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It’s never OK to use ‘holy grail of breast cancer prevention’ when talking about pre-clinical animal study

Existing medicine may prevent cancer in women with breast cancer risk gene

Australian researchers have discovered that an existing medication could have promise in preventing breast cancer in women carrying a faulty BRCA1 gene.

People who carry a faulty BRCA1 gene are at high risk of developing aggressive breast cancer. Currently many women with a gene mutation choose surgical removal of their breast tissue and ovaries to reduce their chance of developing breast and ovarian cancer.

By pinpointing the cells that give rise to breast cancers in women who have inherited a faulty version of the BRCA1 gene, Walter and Eliza Hall Institute researchers have identified that the drug denosumab may have potential to prevent breast cancer from developing. If confirmed in clinical studies, this would provide a non-surgical option to prevent breast cancer in women with elevated genetic risk.

Using samples of breast tissue donated by women carrying a faulty BRCA1 gene, Ms Emma Nolan, Professor Jane Visvader and Professor Geoff Lindeman were able to pinpoint the cells that give rise to breast cancer. The research, which also involved researchers at the Australian familial cancer consortium kConFab and US biotechnology company Amgen was published today in Nature Medicine.

Cancer precursor cells in BRCA1-mutant breast tissue had many similarities to aggressive forms of breast cancer, said Ms Nolan, who is a PhD student at the institute enrolled through The University of Melbourne’s Department of Medical Biology. “These cells proliferated rapidly, and were susceptible to damage to their DNA – both factors that help them transition towards cancer,” she said. “We were excited to discover that these pre-cancerous cells could be identified by a marker protein called RANK.”

Professor Lindeman, who is also a medical oncologist at The Royal Melbourne Hospital, said the discovery of RANK as a marker of cancer precursors was an important breakthrough, because inhibitors of the RANK signaling pathway were already in clinical use. “An inhibitor called denosumab is already used in the clinic to treat osteoporosis and breast cancer that has spread to the bone,” he said. “We therefore investigated what effect RANK inhibition had on the cancer precursor cells in BRCA1-mutant breast tissue.”

The research team showed that RANK inhibition switched off cell growth in breast tissue from women with a faulty BRCA1 gene and curtailed breast cancer development in laboratory models.

“We think this strategy could delay or prevent breast cancer in women with an inherited BRCA1 gene mutation,” Professor Lindeman said. “A clinical trial has already begun to investigate this further.”

“This is potentially a very important discovery for women who carry a faulty BRCA1 gene, who have few other options. Current cancer prevention strategies for these women include surgical removal of the breasts and/or ovaries, which can have serious impacts on people’s lives. To progress this work, denosumab would need to be formally tested in clinical trials in this setting as it is not approved for breast cancer prevention,” Professor Lindeman said.

Professor Visvader said the discovery had its basis in more than a decade of investigations of breast stem cell function. “By thoroughly dissecting how normal breast tissue develops, we have been able to pinpoint the precise cells that are the culprits in cancer formation,” she said. “It is very exciting to think that we may be on the path to the ‘holy grail’ of cancer research, devising a way to prevent this type of breast cancer in women at high genetic risk.”

The research team worked closely with Mrs Avis Macphee, a patient advocate, through the Walter and Eliza Hall Institute’s consumer-researcher buddy system. The research was supported by The National Breast Cancer Foundation, The Qualtrough Cancer Research Fund, The Joan Marshall Breast Cancer Research Fund, the Australian Cancer Research Foundation, Cancer Council Victoria, the Cancer Therapeutics Cooperative Research Centre, an Amgen Preclinical Research Program Grant, the National Health and Medical Research Council, the Victorian Cancer Agency, and the Victorian Government Operational Infrastructure Support Scheme.

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The Walter and Eliza Hall Institute is the research powerhouse of the Victorian Comprehensive Cancer Centre, an alliance of leading Victorian hospitals and research centres committed to controlling cancer.

