Reasons why some breast cancers become resistant to treatment.

Most breast cancers are estrogen receptor-positive, meaning that signals received from estrogen, a hormone, promote the growth of the tumors. To stop these cancers from spreading, estrogen inhibitors are usually prescribed. But what happens when tumors develop treatment resistance?
breast cancer patient considering treatment

In around a third of ER-positive breast cancer cases, the tumors become treatment-resistant. Why is that?

Studies suggest that “approximately 70 percent” of all breast cancers are estrogen receptor-positive (ER-positive).

These types of cancer are typically treated with drugs — such as tamoxifen and fulvestrant — that either lower the levels of the hormone or inhibit the estrogen receptors to prevent the tumors from spreading. This is known as endocrine therapy.

However, around a third of the people treated with these drugs develop resistance to them, which negatively impacts their chances of survival. The mechanisms that underlie the tumors’ resistance to therapy is not well understood and currently poses a major challenge.

Recently, however, specialists from the Dana-Farber Cancer Institute in Boston, MA, have made significant progress in uncovering what exactly happens in the bodies of people in whom endocrine therapy does not work.

Dr. Myles Brown — the director of the Center for Functional Cancer Epigenetics at the Institute — and his colleagues investigated how certain gene mutations render cancer cells more resilient, facilitating metastasis. Their findings, the scientists hope, may eventually lead to more effective approaches for patients who do not respond well to traditional treatments.

The results of the team’s study were published in the journal Cancer Cell.

The mutations that hinder treatment

In a previous study, Dr. Rinath Jeselsohn — who also co-led the new research — and former team saw that mutations of the estrogen receptor gene of cancer cells were largely responsible for the cancer’s resistance to treatment.

On that occasion, the scientists observed these mutations in the metastatic tumors of women who had received endocrine therapy and had not responded to it.

Following on from this discovery, Dr. Jeselsohn and her colleagues analyzed these mutations using laboratory models of ER-positive breast cancer, noting that they supported the cancer’s resistance to the drugs tamoxifen and fulvestrant.

The new study revealed additional mechanisms that researchers had not been aware of previously.

Besides enabling the tumors to adapt to estrogen deprivation, the genetic mutations were also responsible for activating genes that would allow the cancer tumors to spread even further.

Such mutations — which allow genes to gain surprising and novel functions — are referred to as neomorphic mutations.

Therefore, the effect of the genetic mutations is twofold, allowing the cancer tumor to undertake two distinct “lines of attack” at the same time.

“[E]ven though the drug therapies are selecting tumors that can grow without estrogen,” explains Dr. Brown, “the mutations also confer a metastatic advantage to the tumor.”

Combined therapy for resistant cancers

Once they noted the effects of mutations on breast cancer tumors, Dr. Brown and his colleagues turned to modern gene-editing tools — namely, CRISPR-Cas9 — to pinpoint exactly which genes were at the core of estrogen receptor-related alterations.

This revealed that one gene in particular, called CDK7, might lend itself well as a target for new cancer treatments. This gene normally encodes the enzyme cyclin-dependent kinase 7.

Dr. Brown and team took particular interest in the potential of this gene as a target since existing research has already found ways of blocking the expression of CDK7.

Nathanael Gray, also from the Dana-Farber Cancer Institute, experimented with an inhibitor for CDK7 a few years ago. This experimental inhibitor is called THZ1, and it showed potential as an aid for the drug fulvestrant.

The combination of fulvestrant and THZ1 was effective both in cell cultures of ER-positive breast cancer and in animal models of the disease, slowing down tumor growth significantly.

Dr. Brown and his colleagues believe that by putting two and two together, as it were, through the combined findings of all these studies led by the Dana-Farber Cancer Institute, specialists may be able to devise effective treatments for ER-positive breast cancers that don’t respond to endocrine therapy alone.

“These results support the potential of this combination as a therapeutic strategy to overcome endocrine resistance caused by the ER mutants,” the researchers suggest.

