Short title “ROLLIS Trial”. Can the use of low dose radioactive seeds to guide surgical removal of small areas of abnormal breast tissue reduce the rate of second operation compared with standard hook-wire technique? (ROLLIS RCT: Radio-guided Occult Lesion Localisation using Iodine125 Seeds).
Background
The number of non-palpable breast cancers requiring pre-operative image-guided localisation continues to increase due to breast screening and the use of pre-operative chemotherapy. Hook wire localisation (HWL) has been standard of care since the 1970s, but is associated with a high positive margin (20-40%) and re-excision (30-50%) rates. Other disadvantages of HWL include technical difficulties (e.g. wire transection and migration), inefficient use of radiology bookings, and impact on theatre time.
The new method trialed in Australian and New Zealand (Waikato only) is called “ROLLIS”, which stands for Radioguided Occult Lesion Localisation using low activity Iodine 125 Seeds. Instead of using a hook-wire to localise the abnormality, the radiologist inserts a very low dose of radioactive Iodine-125 (I-125) seed into the abnormal area. During the surgery, a handheld detecting “probe” is used by the surgeon to detect the radioactive signal produced by the seed. The seed and the abnormal area is then removed. Other international clinical trials suggest that the ROLLIS method offers benefits to patients that include being able to mark the abnormality as an outpatient procedure up to eight days before surgery. It can also make the surgery easier and faster to perform with a better chance of removing all the abnormality in one operation.
Results
There were 659 women from Australia and New Zealand who took part in this clinical trial. Results showed that re-excision rates after breast conserving surgery were significantly lower after radioactive seed localisation (ROLLIS) compared with hookwire localisation. Patients reported lower levels of anxiety and pain with the ROLLIS compared with the hookwire. The ROLLIS can be carried out up to eight days before surgery, whereas the hookwire can only be inserted on the day of surgery (as the wire protrudes from the breast). The ROLLIS enables flexibility of scheduling of localisation prior to breast conserving surgery.
Both radiologists and surgeons found the low dose radioactive seed easier to use than the hookwire. Some surgeons reported that localising the breast cancer using the seed was faster.
This research based at Waikato Hospital was led by Breast Radiologist Dr Rebecca Hughes and was a massive effort from teams of staff from the Breast Care Centre, Nuclear Medicine, Medical Physics, Theatre and Pathology Departments. The results confirm the ROLLIS technique improves care for women undergoing breast conserving surgery for small breast cancers.
Quality of life and breast reconstruction study
Scientific Title
A prospective Quality of Life study of Immediate & Delayed breast reconstruction in women undergoing mastectomy and adjuvant radiotherapy for breast cancer (Short title “QoLID study”).
Background
Radiotherapy has a detrimental effect on outcomes from breast reconstruction for some women, especially for women undergoing implant based reconstruction. For this reason, some surgeons recommend delaying radiotherapy until after other breast cancer therapy is complete. This is a controversial issue with little good evidence to support the best approach.
Women’s perceptions of the impact of breast reconstruction outcomes and impact on their quality of life are particularly relevant. This study aimed to provide a direct comparison to assess the quality of life impact of immediate reconstruction, delayed reconstruction and no reconstruction in women undergoing mastectomy and post mastectomy radiotherapy for breast cancer by using a comprehensive set of patient reported outcome measures.
Summary of Results
Findings suggest women recover from the negative impact of mastectomy on body image within four years of surgery, whether they have immediate, delayed or no reconstruction.
Empowering women through an educated and informed choice on breast reconstruction, or not, is an important contributing factor for their long-term quality of life.
Empowering women with the choice of breast reconstruction options is an important factor in restoring body image in women undergoing mastectomy, regardless of the breast reconstruction option they choose, or whether no reconstruction is chosen.
It is therefore important for women to make the most appropriate decision for them.
Anastrozole for breast cancer prevention – taking anastrozole for reducing breast cancer risk in women at high risk for breast cancer (International Breast cancer Intervention Study Part 2 or “IBIS II”)
Scientific Title
ANZ02P2: An international multi-center study of anastrozole versus placebo in postmenopausal women at increased risk of breast cancer.