'Holy grail' of breast cancer prevention in high-risk women may be in sight

Our Review Summary

genetic researchThe news release focuses on the potential of a drug called denosumab to prevent breast cancer from developing in women who have a BRCA1 gene mutation that makes them more likely than the general population to develop breast cancer. The relevant research was published in Nature Medicine. However, the release has some significant flaws. For example, it refers to a “holy grail” of breast cancer prevention for high-risk women, only noting much lower in the release that the work has yet to be proven in clinical studies. Further, even if denosumab does prove to be effective in reducing breast cancer risk for women with the BRCA1 mutation, that would not mean that all “high-risk women” would benefit; there are other genetic mutations — such as BRCA2 and other less common mutations — that can increase breast cancer risk. The release also neglects to address well-known health risks associated with denosumab use.

 

Why This Matters

Breast cancer affects many women and, by extension, their loved ones. Men are also affected. According to the National Cancer Institute, approximately 12.3 percent of women will be diagnosed with breast cancer during their lifetime, and approximately 1 in 1000 men will be diagnosed with the disease. For women with the BRCA1 gene mutation, that number jumps to between 55 and 65 percent. Men who inherit the BRCA1 mutation also have an increased risk of developing breast cancer. Women with the BRCA1 mutation often take preemptive steps to decrease their cancer risk, including — in some cases — preemptive mastectomies. This is a complex, highly personal decision and has been the subject of significant public debate in recent years. Breast cancer is a high profile disease, and concerns related to BRCA1 have had a particularly high profile. That means that research into breast cancer prevention, and BRCA1 in particular, is likely to garner public attention. It also means that research institutions have an obligation to promote such research fairly, accurately and responsibly. This release could have done much more to highlight the preliminary nature of the relevant findings.

Criteria

Does the news release adequately discuss the costs of the intervention?

Not Satisfactory

The release doesn’t address costs at all. Given that denosumab is already on the market to treat other conditions, under the trade names XGEVA and Prolia, this is a significant oversight. Costs are listed in various public outlets as ranging from $990 for a six-month course to $1,650 per year (neither estimate includes the cost of clinical care to administer the drug).

Does the news release adequately quantify the benefits of the treatment/test/product/procedure?

Not Satisfactory

Benefits aren’t quantified at all. Clinical trials have not yet been conducted, so it’s impossible to determine how the drug may perform at preventing breast cancer in patients with the BRCA1 mutation. However, the release says that “RANK inhibition switched off cell growth in breast tissue from women with a faulty BRCA1 gene and curtailed breast cancer development in laboratory models.” (RANK proteins were found by the researchers to be markers associated with pre-cancerous cells.) However, the release doesn’t tell us about the amount of denosumab needed to inhibit these RANK proteins. Nor does the release offer any numbers related to these preliminary tests in laboratory models. For example, what does “curtailed breast cancer development in laboratory models” mean? Did it stop the development of cancerous growth completely? Slow it down a little? A lot? Details matter.

This study was performed in laboratory animals and that must be considered when attributing benefits. As we’ve found with other cancer treatments, switching off a protein or blocking a pathway may be effective in killing cancer cells in laboratory or animal models, but does not always translate to clinical benefit when used in patients. The laboratory studies are an extremely important first step, but it is a huge leap to translate this to clinical benefit.

Does the news release adequately explain/quantify the harms of the intervention?

Not Satisfactory

The release doesn’t address potential harms at all. Again, this is particularly problematic given that denosumab is already on the market and has well-documented potential harms. For example, the websites for both XGEVA and Prolia (denosumab’s current trade names), note that the drug can cause a wide variety of problems, including (but not limited to): severe pain in muscles, bones and joints; serious infections that may require hospitalization; severe allergic reactions; osteonecrosis in the jaw; thigh fractures; and nausea.

Does the news release seem to grasp the quality of the evidence?

Not Satisfactory

The release offers very little information about the study itself and doesn’t stress enough that this is pre-clinical data. As noted above, the release states: “RANK inhibition switched off cell growth in breast tissue from women with a faulty BRCA1 gene and curtailed breast cancer development in laboratory models.” But it’s not clear what sort of laboratory models they used. Was this purely in cell samples, or did they use animal models? What sort of dosage did they use? What was the timeframe for the study? Extraordinary claims require extraordinary evidence. This release begins with some extremely optimistic language, but offers very little information about the study that this optimism is based on.

