Australian Associate Professor Guy Hingston confirms that MINDACT proves that less Australian women will now need chemotherapy for breast cancerAugust 30, 2016 - 04:14
Late last week, the investigators of the large international MINDACT (Microarray in Node Negative and 1-3 Positive Lymph Node Disease May Avoid Chemotherapy) Trial, published in the New England Journal of Medicine, proved that potentially 46% of women with clinically high risk oestrogen positive HER2 negative early breast cancer with up to three lymph nodes involved, may receive no benefit from chemotherapy if they return a low risk 70 gene signature (MammaPrint) genomic result.
According to Associate Professor Hingston, he believes that this is the best news in breast cancer management in 2016. “As of late last week, the world of breast cancer treatment has undergone another paradigm shift. We should now manage women with breast cancer differently, by incorporating the 70 gene MammaPrint signature testing in all women who are being considered for chemotherapy – if they have T1c or T2 oestrogen receptor positive HER2 negative disease with up to three nodes involved. We now have Level 1A data confirming the significant clinical utility of MammaPrint testing, and therefore we should all now routinely use this test on the approximately 4,000 Australian women who each year develop this type of breast cancer.”
He is not alone in this view. Dr Clifford Hudis, the current Chief Executive Officer of the American Society of Clinical Oncology (ASCO) has stated in an accompanying editorial in last week’s New England Journal of Medicine that “On the basis of the MINDACT study, clinicians may consider ordering the 70-gene signature for patients in line for chemotherapy who hope to forgo it on the basis of a possibly low genomic risk.”
Associate Professor Hingston is now calling on all medical oncologists to consider using MammaPrint due to the publication of the Level 1A data late last week confirming that the envisaged benefit of chemotherapy in a selected subgroup of Australian women with breast cancer may not actually be present. MammaPrint testing could potentially benefit around 2,000 Australian women each year, preventing them needlessly suffering the risks of chemotherapy – namely long term cardiotoxicity, secondary leukemia, impairment in cognitive function and neurotoxicity.
Further, he is renewing his call to the Australian Government Department of Health Medical Services Advisory Committee, asking that MammaPrint be funded in full by the Government. “MINDACT has now clearly shown that MammaPrint is both prognostic and predictive, and Australian women should join women from all over the world who are now benefitting from this new genomic microarray technology. Approximately 2,000 Australian women each year could benefit from MammaPrint testing, and they should not undergo the harms of chemotherapy if there is no significant benefit to this treatment, just because they can not afford this new test”. The price of MammaPrint has been stable at $USD4,200 for the last several years.
Associate Professor Hingston introduced fixed formalin paraffin embedded (FFPE) MammaPrint testing into Australia in late 2013, and he has personally seen the benefits of this genomic test on many of his own patients. A small part of the breast cancer (either one core of the preoperative core biopsy or a small piece of the surgically resected tumour) is sent overseas to the MammaPrint laboratory located in Los Angeles for testing. There is a 12 – 14 day turn around, and the result is returned as either low risk or high risk. Testing is ordered online by medical or surgical oncologists looking after women with a new diagnosis of early breast cancer.
The 70 gene signature MammaPrint microarray test was initially developed in Holland by Dr Laura Van’t Veer on a sample group of 100 women who had breast cancer. She first published her findings in Nature back in 2002. Since then, MammaPrint testing has been approved by the FDA, and has now been proven in many large retrospective studies. However, MammaPrint is now the first genomic test to provide Level 1A prospective randomized data from a large Phase 3 trial of women with an early diagnosis of breast cancer who have been followed for five years. MINDACT tested MammaPrint on 6,693 women from 111 medical centres from 9 European countries. No other genomic test has yet provided Level 1A prospective randomized data to support its use in clinical practice.
The authors of the MINDACT publication state that “The primary goal of MINDACT was to assess whether, among patients with high-risk clinical features and a low-risk gene expression profile who did not receive chemotherapy, the lower boundary of the 95% confidence interval, for the rate of 5-year survival without distant metastasis would be 92% (i.e. the noninferiority boundary) or higher.”