Background
Worldwide breast cancer is the commonest form of cancer in women with an estimated more than 1,400,000 cases and 370,000 deaths annually. Breast cancer is responsible for about 20% of the deaths from cancer in women in developed countries. Early detection and wider use of chemotherapy and hormone therapy have led to a reduction in breast cancer mortality. A further improvement might be gained from yet more effective use of adjuvant therapies. Early detection through the national breast cancer screening programme can also lead to similar reductions in mortality. However, neither of these approaches will affect cancer incidence. It is clear that with currently available treatments, the prospects for making a major impact on the breast cancer treatment side effects and mortality from breast cancer lie more in the area of prevention. The IBIS-II continues the work started in IBIS-I (Tamoxifen prevention trial) in determining whether a medical prevention option towards breast cancer is beneficial.
Sub Studies
IBIS II mammographic breast density sub-study
As part of the main IBIS II prevention protocol, breast density as a marker of increased risk for breast cancer was investigated.
IBIS II bone sub-study
Background
Aromatase inhibitors prevent breast cancer in postmenopausal women at high risk of the disease but are associated with accelerated bone loss. The IBIS II bone sub-study assesses the effectiveness of oral drug risedronate for prevention of reduction in bone mineral density after three years of follow-up in a subset of patients in the IBIS-II trial.
IBIS II DCIS
Purpose
To evaluate the treatment with the drug anastrozole compared to tamoxifen for women with hormonally sensitive ductal carcinoma in situ (DCIS).
Background
Ductal carcinoma in situ (DCIS) was once a rare diagnosis, but it has become increasingly common following the advent of mammographic breast screening. DCIS is a very early stage of breast cancer. It is also known as non-invasive breast cancer, as the cancer cells are present only in the ducts of the breast and have not spread to other breast tissue or to other parts of the body.
The appropriate treatment for this disease has now become an increasingly important issue. It is generally agreed that adequate local treatment comprises either mastectomy or local excision with clear margins (with or without radiotherapy).
The IBIS II DCIS study investigated whether anastrozole is as effective, or better than, tamoxifen in preventing the development of breast cancer in the same breast as the DCIS or in the opposite breast, in postmenopausal women who have been diagnosed with DCIS. The study will also compare the effects (good and bad) of tamoxifen and anastrozole.
Results of the IBIS II suite of trials and sub-studies
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 2021, 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.
The learnings from IBIS-II have been presented at multiple major international conferences and published in well-respected high impact medical journals.
IBIS II Decision Aid Sub-Study
Purpose
To evaluate the usefulness of using a decision aid booklet developed to assist women who were considering joining IBIS II anastrozole prevention trial. This research looked into how we can improve informed consent/communication of treatment options.
Background
Decision aids may improve informed consent in clinical trial recruitment, but have not been evaluated in this context. This study investigated whether a decision aid can reduce difficulties around decision making among women considering participation in the International Breast Cancer Intervention Study-II (IBIS-II) trial.
Result Publication
Improving decision making about clinical trial participation – a randomised controlled trial of a decision aid for women considering participation in the IBIS-II breast cancer prevention trial. Juraskova I, Butow P, Bonner C, Bell M, Smith B, Seccombe M, Boyle F, Reaby L, Cuzick J, Forbes J. British Journal of Cancer; 1 July 2014; 111(1); 1-7.
Phase 4 – An international field study of the reliability and validity of an EORTC breast reconstruction questionnaire to assess quality of life in all types of breast reconstruction.
Background
Breast reconstruction has shown important consequences on psychological well-being, quality of life, and the ability to cope with the negative emotional and psychological impact that is associated with a mastectomy. In association with the Quality of Life Group of the European Organisation for Research into Treatment of Cancer (EORTC), Waikato surgeons assisted with the development of a questionnaire to be used in the future to evaluate the quality of life of women undergoing different types and timings of breast reconstruction. This research was coordinated through the University of Bristol, England, and enrolled 360 women from around the world.
Results
This study confirmed the European Organisation for Research and Treatment of Cancer (EORTC) questionnaire as valid for evaluating quality of life and satisfaction after breast reconstruction.