Does the news release commit disease-mongering?

Satisfactory

This is borderline. Patients who have the BRCA1 gene mutation will not necessarily get breast cancer. However, they are at high risk of developing breast cancer. The release would have been stronger if it had given readers some numbers related to that elevated risk, rather than using vague language (i.e., “high risk of developing aggressive breast cancer”). But they offered enough of a qualifier to earn a “satisfactory” here.

Does the news release identify funding sources & disclose conflicts of interest?

Not Satisfactory

The release includes Amgen in the sections of the release that list all of the organizations that were involved with conducting the research and which supported the work financially. However, the release does not tell readers that Amgen is the company that currently markets denosumab (under the trade names XGEVA and Prolia).

Does the news release compare the new approach with existing alternatives?

Satisfactory

The release notes that: “This is potentially a very important discovery for women who carry a faulty BRCA1 gene, who have few other options. Current cancer prevention strategies for these women include surgical removal of the breasts and/or ovaries.” That’s enough to merit a satisfactory rating. However, the release would have been much stronger if it had mentioned other options for women with the BRCA1 mutation, such as enhanced screening or chemo-preventive drugs (such as tamoxifen), which may also reduce risk.

Does the news release establish the availability of the treatment/test/product/procedure?

Satisfactory

The release makes clear that denosumab is already used to treat other conditions, but that clinical trials are needed to determine whether denosumab should be used to reduce breast cancer risk for women with the BRCA1 mutation.

Does the news release establish the true novelty of the approach?

Satisfactory

The release makes clear that researchers are targeting a specific protein (RANK), which they found is a marker of pre-cancerous cells. That finding may, in fact, be the real news here — but it is overshadowed in the release by the discussion of denosumab.

Does the news release include unjustifiable, sensational language, including in the quotes of researchers?

Not Satisfactory

The headline reads: “‘Holy grail’ of breast cancer prevention in high-risk women may be in sight.” Phrases such as “holy grail” are overused and, often, misleading. This was no exception. This is not only not a “holy grail,” we don’t know what it is yet. There are, to date, precisely zero results on human trials using denosumab to prevent breast cancer in women with the BRCA1 mutation. What’s more, the category of women who are at high risk of breast cancer extends beyond those women with the BRCA1 mutation. For example, according to the National Cancer Institute, women with the BRCA2 mutation have a 45 percent chance of getting breast cancer by the age of 70. And the research discussed in this release doesn’t have an apparent tie to BRCA2. In other words, the headline overreaches in two ways. Given that the headline is the first part of a release anyone sees, and sets the tone for the rest of the release, it’s important to get it right.

Total Score: 4 of 10 Satisfactory

Comments (2)

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Gary Schwitzer

June 22, 2016 at 6:11 pm

An example of the type of news coverage that may have been spawned by this news release is this story posted by CNN: http://www.cnn.com/2016/06/21/health/brca1-breast-cancer-drug/index.html. It parroted the “holy grail of breast cancer prevention” line, and passed along the researchers’ self-assessment that their results “were promising” and “offer hope for the next generation of women.” There was no independent perspective in the story.

Reply

Marc Beishon

June 23, 2016 at 5:53 pm

I think there are two complementary studies here – indeed one is a mouse model but the other is a breast biopsy taken from women treated with denosumab.

From the abstract:

“Notably, proliferation was markedly reduced in breast biopsies from BRCA1-mutation carriers who were treated with denosumab. Furthermore, inhibition of RANKL in a Brca1-deficient mouse model substantially curtailed mammary tumorigenesis. Taken together, …”

Of course, the release is badly written and does not reach first base in explaining this clearly. Tracking back nearly two years and this short story in the Melbourne Herald Sun does a reasonable job (bar the headline):
http://www.heraldsun.com.au/news/victoria/drug-offers-alternative-to-radical-breast-removal-surgery-for-women-at-risk-of-breast-cancer/news-story/7798a9864fd4bbd75c13315963f94a2a

Reply