced by 54% (HR 0·46, 95% CI 0·33–0·65, p<0·0001), with a continued significant effect in the period after treatment. A 59% reduction in ductal carcinoma in situ was observed (0·41, 0·22–0·79, p=0·0081), especially in participants known to be oestrogen receptor-positive (0·22, 0·78–0·65, p<0·0001). No significant difference in deaths was observed overall (69 vs 70, HR 0·96, 95% CI 0·69–1·34, p=0·82) or for breast cancer (two anastrozole vs three placebo). A significant decrease in non-breast cancers was observed for anastrozole (147 vs 200, odds ratio 0·72, 95% CI 0·57–0·91, p=0·0042), owing primarily to non-melanoma skin cancer. No excess of fractures or cardiovascular disease was observed.

Interpretation
This analysis has identified a significant continuing reduction in breast cancer with anastrozole in the post-treatment follow-up period, with no evidence of new late side-effects. Further follow-up is needed to assess the effect on breast cancer mortality.

Treatment and survival of Asian women diagnosed with breast cancer in New Zealand

Chunhuan Lao, Ross Lawrenson, Melissa Edwards and Ian Campbell

Purpose
This study aims to examine the differences in characteristics, treatment and survival between Asian and European women diagnosed with stage I–III breast cancer in New Zealand.

Methods
The studied population included European women and Asian women diagnosed with stage I–III breast cancer between June 2000 and May 2013 identified from the combined Waikato and Auckland Breast Cancer Registers. Characteristics and treatment were compared between Asian and European women. Kaplan–Meier method was used to examine the
survival difference. Cox proportional hazards model was used to estimate the hazard ratio (HR) of mortality.

Results
The studied cohort included 8608 European and 949 Asian women. Asian women were younger, had less comorbidities and were less likely to be obese than European women. Asian women were more likely to have grade 3, larger and HER2+ breast cancers. Asian women were more likely to receive mastectomy, less likely to have reconstruction after mastectomy, less likely to have chemotherapy, less likely to be treated with trastuzumab if HER2+, and had better adherence to endocrine therapy (adjusted odds ratio: 1.54; 95% CI 1.22–1.93). Asian women had better cancer-specific survival and all-cause survival than European women. The adjusted HR of cancer-specific mortality and all-cause mortality were 0.64 (95% CI 0.49–0.82) and 0.68 (95% CI 0.55–0.84), respectively.

Conclusions
Asian women are more likely to have high grade, larger and HER2+ breast cancers than European women. In spite of this, they had better breast cancer outcomes. Possible explanations include the differences in adherence to endocrine therapy, age, BMI and comorbidities.

Surgical treatment of early stage breast cancer in Auckland and Waikato regions of New Zealand

Ian Campbell, Chunhuan Lao, Tania Blackmore, Melissa Edwards, Louise Hayes, Alex Ng and Ross Lawrenson

Background
The aim of this study was to understand the factors influencing the use of surgical options by New Zealand wāhine/women with newly diagnosed breast cancer.

Methods
Using data from the Auckland and Waikato breast cancer registers, 11, 798 women diagnosed with stage I-III breast cancer from June 2000 to May 2013 were included. The characteristics of women receiving different surgical treatments and having immediate breast reconstruction following mastectomy were examined. A logistic regression was used to estimate the odds ratio of having breast-conserving surgery (BCS) versus mastectomy and immediate post-mastectomy reconstruction. Bilateral breast cancer cases and women with unilateral breast cancer, but who had bilateral surgery, were also identified.

Results
Fifty‐two percent of women received BCS and 44% had mastectomy over the study period. Key influences associated with BCS were age, mode of diagnosis, socio‐economic status and public or private treatment. Just under half of the women who underwent bilateral surgery did not have bilateral cancer. Nineteen percent of women undergoing mastectomy underwent immediate reconstruction. Implant use increased slightly over the study period but there was a decrease in the use of autologous flap procedures.

Conclusion
Surgical management of women with localized breast cancer was generally in line with guidelines, but with potential to further increase the use of breast conservation and immediate reconstruction in suitable cases.