Study drug (GDC-0941) with Fulvestrant versus Fulvestrant alone in advanced or metastatic breast cancer (short title “FERGI" trial)
Scientific Title
A Phase 2, double-blind, placebo-controlled, randomsed study of GDC-0941 or GDC-0980 with fulvestrant versus fulvestrant in advanced or metastatic breast cancer in patients resistant to aromatase inhibitor therapy.
Results
Addition of pictilisib to fulvestrant did not significantly improve progression-free survival in this trial. Dosing of pictilisib was limited by toxicity, potentially limiting its efficacy. For future assessment of PI3K inhibition as an approach to overcome resistance to hormonal therapy, inhibitors with greater selectivity than that of pictilisib might be needed to improve tolerability and potentially increase efficacy.
Note one patient at our Waikato centre tolerated pictilisib well and went into remission for six years whilst taking P13 kinase inhibitor treatment. Clinical trials of other P13 kinase inhibitor treatments in metastatic breast cancer are ongoing.
Study of Letrozole Extension (SOLE) trial
Scientific Title
IBCSG 35-07/BIG 1-07. A phase III trial evaluating the role of continuous letrozole versus intermittent letrozole following 4 to 6 years of prior adjuvant endocrine therapy for postmenopausal women with hormone-receptor-positive, node-positive early-stage breast cancer
Background
Previous research has indicated that breast cancers may be more sensitive to intermittent treatment with letrozole.
Results
SOLE trial results showed that letrozole taken for 9 out of every 12 months, is as good as continuous letrozole in the extended treatment of early-stage breast cancer. No new side effects were noted, beyond what is already known about letrozole. Importantly, women who took intermittent letrozole reported that their quality of life was better, compared with those who took continuous letrozole. This may be because they were able to have time off letrozole, and the side effects were less during that break.
Now, because of this trial, women who have a sufficiently high chance of breast cancer recurrence to require 10 years of hormone-blocking therapy can safely have a break from that treatment for 3 months every year. This strategy may be particularly worthwhile for women who are experiencing troublesome side effects but want to remain on the medication to minimise their chance of breast cancer recurrence.
ANZ 0501 LATER TRIAL (Later Adjuvant aromatase inhibitor Therapy for postmenopausal women with Endocrine Responsive breast cancer)
Background
The standard length of time that hormonal or endocrine treatment is taken (daily) is five years. However, after reaching the end of their treatment there is still an ongoing risk for a woman of developing another breast cancer, or her original breast cancer returning in another part of her body. We know that 50% of recurrences occur after the first five years. Long term management of early breast cancer after completion of five years of hormonal treatment, has until recently, been confined to annual checks and mammography.
Research has also shown that extending hormone or endocrine treatment with an aromatase inhibitor, after five years of tamoxifen, improves breast cancer outcomes. It is not certain if this is the case after five years of treatment including an aromatase inhibitor.
Results
The results of the LATER trial should be considered exploratory, but lend weight to data from other trials supporting longer duration endocrine therapy for hormone receptor-positive breast cancer, and offer insight into the reintroduction of AI therapy.
SNAC2 Decision Aid Study
Scientific Title
Improving informed consent: The development and pilot of a decision aid for women invited to participate in the Sentinel Node biopsy versus Axillary Clearance Part 2 (SNAC 2) trial.
Background
As clinical trials are increasing in complexity, trial consent documents have become longer and more difficult to understand. Limited doctor-patient communication and patient understanding of the clinical trial rationale and procedure may not only compromise patient recruitment but also the process of informed consent. Decision aids (DAs) can potentially address this issue by improving patient understanding in the clinical trial setting.
Results
The development and two-stage piloting process for this decision aid resulted in a resource that women found very acceptable and helpful in assisting decision-making about SNAC-2 trial participation. The process and findings provide a guide for developing other trial decision aids.
The Cognitive Function Sub-study to the Suppression of Ovarian Function Trial (SOFT)
Background
It is known that oestrogen has an important role in brain function and so it is possible that these hormone treatments might affect cognitive function, however very few studies have been completed to investigate this. It is important to clarify any effect of hormonal treatments on cognitive function in younger women so that in the future women with breast cancer will have better information on which to base their treatment choices.
Results
The Co-SOFT study provides no evidence that adding ovarian function suppression to oral endocrine (hormonal) therapy substantially affects overall cognitive function.