The MINDACT results have shown that out of 1,550 women who were allocated to the high clinical risk:low genomic risk subgroup, that the rate of survival without distant metastasis was 94.7% (95% confidence interval, 92.5 to 96.2) among those not receiving chemotherapy. The authors of MINDACT therefore conclude that “Given these findings, approximately 46% of women with breast cancer who are at high clinical risk might not require chemotherapy” if they return a low genomic risk MammaPrint result.
MINDACT has now confirmed beyond any reasonable doubt that MammaPrint genomic testing represents a new paradigm shift in modern breast cancer management. Dr Bernard Fisher published back in 2002 the National Surgical Adjuvant Breast and Bowel Project (NSABP) 25 year follow up data confirming that partial mastectomy and radiotherapy had the same long term survival rates as mastectomy. This was the first major paradigm shift in modern breast cancer management, and sentinel node biopsy has now been accepted as being the second significant paradigm shift, replacing axillary clearance in the majority of women with breast cancer. Associate Professor Hingston now states that MammaPrint testing, as shown by the Level 1A prospective randomized MINDACT data, is being recognized as being the next significant paradigm shift in modern breast cancer management, and clinicians the world over are now embracing this MammaPrint technology on behalf of their patients.
Associate Professor Guy Hingston is a surgical oncologist with nearly 20 years experience in the oncoplastic management of women with breast cancer. He resides in Port Macquarie providing comprehensive breast cancer surgical service in a private capacity to women from northern New South Wales. He is currently setting up a breast cancer genomic study through the University of Newcastle’s Hunter Medical Research Institute, using next generation sequencing and droplet digital polymerase chain reaction equipment to individually characterise mutations in breast cancer, and he is hoping to shortly commence measurement of circulating tumour DNA in women with breast cancer. He is a new breed of oncoplastic breast cancer surgeon who believes that modern genomic assessment (like MammaPrint) is now part of the future management of all women who develop breast cancer. He is also currently the surgical oncology representative on the TransTasman Radiation Oncology Group Scientific Trials Independent Data Safety & Monitoring Committee.
by Kate Aubusson, The Sydney Morning Herald
It’s a gruelling decision every breast cancer patient and their doctor must consider: do we need to start chemotherapy, or could we spare you the ravages of the toxic, yet potentially life-saving treatment?
A genetic test could see thousands of Australian women with early-stage breast cancer safely avoid chemotherapy, a landmark trial shows.
Based the genetic profile of their tumours, nearly half of women (46 per cent) with early-stage breast cancer who are at high clinical risk of the cancer returning may not require chemo, found one of the largest and most robust studies of genetic testing published.
The trial investigated whether the test (dubbed MammaPrint in Europe and Australia) could identify which patients had a low genetic risk of their cancer re-emerging among women in the early stages of the most common type of breast cancer: HER2 negative tumours.
Researchers screened more than 6600 patients and found 1550 had a high clinical risk, but low genetic risk, of their cancer returning.
Women deemed to have a high clinical risk of recurrence are usually treated with chemo.
The researchers randomly assigned these women to chemo treatment or no chemo after their first-line treatments (surgery, hormone therapy and radiation).
After five years, 94.4 per cent of the women who did not receive chemo had no distant metastasis; their cancer hadn’t spread, found the study published in the New England Journal of Medicine on Thursday.
There was only 1.5 percentage points that separated them from the women who did receive chemo, with 95.9 per cent of these patients showing no distant metastasis at the five-year mark.
“We found that chemotherapy with its toxic effects could be avoided in these patients,” the authors concluded. They plan to follow the women for another five years to document their ongoing survival rates.
“Given these findings, approximately 46 per cent of women with breast cancer who are at high clinical risk might not require chemotherapy, they said.
The risks from certain types of chemo increase with the patient’s age. The risk of leukemia is about 0.5 per cent to 1 per cent, and the heart risk can reach 4 per cent or 5 per cent in older women, Dr Freedman said.
Australian oncologist Associate Professor Guy Hingston – who pioneered access to MammaPrint for Australian women – recommended all Australian women who were about to undergo chemo should check with their oncologist to see if they would benefit from the test.
