Results of the IBIS II suite of trials

The IBIS-II suite of trials was unified in the goal of preventing breast cancer in women who were at higher than average risk of developing breast cancer due to family history and/or previous breast abnormalities. These trials were: – IBIS-II prevention: a randomised comparison of anastrozole to placebo in women without a history of breast cancer or ductal carcinoma in situ (DCIS); – IBIS-II DCIS: a randomised comparison of anastrozole to tamoxifen in women with a history of treated DCIS; – IBIS-II bone substudy: a randomised comparison of risedronate to placebo to examine the impact on bone density.

Internationally, 3864 women participated in the prevention trial (818 in Australia and New Zealand[ANZ]), 2980 in DCIS (178 ANZ), and 1410 in the bone substudy (229 ANZ). This trial opened in ANZ in 2005, and during the subsequent 16 years until now, an enormous amount has been learnt. Here only the main findings will be summarised:

  • Anastrozole, taken for 5 years, reduces the chance of developing breast cancer by 54% and DCIS by 59%, and continues to reduce the chance of these events for at least 5 years after completing anastrozole treatment.
  • In women who have had treatment for DCIS, anastrozole and tamoxifen were both similarly effective in preventing recurrence of DCIS, or occurrence of invasive breast cancer. There was also an ongoing protective effect after stopping. Side effects were different between the two treatments and may influence treatment choice.
  • In women taking anastrozole, who are at risk of low bone density, risedronate reduced the chance of anastrozole-related loss of bone density in the spine, but not in the hip. After stopping anastrozole and risedronate, bone density improved in the lumbar spine and stabilised in the hip in patients allocated to receive risedronate.

The main side effects seen with anastrozole were similar to those seen in other clinical trials and in routine practice: menopausal symptoms, arthritis/stiffness, and fractures. In the DCIS group, tamoxifen was associated with menopausal symptoms, deep vein thrombosis (uncommon), muscle spasm, and gynaecological changes. Overall, the treatments were well tolerated.

As a result of this trial, women at higher than average risk of developing breast cancer now have an additional effective option to reduce their risk. Women with treated DCIS can consider the use of either anastrozole or tamoxifen to prevent future breast cancer or DCIS. Clinical practice has changed worldwide leading to benefits flowing on to patients in the clinic. Further analyses are expected from the data that has already been collected.

Conference presentations and main publications:

The learnings from IBIS-II have been presented at multiple major international conferences and published in well-respected high impact medical journals. A selection of important trial publication references are listed below: Use of anastrozole for breast cancer prevention (IBIS-II): long-term results of a randomised controlled trial. Cuzick J, Sestak I, Forbes JF, Dowsett M, Cawthorn S, Mansel RE, Loibl S, Bonanni B, Evans DG, Howell A, on behalf of the IBIS-II investigators. The Lancet. 2020; 395(10218):117-122, https://doi.org/10.1016/S0140- 6736(19)32955-1.

Comparison of risedronate versus placebo in preventing anastrozole-induced bone loss in women at high risk of developing breast cancer with osteopenia. Sestak I, Blake GM, Patel R, Colemen RE, Cuzick J, Eastell R. Bone. 2019; 124:83-88, https://doi.org/10.1016/j.bone.2019.04.016.

Anastrozole versus tamoxifen for the prevention of locoregional and contralateral breast cancer in postmenopausal women with locally excised ductal carcinoma in situ (IBIS-II DCIS): a double-blind, randomised controlled trial. Forbes JF, Sestak I, Howell A, Bonanni B, Bundred N, Levy C, von Minckwitz G, Eiermann W, Neven P, Stierer M, Holcombe C, Coleman RE, Jones L, Ellis I, Cuzick J, on behalf of the IBIS-II investigators. The Lancet. 2016; 387(10021):866-873, https://doi.org/10.1016/S0140-6736(15)01129-0

ABCpro study

A study evaluating a new online service for managing self-reported symptoms by people with advanced breast cancer (ABCpro study)

Purpose:

The oncology service at Waikato Hospital is partnering with Breast Cancer Foundation NZ to improve our service for patients with advanced breast cancer (ABC). ABC is also known as metastatic, stage 4 or incurable breast cancer.