Femara versus Anastrozole Clinical Evaluation (FACE) trial
Scientific Title
A randomised multi-centre phase IIIb, open-label study of Letrozole versus Anastrozole in the adjuvant treatment of postmenopausal women with hormone receptor and node-positive breast cancer (Study No. CFEM345D2411)
Background
Almost 80% of all breast cancers are hormone receptor-positive. Both letrozole and anastrozole are selective aromatase inhibitors (drugs that interfere with the making of oestrogens, one of the natural female hormones). They have been widely used in post-menopausal patients with advanced hormone-sensitive cancer and will control disease in a proportion of patients. They have also been used in post-menopausal women with early hormone-sensitive breast cancer and are more effective than tamoxifen in preventing recurrence after surgery. This trial assesses head to head the relative effectiveness of these two aromatase inhibitors and also to evaluate their benefit in higher-risk patients with node-positive disease (spread of cancer to the armpit lymph nodes).
Results
Letrozole did not demonstrate significantly superior efficacy or safety compared with anastrozole in this clinical trial involving more than 4,000 patients worldwide.
Sub-study Biomarker sub-study to the FACE trial
This exploratory research investigated how genes and proteins influence the different responses people have to the drugs anastrozole and letrozole.
International breast cancer study group (IBCSG) study 23
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 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.
A cross-sectional study to evaluate the local incidence of lymphoedema and sensory changes following surgery for breast cancer
Background
A serious side effect of axillary node dissection surgery is lymphoedema (arm swelling). Lymphoedema is a build-up of lymphatic fluid in the arm caused by damage to arm lymphatic drainage when axillary lymph nodes are removed. With moderate or severe lymphoedema, the affected arm can be painful, tired and heavy.
There are several different measurement techniques in use, and consensus on the definition of lymphoedema, particularly with arm circumference measures, is poor. The incidence of lymphoedema is also changing over time as surgery and treatment techniques change. Due to these two factors the reported incidence ranges from 2–56%.1 This wide variation makes it difficult to compare studies and to know how a particular cancer center measures up to the published literature. It is important for both patients and surgeons to know the local risk for developing lymphoedema after axillary node dissection. There is only one study to date in New Zealand to report local incidence of lymphoedema and it was a retrospective study based on postal questionnaires.
Results
193 Waikato women who had undergone axillary node dissection were analyzed. The average age was 61 years and the average time since surgery was 56 months. The overall incidence of lymphoedema was 23.3%. Circumference measures are a simple office method of screening for lymphoedema. A patient history and ≥10% increase in any circumference are optimal for determining lymphoedema after axillary node dissection. Significant risk factors for lymphoedema were age, radiotherapy, and infection to the operated arm.
To Infiltrate or Not? Local Anaesthetic in Breast Surgery
Background
Wound infiltration is commonly used as standard practice during surgical procedures; however there is limited evidence to support its use in breast surgery. The objective of this Waikato study was to determine evidence for wound infiltration with local anaesthetic (Marcain) in breast surgery.
Results
There were no significant differences in postoperative pain scores or complications. Overall pain scores were low, suggesting effective analgesic use given by nursing staff. Local anaesthetic infiltration during breast surgery has a marked opioid sparing effect, which has significant benefits for patients as well as reducing nursing workload and drug costs.
Communication about clinical trials and treatment options: A randomised controlled trial of a consultation skills training package
Background
Patients and clinicians commonly report difficulties with the process of informed consent and audio-tape audits have shown that critical information is often omitted or poorly presented. It is expected that a communication training programme will alter doctor behaviours during consultations, and impact on patient and doctor outcomes by improving patient’s quality of life, increasing patient understanding and satisfaction with decision-making. Participating doctors were randomised to receive training or not. This study was coordinated through the Medical Psychology Unit at Sydney University.
Results
Training can improve the process of gaining informed consent and should be made available to cancer doctors.
The use of zoledronic acid for the prevention of bone loss in women receiving letrozole (short title “Zometa trial”)
Scientific Title
An Open-Label, Randomized, Multicenter Study to Evaluate the Use of Zoledronic Acid in the Prevention of Cancer Treatment-Related Bone Loss in Postmenopausal Women with ER+ and/or PgR+ Breast Cancer Receiving Letrozole as Adjuvant Therapy.