Between 4000 and 5000 Australian women diagnosed with breast cancer every year would be eligible for the test. The study results suggest roughly 2000 to 2500 women could be spared chemo every year.
“We now live and work in a different world of breast cancer management. Women already shattered with a new diagnosis of breast cancer, should not needlessly be put through chemotherapy, if genomically their cancer can be shown to have a low risk of recurrence,” Associate Professor Hingston said.
“As a medical profession, we are here to help women, not hurt them, and this form of genomic testing is a great step forward in our ability to more accurately target treatment and provide personalised cancer therapy.”
But MammaPrint is not universally accessible. Australian samples are sent to Los Angeles for testing and come with an out of pocket cost of roughly $5500 in Australia.
The medical services advisory committee is assessing an application for government funding.
A sobering editorial published alongside the study findings warned the trial was not the final proof that chemotherapy could be tossed aside for this group of patients.
“The immediate question for many observers is this: Was withholding chemotherapy in such patients actually safe?” wrote Drs Clifford Hudis and Maura Dickler at the Memorial Sloan Kettering Cancer Center, New York.
“[A] difference of 1.5 percentage points, if real, might mean more to one patient than to another.
“What doctors and their patients do with the results of such testing will be highly individualised — and will inevitably be finessed by the findings from future studies,” they wrote.
Dr Martine Piccart and her colleagues have today published in the New England Journal of Medicine their results of the landmark international prospective randomized Microarray In Node negative Disease May Avoid Chemotherapy (MINDACT) study. MINDACT assessed MammaPrint genomic testing of nearly 7,000 women with early breast cancer. In Australia, Associate Professor Guy Hingston says that this is the biggest news in breast cancer management in 2016!
Going against the prevailing Australian view at the time, Associate Professor Guy Hingston commenced using this modern international genomic test in northern NSW in 2014, and published his initial MammaPrint results back then in the Asia Pacific Journal of Oncology. However, with the publication of MINDACT today, Associate Professor Guy Hingston considers that MammaPrint is now set to become the international standard of care in genomic testing in breast cancer. “MammaPrint testing has now been shown to be the most reliable international testing platform for the genomic assessment (of approximately one third) of women who present with a new diagnosis of early breast cancer. This means that each year in Australia, around 5,000 Australian women could benefit from this new technology.”
“MammaPrint is the first genomic test in early breast cancer that has been shown through a prospective randomised international five year follow up cohort of nearly 7,000 women to be both prognostic and predictive.” As of today, Associate Professor Guy Hingston recommends that all Australian women who are about to undergo chemotherapy for early breast cancer should now check with their medical oncologist to see if they could benefit from MammaPrint testing. He has made this bold statement because MINDACT has shown that there is a 46% reduction in the need for adjuvant chemotherapy in the subgroup of women who have hormone positive breast cancers between 20mm and 50mm in diameter, including those with node negative or node positive disease (with up to three nodes involved).
According to Associate Professor Guy Hingston, MINDACT has shown that there is no advantage for undergoing chemotherapy if the MammaPrint genomic test returns a low risk result, as the large group of women in MINDACT randomized to receive or not receive chemotherapy obtained no statistically significant benefit in terms of 5 year distant metastasis free survival or overall survival. Therefore, Associate Professor Guy Hingston asks why women should needlessly undergo all of the side effects, and run the risk of major complications of having chemotherapy, if no benefit is to be obtained? More information about MINDACT and MammaPrint testing can be obtained online at www.mammaprint.com.au.
Back in late 2013, and to help Australian women access this new technology, Associate Professor Guy Hingston set up a company called Genome Investigation Pty Ltd which now assists Australian women to obtain this form of breast cancer testing. Genome Investigation also commenced an application for public funding of MammaPrint through the Australian Government Department of Health Medical Services Advisory Committee. While this application remains afloat, it is Associate Professor Guy Hingston’s view that today’s publication of MINDACT means that the Department of Health should now immediately commence funding of MammaPrint testing for those women who are eligible, after appropriate referral from a specialist oncologist.