 

International comparison of cosmetic outcomes of breast conserving surgery and radiation therapy for women with ductal carcinoma in situ of the breast

Ivo A. Olivotto, Emma Link, Claire Phillips, Timothy J. Whelan, Guy Bryant, Ian H. Kunkler, A. Helen Westenberg, Kash Purohit, Verity Ahern, Peter H. Graham, Mohamed Akra, Orla McArdle, Joanna J. Ludbrook, Jennifer A. Harvey, John H. Maduro, Carine Kirkove, Guenther Gruber,
Joseph D. Martin, Ian D. Campbell, Geoff P. Delaney, Boon H. Chua, on behalf of the BIG 03-07/TROG 07.01 trial investigators

Purpose

To assess the cosmetic impact of breast conserving surgery (BCS), whole breast irradiation (WBI) fractionation and tumour bed boost (TBB) use in a phase III trial for women with ductal carcinoma in situ (DCIS) of the breast.

Materials and methods

Baseline and 3-year cosmesis were assessed using the European Organization for Research and Treatment of Cancer (EORTC) Cosmetic Rating System and digital images in a randomised trial of non-low risk DCIS treated with postoperative WBI +/ TBB. Baseline cosmesis was assessed for four geographic clusters of treating centres. Cosmetic failure was a global score of fair or poor. Cosmetic deterioration was a score change from excellent or good at baseline to fair or poor at three years. Odds ratios for cosmetic deterioration by WBI dose-fractionation and TBB use were calculated for both scoring systems.

Results

1608 women were enrolled from 11 countries between 2007 and 2014. 85–90% had excellent or good baseline cosmesis independent of geography or assessment method. TBB (16 Gy in 8 fractions) was associated with a >2-fold risk of cosmetic deterioration (p < 0.001). Hypofractionated WBI (42.5 Gy in 16 fractions) achieved statistically similar 3-year cosmesis compared to conventional WBI (50 Gy in 25 fractions) (p > 0.18). The adverse impact of a TBB was not significantly associated with WBI fractionation (interaction p > 0.30).

Conclusions

Cosmetic failure from BCS was similar across international jurisdictions. A TBB of 16 Gy increased the rate of cosmetic deterioration. Hypofractionated WBI achieved similar 3-year cosmesis as conventional WBI in women treated with BCS for DCIS.

Outcomes in different ethnic groups of New Zealand patients with screen-detected vs. non-screen detected breast cancer

Ross Lawrenson, Chunhuan Lao, Gregory Jacobson, Sanjeewa Seneviratne, Nina Scott, Diana Sarfati, Mark Elwood and Ian Campbell

Objective
To compare characteristics and survival of New Zealand European, Māori, and Pacific women with screen-detected vs. non-screen-detected breast cancer.

Methods
Women aged 45-69 diagnosed with invasive breast cancer between January 2005 and May 2013 were identified from the Waikato and Auckland Breast Cancer Registries. Patient demographics and tumour characteristics were described by detection mode and ethnicity. Kaplan-Meier method was used to estimate the five-year breast cancer-specific survival of women with stage I-III breast cancer by ethnicity and detection mode.

Results
Women with screen-detected cancers were older, had smaller tumours, fewer stage IV (0.8% vs. 7.6%), fewer high grade (16.8% vs. 39.0%), and fewer lymph node positive diseases (26.3% vs. 51.5%) than women with non-screen-detected cancers. There were more Luminal A (70.0% vs. 54.0%), fewer human epidermal growth factor receptor 2 positive non-Luminal (4.4% vs. 8.8%), and fewer triple negative cases (7.0% vs. 13.8%) in screen-detected than non-screen-detected cancers. If not screen detected, 22.7% of breast cancers in Pacific women were stage IV compared with 2.4% if screen detected. If not screen detected, the five-year breast cancer-specific survival was 91.1% for New Zealand European women, 84.2% for Māori women, and 80.2% for Pacific women (p-value <0.001). For screen-detected breast cancer, survival between different ethnic groups was similar.

Conclusions
Breast cancers detected through screening are diagnosed at an earlier stage and have a greater proportion of subtypes, with better outcome. Variations in survival for Māori and Pacific women are only found in women with non-screen-detected breast cancer.

Impact of radiotherapy on cardiovascular health of women with breast cancer

Ross Lawrenson, Chunhuan Lao, Ahmed Ali and Ian Campbell

Introduction
This study aims to examine the impact of radiotherapy on the cardiovascular health of women diagnosed with breast cancer in the Waikato region in New Zealand.

Methods
Women diagnosed with stage 0–III breast cancer and recorded in the Waikato Breast Cancer Registry were divided into two groups: a radiotherapy group and a no-radiotherapy group. Baseline characteristics and treatments were compared in the two groups. Kaplan–Meier survival analysis was performed to compare cardiovascular morbidity and mortality. Cox Proportional Hazard regression analysis was used to estimate the hazard ratio of radiotherapy on the risk of cardiovascular morbidity and mortality while adjusting for other factors.