Background
Bone health is important for women who are diagnosed with breast cancer as all women (particularly postmenopausal women) are at some risk of osteoporosis (loss of bone strength or density). Hormonal or endocrine treatments (called aromatase inhibitors) may reduce the density of bone and increase fracture risk in women receiving these drugs.
Results
Adding a drug to protect the bone (called a bisphosphonate), improves bone density, and reduces the risk of fracture in women with breast cancer. An unexpected finding was that Zoledronate (given six-monthly during letrozole treatment), also reduces the risk of breast cancer recurring. A large amount of research continues to be done looking at the anti-cancer effect of bisphosphonate drugs.
Sentinel node biopsy versus axillary clearance part 1 (SNAC 1)
Scientific Title
Sentinel node biopsy versus axillary clearance in operable breast cancer. The RACS SNAC Trial. A multicentre randomised trial of the Royal Australasian College of Surgeons Section of Breast Surgery in collaboration with the NHMRC Clinical Trials Centre.
Background
The status of the axillary or armpit lymph nodes remains the most important indicator of outcome for women with breast cancer and helps predict the need for further treatment (e.g. chemotherapy or radiotherapy). Traditionally, axillary node status has been determined by removal of most of the nodes (axillary clearance or dissection). This operation may lead to arm swelling (lymphoedema), pain, some abnormal skin sensation, or shoulder stiffness.
Results
This study has established that for women with small unifocal (single) breast cancers the surgical removal of the “sentinel” nodes (i.e. the first lymph node/s draining from the region of the breast cancer) provides accurate information as to whether axillary nodes are involved with cancer or not. SNAC1 has shown significantly reduced side effects with removal of sentinel nodes compared with axillary dissection. This trial has also shown a small, but increased risk of local recurrence in the axilla with sentinel node based management. This is not big enough to influence decision making for women with smaller breast cancers but is of greater importance in the discussion for women with larger and bad biology cancers.
In 2023 the ten-year follow-up results of the 1080 ANZ women participating in the SNAC1 trial were published. These results confirmed that axillary recurrence is low in women meeting the SNAC1 eligibility criteria; including mainly good outlook biology and unifocal cancers; but was more frequent with sentinel node based management (1.85%) compared to those women who underwent axillary clearance (0.37%).
The ten-year results confirmed that sentinel node based management should remain the treatment of choice in this lower risk group of women and is now the international standard of care in the surgical treatment of early breast cancer. However, for those with higher risk breast cancers, further study is needed because the frequency of axillary recurrence might alter the choice of axillary surgery for these women.
BIG 1-98/IBCSG18-98: Adjuvant Letrozole trial. A phase III study to evaluate Letrozole as adjuvant endocrine therapy for postmenopausal women with receptor (ER and/or PgR) positive tumours.
Background
Previously we did not know whether it would be better to start with anti-oestrogen treatments called Letrozole (an aromatase inhibitors or “AI” for short) soon after diagnosis and continue for five years, or if giving both drugs in a sequence (of letrozole followed by tamoxifen or tamoxifen followed by letrozole) would show superior results. Further results from the Breast International Group (BIG) trial, coordinated in Australia and New Zealand through the ANZ Breast Cancer Trials Group (ANZBCTG) show that it seems to be the most promising strategy to start treatment with letrozole and continue for five years, but if necessary patients, who have particular side effects on letrozole, can switch to tamoxifen after two years without loss of effectiveness.
Results
Letrozole alone is more effective than tamoxifen alone. In terms of what is the best sequence (of letrozole followed by tamoxifen or tamoxifen followed by letrozole), results showed it appears to be better to start treatment with letrozole and continue for five years, but if necessary patients can switch to tamoxifen after two years without loss of effectiveness.
Beyond 10 years results continued to show trends favouring letrozole. Letrozole reduced contralateral breast cancer frequency in the first 10 years, but this wasn’t shown beyond 10 years.
BIG Trial 1-98/ IBCSG18-98 Fingernail Pilot Sub study Investigating chemical properties of fingernails to determine the efficacy of nail structure for evaluating bone fragility.