“As of today, and because of MammaPrint testing proven through MINDACT, we now live and work in a different world of breast cancer management. Women already shattered with a new diagnosis of breast cancer, should not needlessly be put through chemotherapy, if genomically their cancer can be shown to have a low risk of recurrence. As a medical profession, we are here to help women, not hurt them, and this form of genomic testing is a great step forward in our ability to more accurately target treatment and provide personalized cancer therapy.”
Further, Associate Professor Guy Hingston states that we are now heading into an exciting era of breast cancer management, where over-treatment is being replaced with targeted treatment. Surgical oncologists initially lead the way with partial mastectomy (avoiding mastectomy), and then sentinel node biopsy (avoiding unnecessary axillary clearance). However, proven MammaPrint genomic testing is now leading the way with more personalized targeted medical treatment options, and this is great news for all those involved in breast cancer management, both patients and clinicians alike.”
Associate Professor Guy Hingston is an expert in the clinical management of breast cancer, with nearly 20 years of clinical experience as a specialist surgical oncologist. He currently resides in Port Macquarie, where he maintains a private practice in oncoplastic breast care. However, he is currently trying to establish a significant breast cancer research project through the Hunter Medical Research Institute, and is focused on establishing the genomic basis of breast cancer using next generation sequencing technology looking for the underlying somatic breast cancer mutations. He sees this as the next important practical step which is needed to help women with a new diagnosis of breast cancer. For further information on Associate Professor Guy Hingston, please visit www.drguy.com.au.
Article by Wayne Kuznar
A 70-gene signature (MammaPrint) demonstrated a high level of accuracy at identifying a large subset of women with clinically high-risk early stage breast cancer for whom adjuvant chemotherapy was unlikely to produce benefit, according to findings from a phase III trial presented at the AACR Annual Meeting 2016.
In the study known as MINDACT, patients deemed high risk clinically but low risk by the gene signature had a similar 5-year rate of distant metastasis-free survival (DMFS) whether randomized to adjuvant chemotherapy or not, said Martine Piccart, MD, PhD. “The important message here is among the clinically high-risk patients, the clinical use of MammaPrint is associated with almost a halving of the use of chemotherapy,” she said
The rate of 5-year DFMS in women who were clinically high risk/genomically low risk and randomized to no chemotherapy was the primary statistical test for MINDACT. In this group, in which 48% of the women had positive nodes, the 5-year DMFS was 94.7% (95% CI, 92.5%-96.2%), which passed the bar for significance of 92%.
Overtreatment with adjuvant therapies, especially chemotherapy, is common for patients with breast cancer, in an attempt to eradicate micrometastases. In this setting, overtreatment is considered adjuvant chemotherapy that is associated with a small survival benefit, in the range of 2%, while exposing the patient to long-term risks such as secondary cancers, secondary leukemia, and congestive heart failure, said Piccart, Head, Department of Medicine, Jules Bordet Institute in Brussels, Belgium, and Co-Founder and Chair of the Breast International Group.
The MINDACT trial was opened in 2007 and originally included women with negative nodes, but was amended in 2009 to enroll women with one to three positive nodes. “Essentially, we got very confident that the genomic assay would outperform the clinical criteria by reducing the prescription of adjuvant chemotherapy without impairing patient outcome,” said Piccart. As such, MINDACT is the only clinical trial pitting tumor biology against tumor anatomy with a few biological features added, she said.
MINDACT enrolled 6693 patients with early breast cancer from 112 centers in nine European countries who had their risk of tumor recurrence following surgery assessed in two ways: through use of MammaPrint, performed on frozen tumor tissue, and also via Adjuvant! Online. Overall, 2745 women were categorized as low risk using both methods, 1806 were categorized as having high risk of recurrence by both methods, 592 were categorized as high risk of recurrence by MammaPrint and low risk of recurrence by Adjuvant! Online, and 1550 were categorized as low risk of recurrence by MammaPrint and high risk of recurrence by Adjuvant! Online.
Patients characterized by both assessments as low risk were spared adjuvant chemotherapy while chemotherapy was advised for those characterized as high risk by both methods. Those with discordant results were randomized to adjuvant chemotherapy or no adjuvant chemotherapy.