Dr. Joy and her colleagues are currently trying to develop appropriate CDK7 inhibitors, and they “hope to test these drugs and develop a clinical trial for patients with ER-positive metastatic breast cancer.”


What!!! -Risk of breast cancer’s return continues long after treatment ends!

A recent analysis has found that even 20 years after receiving a diagnosis of estrogen receptor-positive breast cancer, the risk of the cancer’s return looms large. Should treatment be extended?
Nurse with breast cancer ribbon

A new study brings the length of breast cancer follow-up treatment into question.

Estrogen receptor-positive (ER-positive) breast cancer is the most common breast cancer type, accounting for around 80 percent of all breast cancer cases.

In short, ER-positive breast cancer flourishes in response to estrogen. The standard treatments for this cancer type are tamoxifen, which blocks the effects of estrogen, or aromatase inhibitors, which stop the production of estrogen.

Even once the cancer has gone, these drugs are taken daily for 5 years. Tamoxifen reduces recurrence by half during treatment, and by almost a third in the 5 years following treatment.

Aromatase inhibitors, which will only work in women who are postmenopausal, are even better at reducing the risk of recurrence.

Should treatment be extended?

Over recent years, research has found that extending the length of time that these medications are taken could reduce risks further still. Some cancer researchers are asking whether they should be continued for 10 years.

But these drugs are not without disadvantages. Although side effects are rarely life-threatening, they can substantially impact a woman’s quality of life. Side effects often mimic menopause and include hot flashes, night sweats, mood changes, and vaginal dryness. Aromatase inhibitors also carry an increased risk of osteoporosis, among other conditions.

As the authors of the current study write, “[D]ecisions about extending adjuvant endocrine therapy after 5 years without any recurrence need to balance additional benefits against additional side effects.”

The analysis was carried out by researchers from the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). This group has been pooling research into a single dataset since the 1980s, looking at all aspects of breast cancer.

For this study, they took data from 88 clinical trials, including those of 62,923 women with ER-positive breast cancer. Their findings are published this week in the New England Journal of Medicine.

Long-term risk of recurrence

They found that in women who were cancer-free and in therapy for 5 years, a substantial number saw the cancer spread throughout the body over the following 15 years.

Even though these women remained free of recurrence in the first 5 years, the risk of having their cancer recur elsewhere (for example in the bone, liver, or lung) from years 5 to 20 remained constant.”

Senior study author Dr. Daniel F. Hayes

The risk was directly related to the size of the original cancer and the number of lymph nodes that it affected. Specifically, larger cancers and those that affected four or more lymph nodes carried the greatest long-term risks.

Even if the patients were recurrence-free when they stopped the endocrine therapy, they had a 40 percent risk of cancer recurrence within 15 years.

Women whose original cancers were smaller and did not involve the lymph nodes had a 10 percent risk over 15 years.

As lead study author Hongchao Pan, Ph.D. — from the University of Oxford in the United Kingdom — says, “It is remarkable that breast cancer can remain dormant for so long and then spread many years later, with this risk remaining the same year after year and still strongly related to the size of the original cancer and whether it had spread to the nodes.”

Medical News Today got the opportunity to speak to Dr. Hayes, and when asked whether or not he was surprised by the results, he replied, “There have been much smaller studies to suggest this phenomenon […] Our results absolutely validate these and confirm the relentless risk of distant recurrence over the 2 decades after diagnosis.”

What happens next?

The team now wants to understand whether there is a subset of women with ER-positive breast cancer that has a low enough risk so that extended endocrine treatment would not be needed.

Although the analysis took thousands of women into account, the researchers are quick to note that they received their diagnosis decades ago and treatment has since improved. Dr. Hayes told MNT that “it appears that prognosis is better for patients diagnosed over the last 10–15 years.”

He added, “More than half of our patients were entered before 2000, and of course, we only have 20 years of follow-up on patients who were followed for 20 years — so, overall, it is possible that the data in our paper overestimate the absolute risk distant recurrence/year.”