Purpose
This pilot research is a sub-study to one of the existing drug trials called the BIG 1-98 Letrozole trial (above). Research investigating the fingernail as a predictor of bone density. A team of researchers at the University of Limerick in Ireland investigated whether or not the composition of the fingernail can be a predictor of bone density.
Background
The relationship between nail and bone may be measurable, thus making the fingernail a potentially valuable tool for assessing bone health for women receiving treatment for breast cancer.
Results
The relationship between nail and bone may be measurable, thus making the fingernail a potentially valuable tool for assessing bone health for women receiving treatment for breast cancer. This small exploratory study showed effects in the chemical structure in the fingernail in women on endocrine therapy and are an incentive for larger studies looking at the usefulness of fingernail analysis.
IBCSG 21-99/NCCTG N9431: Menstrual Cycle and surgical treatment of breast cancer.
Background
Controversy regarding a possible link between menstrual cycle phase (follicular or luteal) at the time of surgery for breast cancer, and breast cancer outcome existed over the 1980s-1990s. A majority of past information on the menstrual phase had been obtained from research looking back at charted documentation of a woman’s last menstrual period. This approach lacked the accuracy of the date of the last menstrual cycle.
Results
This large international collaborative study where menstrual phase was determined by the measuring of hormonal levels in blood samples taken within one day of surgery has finally put this issue to rest. Results showed there is no relationship between breast cancer recurrence or overall survival and timing of surgery on the basis of the menstrual cycle phase for premenopausal (still having periods) women with early-stage breast cancer.
Arimidex (anastrozole), Tamoxifen alone or in Combination (ATAC) trial
Background
The dependence of many breast cancers on oestrogens for their continued growth has long been recognised and many current therapies involve hormonal treatment. Hormonal therapy can achieve this goal, either by reducing circulating concentrations of the female hormone oestrogen, or by blocking the effects of oestrogens on a breast tumour. At the time of commencement of the ATAC trial tamoxifen was currently the drug of choice as hormonal/endocrine therapy for breast cancer. Aromatase inhibitors, a class of drugs that prevented oestrogen production in tissues had shown benefit in trials for advanced breast cancer. Anastrozole, an aromatase inhibitor, was shown to be well tolerated and effective in treating advanced breast cancer and was thought to be more effective than tamoxifen. Alternatively, it was thought to be synergistic with tamoxifen. The ATAC trial was an international trial that introduced anastrozole to early breast cancer treatment in the early 2000s. It is still prescribed for many women.
Results
Trial information confirms the long-term superior efficacy and safety of anastrozole over tamoxifen as initial adjuvant therapy for postmenopausal women with hormone-sensitive early breast cancer.
ATAC quality of life sub-study
The Quality of Life sub-study showed that anastrozole was associated with a lower risk of endometrial (womb lining) abnormalities than tamoxifen resulting in significantly fewer gynaecological investigations and operations. There was also a lower incidence of blood clotting events with anastrozole compared with tamoxifen after five years of treatment. Menopausal side effects such as hot flushes were similar as was the quality of life for women receiving anastrozole or tamoxifen.
BIG 2-97/IBCSG 16-98: Intergroup Exemestane Study. A randomised double-blind trial in postmenopausal women with primary breast cancer who have received adjuvant tamoxifen for 2-3 years, comparing subsequent adjuvant exemestane treatment with further tamoxifen.
Background
Tamoxifen, taken for five years, at the time of this trial, was the standard hormonal treatment for postmenopausal women with primary, oestrogen receptor-positive breast cancer. Despite this treatment, however, some patients relapse.
Results
This research showed that switching from tamoxifen after two to three years of treatment to exemestane, significantly reduced breast cancer recurrence. Exemestane also showed a modest but significant reduction in the risk of death for women who switched to treatment with exemestane. This was the first adjuvant aromatase inhibitor trial to show a survival benefit.
Tamoxifen for breast cancer prevention
Scientific Title
ANZ 92P1: International Breast cancer Intervention Study (IBIS)-I
Background
The belief that oestrogen is the primary promotional factor for breast cancer has a long history and is now well established. Early trials of the drug tamoxifen when used to treat early breast cancer showed a striking reduction (50%) of new tumours in the opposite breast. With its apparently low side effect profile, it was proposed that tamoxifen prevention might be a suitable approach to reducing breast cancer in high-risk women.