Altogether, 88% of the patients enrolled had hormone receptor (HR)-positive tumors and 10% had biologically aggressive HER2-positive disease. After a median follow-up of 5 years, 3% of the study population died and 5.4% experienced either distant metastases or death.
Five-year DMFS was 97.6% among the women who were low risk by both assessment methods. In contrast, DMFS was 90.6% among the women who were high risk by both methods and received adjuvant chemotherapy. “The low-risk patients were mostly node-negative [with] small tumors with hormone receptors,” said Piccart. The high-risk patients had larger tumors, were node-positive in 25% of the cases, and triple-negative in about one third of cases, she added.
The “discordant” groups, meaning low by one measure and high by another, had a rate of DMFS in between that of the “concordant” groups (low-low and high-high). The 5-year DMFS rates were 94.8% and 95.1% in the patients who were clinically low risk/genomically high risk and clinically high risk/genomically low risk, respectively.
The trial was not powered to detect a clinical benefit to chemotherapy in discordant risk groups, she explained, but on intent-to-treat analysis, a 22% relative reduction in the risk of 5-year DMFS with chemotherapy was observed “which would translate into a very small absolute benefit that would not justify the risks of chemotherapy,” she said.
Among the entire MINDACT population, using a clinical strategy to assign chemotherapy would result in 50% of patients receiving chemotherapy, compared with only 36% using the genomic strategy, for an absolute reduction of 14% in chemotherapy prescription, Piccart noted.
“MINDACT provides level 1A evidence of the clinical utility of MammaPrint,” she concluded. This is the highest level of evidence shown to date for a risk assessment tool for determining whether chemotherapy should be used.
Because nearly all ER-negative or HER2-postive tumors would be expected to rate as both clinically and genomically high risk, MammaPrint and the MINDACT results bear mostly on the heterogeneity within ER-positive, HER2-negative cancers, commented Harold Burstein, MD, PhD, clinical oncologist at Dana-Farber Cancer Institute, Boston.
The study “confirms the primary hypothesis that integration of genomic signature permits identification of a cohort of ER-positive tumors with good prognosis with endocrine therapy alone, regardless of larger T stage and N1 status,” he said, advocating that most ER-positive, HER2-negative stage 1 and 2 cancers, including N1, warrant tumor genomic profiling for optimal adjuvant decision-making.
This user-friendly, interactive calculator is intended for use by women who have not had breast or ovarian cancer. It will help you to gain a good understanding of your level of risk for breast cancer compared to another woman of your age group. National Breast Cancer Centre* has based the questions in this calculator on the most important risk factors for breast cancer based on an up-to-date review of international evidence.
The calculator only takes a few minutes to complete, and the relevant risk factor is explained at each stage.
It is important to remember that the results of this calculator are not a guarantee of your risk levels, and that all women are at risk for breast cancer, no matter what their risk category. Some women at increased risk never develop breast cancer, and some women at low risk may develop the disease.
Exercise can reduce the risk of breast cancer by up to 30 per cent, a study has found. US researchers have found that women who exercise at any level of intensity from 10 to 19 hours a week are most likely to cut the risk. The results have been welcomed by Cancer Council SA, which states the study provides further evidence of the benefits of regular exercise in cancer prevention. Researchers found a limitation of the study was the results were “not readily applicable to all women” because participants were more affluent and educated than the average, and future studies into the relationship between exercise and breast cancer should be expanded with a more diverse selection.
The life-saving National Bowel Cancer Screening Program will be expanded under the 2012-13 Budget to provide additional screenings to people aged 60 and 70. The program will receive a $49.7 million boost and be extended to screen Australians turning 60 from 2013 and 70 from 2015. This achieves regular five yearly screening for the at-risk population between 50 and 70 years of age. The program will be further extended in 2017-18, when a phased implementation of biennial screening will commence, beginning with 72 year olds. Invitations to undergo screening every two years will then be progressively extended to all Australians between 50 and 74 years of age. Currently, bowel cancer screening is provided free to people aged 50, 55 and 65.