However, we are pretty certain that they do not overestimate the concept that distant recurrences continue without abatement.”

Dr. Daniel F. Hayes

MNT also asked Dr. Hayes about future research to be conducted by the EBCTCG. He said, “There are several ongoing analyses asking a number of questions. We will continue to address issues of the risks of recurrence, and the benefits of various endocrine therapy strategies as we gather more data.”

It is likely that these findings and others like them will be used to advise longer treatment plans for women with more aggressive ER-positive tumors. As Dr. Hayes told us, “[O]ur data will help patients make a better-informed decision.”

Poor diet during teens, early adulthood may raise breast cancer risk!

The risk of developing premenopausal breast cancer may be higher for women who have a poor diet during adolescence and early adulthood, new research finds.
[A woman eating a burger]

Researchers have associated an unhealthful diet in adolescence or early adulthood with greater risk of developing premenopausal breast cancer.

Previous studies have associated an unhealthful diet – particularly one that is low in vegetables, high in refined sugar and carbohydrates, and high in red and processed meats – with chronic inflammation, which may raise the risk of certain cancers.

According to the new study, it is this diet-induced inflammation that may increase a woman’s risk of breast cancer prior to menopause.

Study co-author Karin B. Michels, Ph.D. – professor and chair of the Department of Epidemiology at the Fielding School of Public Health at the University of California-Los Angeles – and colleagues recently reported their findings in the journal Cancer Epidemiology, Biomarkers & Prevention.

After skin cancer, breast cancer is the most common cancer among women in the United States. This year, around 252,710 new cases of invasive breast cancer will be diagnosed, and more than 40,000 women will die from the disease.

“About 12 percent of women in the U.S. develop breast cancer in their lifetimes,” notes Michels. “However, each woman’s breast cancer risk is different based on numerous factors, including genetic predisposition, demographics, and lifestyle.”

For this latest study, Michels and colleagues set out to determine how a pro-inflammatory diet during adolescence or early adulthood might influence women’s risk of breast cancer in later life.

Up to 41 percent greater breast cancer risk with pro-inflammatory diet

The researchers analyzed the data of 45,204 women who were part of the Nurses’ Health Study II.

Some of the women completed a food frequency questionnaire in 1991, when they were aged between 27 and 44 years, which disclosed details of their diet in early adulthood. The questionnaire was completed again every 4 years thereafter.

In 1998 – when aged between 33 and 52 – some women completed a food frequency questionnaire that detailed their diet during high school.

Using a technique that associates food intake with markers of inflammation in the blood, the researchers allocated an inflammatory score to each woman’s diet. The women were then divided into five groups based on their inflammatory score.

Compared with women who had the lowest inflammatory diet score during adolescence, those who had the highest score were found to be at a 35 percent higher risk of developing premenopausal breast cancer.

Women with the highest inflammatory diet score during early adulthood were found to have a 41 percent increased risk of premenopausal breast cancer, compared with those who had the lowest inflammatory diet score.

A pro-inflammatory diet was not associated with the overall incidence of breast cancer or the risk of postmenopausal breast cancer, the team reports.

Although the study cannot prove cause and effect between a pro-inflammatory diet during adolescence or early adulthood and premenopausal breast cancer, the team believes that the results further highlight the importance of a healthful diet.

Our study suggests that a habitual adolescent/early adulthood diet that promotes chronic inflammation may be another factor that impacts an individual woman’s risk.

During adolescence and early adulthood, when the mammary gland is rapidly developing and is therefore particularly susceptible to lifestyle factors, it is important to consume a diet rich in vegetables, fruit, whole grains, nuts, seeds, and legumes and to avoid soda consumption and a high intake of sugar, refined carbohydrates, and red and processed meats.”

Karin B. Michels, Ph.D.

There are a number of limitations to the study. For example, participants reported their adolescent diet years later, so their recollections could be subject to error. Additionally, the researchers did not have access to subjects’ measurements of inflammatory blood markers during adolescence or early adulthood.

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