Results
The results of the IBIS-I study found that tamoxifen can prevent breast cancer in healthy women at increased risk, with 32% fewer breast cancers diagnosed in IBIS-I women who took tamoxifen. Additional long-term follow up showed that the preventative effect of tamoxifen continued for at least 20 years, so it continued for at least 15 years after completion of the 5 years of tamoxifen therapy.
IBIS Quality of life sub-study
729 IBIS-1 participants randomised to tamoxifen or placebo completed health-related quality of life and global health status questionnaires at baseline, year 1, year 3, and year 5 on the study. Conclusions from this study showed that tamoxifen does worsen vasomotor (e.g. hot flushes) and gynecological symptoms in an extra 10-12% of women over placebo. These effects do not appear to adversely affect overall health status, so they are unlikely to outweigh the benefits of reducing breast cancer incidence.
IBCSG 17-98/BIG 3-97 HABITS – A randomised clinical trial concerning hormonal replacement therapy (HRT) after previous radical breast cancer treatment. Short title: Hormone replacement therapy After Breast cancer is IT Safe?
Background
There are now more breast cancer survivors with menopausal symptoms due to increased incidence of breast cancer and improved survival times after treatment. Second, many cancer treatments (e.g. chemotherapy) cause early menopause and symptoms that are difficult to manage by non-hormonal means.
Hormone replacement therapy (HT) is known to increase the risk of breast cancer in healthy women, but its effect on breast cancer risk in breast cancer survivors is less clear. It is possible that the mechanism whereby hormone replacement therapy (HRT) induces and promotes tumor growth in healthy women may be different from its ability to promote the growth of micro-deposits of tumor cells in breast cancer survivors. Prior observational studies and analyses of clinical case series whose results seemed reassuring in general in that they found no increased risk of breast cancer recurrence following HRT.
Results
The HABITS trial was stopped early due to suspicions of an increased risk of new breast cancer events following HRT. These results raise a challenge for researchers of finding non hormonal relief for bothersome menopausal symptoms in breast cancer survivors.
Arimidex (anastrozole), Tamoxifen alone or in Combination (ATAC) trial.
Background
The dependence of many breast cancers on oestrogens for their continued growth has long been recognised and many current therapies involve hormonal treatment. Hormonal therapy can achieve this goal, either by reducing circulating concentrations of the female hormone oestrogen, or by blocking the effects of oestrogens on a breast tumour. At the time of commencement of the ATAC trial tamoxifen was currently the drug of choice as hormonal/endocrine therapy for breast cancer. Aromatase inhibitors, a class of drugs that prevented oestrogen production in tissues had shown benefit in trials for advanced breast cancer. Anastrozole, an aromatase inhibitor, was shown to be well tolerated and effective in treating advanced breast cancer and was thought to be more effective than tamoxifen. Alternatively, it was thought to be synergistic with tamoxifen. The ATAC trial was an international trial that introduced anastrozole to early breast cancer treatment in the early 2000s. It is still prescribed for many women.
Results
Trial information confirms the long-term superior efficacy and safety of anastrozole over tamoxifen as initial adjuvant therapy for postmenopausal women with hormone-sensitive early breast cancer.
ATAC quality of life sub-study
The Quality of Life sub-study showed that anastrozole was associated with a lower risk of endometrial (womb lining) abnormalities than tamoxifen resulting in significantly fewer gynaecological investigations and operations. There was also a lower incidence of blood clotting events with anastrozole compared with tamoxifen after five years of treatment. Menopausal side effects such as hot flushes were similar as was the quality of life for women receiving anastrozole or tamoxifen.
Pilot sentinel node biopsy study
Scientific Title
Pilot study comparing the accuracy of lymphoscintigraphy sentinel lymph node localisation with axillary node dissection in women with operable breast cancer.
This was a local Waikato pilot study carried out by Dr Berry Allen (Nuclear Medicine Scientist, Waikato Hospital) for his PhD thesis. Dr Allen also investigated the best radiotracer to use to identify sentinel nodes.