This study is introducing a new service where patients complete weekly online surveys about common symptoms of ABC and side effects associated with ABC treatments. The survey responses are then sent to an ABC nurse who will use the responses to assist patients to better manage symptoms and side effects from home in between regular clinic visits. The survey responses will also help your oncology team to decide if you need further tests or treatments.

Scientific Title

Patient Reported Outcome Measures for Individualised Symptom Evaluation and Management in Advanced Breast Cancer: A pre-post cohort study. Short Title: ABCpro study

Background:

Each year, up to 400 women in New Zealand are diagnosed with advanced breast cancer (ABC) where breast cancer has spread to other parts of the body.

Management of symptoms in patients with ABC is mainly addressed at follow-up medical oncology appointments, or during medical oncology treatment visits. This approach to management of symptoms, results in many patients (particularly when on endocrine therapies) having long intervals without interaction with the health care system and their specialist oncology team. As a consequence, women endure chronic symptoms that they largely have to manage themselves, often with poor quality of life.

The aim of this study is to assess the impact and acceptability of a customised, electronic, nurse-initiated patient symptom management programme, integrated with clinical decision support, for reporting and managing of symptoms of patients with ABC. The effect on symptom management,  quality of life and unscheduled hospital care will be evaluated. The use of an electronic symptom management programme (ABCpro survey) combined with integrated clinical decision support  is unique and a novelty, that has not  been used in the oncology setting before. The transition to telehealth care in the COVID-19 era has encouraged the use of Patient Reported Outcome Measures (PROMs) in clinical practice.

Enrolment: Open

This is a Waikato Hospital pilot study currently. Ask your Oncologist if this trial is suitable for you.

PersevERA trial

A study to compare GDC-9545 plus palbociclib versus letrozole plus palbociclib in people with estrogen receptor-positive, HER2-negative metastatic breast cancer (PersevERA trial)

Purpose:

GDC-9545 (also known as giredestrant) is an investigational new drug designed to block the female sex hormone called estrogen that contributes to the growth and progression of estrogen receptor-positive breast cancer.  Investigational means that the drug has not been approved by health authorities for cancer treatment or treatment of any other disease.  Palbociclib (IBRANCEâ and letrozole the two other drugs being used in this study, are currently approved therapies in New Zealand for estrogen receptor-positive metastatic breast cancer).

The purpose of this study is to compare the effects, good or bad, of GDC-9545 given in combination with palbociclib versus letrozole given in combination with palbociclib, on patients with ER-positive, HER2-negative locally advanced or metastatic breast cancer.   We need to find out which combination works best for ER positive breast cancer that has spread to other parts of the body, find out more about side effects, and how treatments affect quality of life.

Scientific Title:

A Phase III randomized, double-blind, placebo-controlled, multicenter study evaluating the efficacy and safety of GDC-9545 combined with palbociclib compared with letrozole combined with palbociclib in patients with estrogen receptor-positive, HER2-negative locally advanced or metastatic breast cancer. Protocol BO41843

Background:

Women and men have the hormone estrogen in their body and estrogen can make some breast cancers grow. These are estrogen receptor (ER) positive breast cancers. Treatment for these cancers are either to block the hormone getting to the cancer cells, or to lower the amount of the hormone in the body. These treatments are called hormone therapy. Giredestant is a new hormone therapy drug. It blocks estrogen from getting to the breast cancer cells.

Letrozole is a hormone therapy for women who have gone through the menopause. It works by lowering the level of estrogen in the body. Palbociclib is a targeted drug called a cancer growth blocker. It works by blocking proteins that cancer cells use to grow and divide. Doctors use palbociclib for breast cancer that has spread to the surrounding tissue or to another part of the body. Researchers think that adding giredestrant to palbociclib might work better for people with ER positive breast cancer that has spread.

Enrolment: Open

Ask your Oncologist if this trial is suitable for you.

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.

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