Results
A total of 3528 women were included in this study, with 2303 in the radiotherapy group and 1225 in the no-radiotherapy group. At 10-year followup, 11.7% of women in the radiotherapy group and 19.4% in the no-radiotherapy group experienced cardiovascular events. Only 2.3% of patients who received radiotherapy died of cardiovascular disease by 10  years compared to 7.0% in the no-radiotherapy group. After adjusting for clinically significant factors, there was unexplained reduced risk of developing cardiovascular disease in the radiotherapy group compared to the no-radiotherapy group (HR 0.73, 95% CI: 0.59–0.92). No significant difference was found in cardiovascular mortality between the two groups.

Conclusions
Radiotherapy appears less likely to be offered to patients at higher risk of cardiovascular disease. No evidence of increased risk of a cardiovascular event was found in the group of women with breast cancer treated with radiotherapy and current regimens appear safe. Traditional cardiovascular risk factors remain the main culprits in this setting. Clinicians should work with patients in managing these risk factors for optimal results.

 

Receipt of radiotherapy after mastectomy in women with breast cancer: Population-based cohart study in New Zealand

Phyu Mon Latt, Sandar Tin Tin, Mark Elwood, Ross Lawrenson and Ian Campbell

Purpose
To investigate the receipt of postmastectomy radiotherapy (PMRT) in breast cancer patients in New Zealand for whom radiotherapy is strongly recommended in current clinical guidelines.

Method
This study involved all women who were diagnosed with primary invasive breast cancer in two health regions, had undergone a mastectomy, and met the ‘strong recommendation’ criteria for PMRT based on New Zealand National Guidelines. We performed logistic regression analyses to identify demographic and clinical factors associated with the receipt of PMRT.

Results
Of the 1,455 patients with stage II to III cancers included in this analysis, 1195 (82%) received radiotherapy. The receipt of PMRT decreased with increasing age, and was significantly lower in rural residents, Māori and Pacific women, those with more comorbidity, those who receive primary cancer care in the a public facility, and those diagnosed with stage III cancer. Although not significant, the receipt was also lower in patients who resided in more deprived neighborhood, and those with comorbidities. The findings restricted to stage III patients (n = 1325), and to those diagnosed since 2010 (n = 422), after the current guidelines were published, which were very similar to the whole cohort.

Conclusion
Disparities exist in the receipt of PMRT in breast cancer patients in New Zealand, underscoring the need for a greater equity focus in management of breast cancer.

 

International Breast Cancer Study Group (IBCSG) Study 23

Purpose

To answer the question of appropriate management for women who have micrometastases (very tiny/microscopic deposits (< 2mm) of cancer spread) found in the sentinel nodes. This research aims to answer the question of whether these women require axillary clearance or is it safe to manage these women without further surgery?

Scientific Title

IBCSG 23-01: A randomised trial of axillary dissection versus no axillary dissection for patients with clinically node negative breast cancer and micrometastases (< 2mm) in the sentinel node.

Background

Breast surgical oncologists have rapidly and successfully transitioned from the routine use of axillary lymph node dissection (ALND) to sentinel lymph node (SLN) biopsy for staging the axilla in clinically node negative patients. This approach limits the use of ALND to those patients with pathologically-proven axillary lymph node metastases and has prompted great current interest in whether or not all SLN-positive patients benefit from a completion ALND. Analysis of population-based data shows a decades-long trend towards omitting ALND in patients with low volume axillary disease.  For selected patients, mainly those with small, estrogen receptor-positive tumors with low nodal disease burden undergoing breast conservation with radiation and adjuvant systemic therapy, ALND might be avoided safely.

Results

The findings of the IBCSG 23-01 trial after a median follow-up of 9·7 years support the practice of not doing an axillary dissection when the tumour burden in the sentinel nodes is minimal or moderate in patients with early breast cancer. The results showed no difference in disease-free survival between no ALND and ALND.

Publications

Axillary dissection versus no axillary dissection in patients with sentinel-node micrometastases (IBCSG 23-01): a phase 3 randomised controlled trial

Galimberti V, Cole BF, Viale G, Veronesi P, Vicini E, Intra M, Mazzarol G, Massarut S, Zgajnar J, Taffurelli M, Littlejohn D, Knauer M, Tondini C, Di Leo A, Colleoni M, Regan MM, Coates AS, Gelber RD, Goldhirsch A; International Breast Cancer Study Group Trial 23-01 investigators. Lancet Oncology; 19 October 2018; 10: 1385-1393.

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