Results
A high proportion of sentinel nodes were demonstrated by lymphoscintigraphy and were subsequently removed surgically. In this small series sentinel lymph node status correctly predicted axillary node status in 100% of patients for whom sentinel nodes were retrieved supporting the concept of sentinel node biopsy only for women with normal sentinel lymph nodes. Evidence from randomised trials that sentinel node based management does not compromise regional control of breast cancer or survival, is awaited.
Australia New Zealand Breast Cancer Trials Group Study No. 9002. The Management of Screen Detected Ductal Carcinoma Insitu (DCIS) of the breast.
Background
Ductal carcinoma in situ (DCIS) is usually an asymptomatic disorder that is confined within the milk ducts of the breast. Breast cancer screening has led to a substantial increase in the diagnosis of DCIS over the past three decades. This study investigated the role of radiotherapy and hormonal therapy in the treatment of DCIS.
Results
Radiotherapy should be considered for all women with complete excision of localised DCIS. Whether women with smaller lower grade lesions can avoid radiotherapy has not been adequately addressed in this research. The role of endocrine treatments (tamoxifen or anastrozole) remains uncertain and a further study, the International Breast cancer Intervention (IBIS) II is investigating this.
IBCSG 10-93 Surgical therapy with or without axillary node clearance for breast cancer in older patients who receive adjuvant therapy with tamoxifen.
Background
The incidence of breast cancer increases with age and breast cancer is the most common cancer in women older than 70 years old. Given that populations are aging, increasing numbers of breast cancer occurrences can be expected among older women. The development of medical conditions also increases with age. Because some medical conditions may limit the duration and extent of a surgical procedure, there is a potential advantage to avoiding axillary surgery if it does not compromise tumor control. Avoiding axillary surgery may also reduce postoperative effects on arm pain, mobility, and lymphoedema.
Results
Avoiding axillary clearance for women 60 years or older (median age 74 years in both treatment groups); who have clinically node-negative disease and who receive tamoxifen; results in similar efficacy with better early quality of life.
TAILORx Trial
Trial Assigning Individualised Options for Treatment
Results
Many women who are diagnosed with hormone-receptor positive breast cancer are adequately treated with hormone therapy alone and may not need the addition of chemotherapy. The decision to include chemotherapy as part of a patient’s treatment is largely based on the characteristics of the tumour’s pathology and size. However, there is currently no effective way to determine which women could safely avoid chemotherapy and avoid the side effects associated with this treatment. Throughout history, clinical trials have led to major improvements in patient care.
The TAILORx clinical trial used a genetic test called Oncotype DX® to search for the presence of 21 specific breast cancer related genes in breast cancer tissue and produce a score between 0 and 100, known as the Recurrence Score®, that predicts the risk of breast cancer returning. Research has previously shown that the higher the Recurrence Score, the greater the chance that breast cancer will return. In TAILORx, treatment was assigned based on the Recurrence Score:
Women with a Recurrence Score of 10 or less were treated with hormone therapy alone;
Women with a Recurrence Score of greater than 25 received hormone therapy plus chemotherapy;
Women with a mid-range Recurrence Score from 11-25 were randomised to receive hormone therapy with chemotherapy, or hormonal therapy alone.
What has been learned from this clinical trial?
The TAILORx results were published in 2018* showed that the 69% of women with an intermediate score could safely avoid having chemotherapy. These patients only needed hormone treatment. This study has changed practice around the world, allowing many patients to be spared the short and long-term side effects of chemotherapy. Further information is available at https://www.breastcancertrials.org.au/the-tailorx-breast-cancer-clinical-trial/
Publication:
* Sparano JA, Gray RJ, Makower DF, et al. Adjuvant chemotherapy guided by a 21-gene expression assay in breast cancer. New England Journal of Medicine. 2018; 379 (2) 111-121 (epub 3 June 2018) DOI: 10.1056/NEJMoa1804710.
The ANZ 0901/PACCT-1 TAILORx clinical trial was conducted in Australia and New Zealand by Breast Cancer Trials (formerly the Australia & New Zealand Breast Cancer Trials Group (ANZBCTG)) based in Newcastle, NSW, Australia. www.breastcancertrials.org.au.
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