Tag: HER-2 positive breast cancer

New Metastatic Breast Cancer Treatments have Aided Mortality Decline

Photo by National Cancer Institute on Unsplash

Deaths from breast cancer dropped 58% between 1975 and 2019 due to a combination of screening mammography and improvements in treatment, according to a new study led by Stanford Medicine clinicians and biomedical data scientists.

Nearly one-third of the decrease (29%) is due to advances in treating metastatic breast cancer, also known as stage 4 breast cancer or recurrent cancer. Although these advanced cancers are not considered curable, women with metastatic disease are living longer than ever.

The analysis helps cancer researchers assess where to focus future efforts and resources.

“We’ve known that deaths from breast cancer have been decreasing over the past several decades, but it’s been difficult or impossible to quantify which of our interventions have been most successful, and to what extent,” said Jennifer Caswell-Jin, MD, assistant professor of medicine. “This type of study allows us to see which of our efforts are having the most impact and where we still need to improve.”

Caswell-Jin and Liyang Sun are co-first authors of the study, which was published in the Journal of the American Medical Association. Sylvia Plevritis, PhD, professor and chair of biomedical data science, and Allison Kurian, MD, MSc, professor of medicine and of epidemiology and population health, are co-senior authors.

The study was a collaborative effort by a national consortium of researchers called CISNET, or the Cancer Intervention and Surveillance Modeling Network. CISNET was established in 2000 by the National Cancer Institute to understand the impact of cancer surveillance, screening and treatment on incidence and mortality. Doing so requires sophisticated computer algorithms capable of modelling the natural course of the disease and the typical treatment paths of individual patients, then translating that information to population-level data collected by the national Surveillance, Epidemiology, and End Results Program, or SEER registry, from 1975 to 2019.

The study is the third in a trio of papers from CISNET published since 2005 that assess the relative contributions of regular screening and treatment advances on breast cancer deaths. The previous two papers informed national guidelines and helped cancer researchers focus their efforts on the most intractable problems.

“Twenty years ago, there was a question whether routine screening mammography actually decreased the number of deaths from breast cancer,” Plevritis said. But in 2005, she and other CISNET researchers published a paper in the New England Journal of Medicine that conclusively demonstrated that screening was responsible for anywhere from 28% to 65% (different models came up with varying degrees of impact) of the reduction in mortality by 2000 between 1975 and 2000.

The second paper, published in 2018 in the Journal of the American Medical Association, highlighted the differences in treatment responsiveness and survival outcomes among women with differing breast cancer subtypes from 2000 to 2012, pinpointing subgroups with poorer survival.

“We found that, while screening still had an important impact, most of the decline in annual deaths was due to improvements in treating early-stage breast cancer based on each cancer’s molecular profile,” Plevritis said.

The current study is the first to explicitly include patients with metastatic breast cancer in its models. The finding that 29% of the decrease in mortality is due to advances in treating metastatic breast cancer both surprised and gratified the researchers.

“Initially, we assumed that treatment of advanced disease was unlikely to make a significant contribution to the declines in mortality we documented in the previous two papers,” Caswell-Jin said. “But our treatments have improved, and it’s clear that they are having a significant impact on annual mortality.”

The CISNET researchers used four computer models to assess the SEER data from 1975 to 2019 — one developed at Stanford Medicine in the Plevritis Lab, one by researchers at the Dana-Farber Cancer Institute, one at MD Anderson Cancer Center, and another jointly developed by researchers at the University of Wisconsin and Harvard Medical School. The four models came up with remarkably similar estimates for the impact of each intervention: screening mammography, treatment of early-stage (stages 1, 2 or 3) breast cancer and treatment of metastatic breast cancer.

The models reproduced the decline in mortality in breast cancer known from SEER data, from 48 per 100 000 women dying of breast cancer each year in 1975 to 27 per 100,000 in 2019, a decrease of about 44%. The models arrived at a larger estimated reduction in mortality of about 58% because the incidence of breast cancer has risen during the same period and more women would have died had screening and treatments not improved.

The models concluded that about 47% of this reduction in mortality is the result of improved treatments for early-stage breast cancer, and about 25% is attributed to screening mammography. The remainder, or about 29%, is due to improvements in treating metastatic disease.

“Designing the new model, which had to account for individuals with non-metastatic cancer who underwent treatment but later progressed to metastatic cancer, and who may have been treated with multiple drugs over the course of their disease, was extremely complex,” Plevritis said. “It took about four years. But it was really satisfying when we were able to validate the model’s behaviour and see that all four models from different institutions, which used the new model inputs in different ways, delivered consistent findings. The models not only make sense, but also produce meaningful insights.”

The impact of treating metastatic disease is exemplified by the increases in median survival time after metastasis: Patients diagnosed in 2000 with metastatic disease lived an average of 1.9 years versus an average of 3.2 years for those diagnosed in 2019. Survival time varies by subgroup status, however. Patients with what are known as oestrogen receptor-positive and HER2 positive cancers saw an average increase in survival time of 2.5 years. Those with oestrogen receptor-positive and HER2-negative cancers lived an average of 1.6 years longer, but those with cancers that are oestrogen receptor-negative and HER2-negative lived about 0.5 years longer in 2019 than in 2000.

“It was meaningful as a breast oncologist to spend time with this history and see real progress over the past decades,” Caswell-Jin said. “There is much more work to be done; metastatic breast cancer isn’t yet curable. But it is rewarding to see that advances have made a difference in these numbers,” she added. “Our scientific and clinical work is helping our patients live longer, and I believe deaths from breast cancer will continue to steadily decline as innovation continues to grow.”

Source: Stanford Medicine

‘Landmark’ Drug Doubles Progression Time of Advanced Breast Cancer

Source: National Cancer Institute

A new type of targeted medicine has shown ‘remarkable’ benefits for patients with advanced breast cancer in a major phase III clinical trial. Combined with hormone therapy, the drug capivasertib doubled the time it took for cancer to progress in people with advanced forms of the most common type of breast cancer.

Capivasertib is a potential first-in-class drug that blocks activity of the cancer-driving protein molecule AKT.

The findings, presented at the San Antonio Breast Cancer Symposium, show that capivasertib is a potential new treatment for people with oestrogen receptor (ER) positive, human epidermal growth factor receptor 2 (HER-2) negative breast cancer.

‘Effective across all patients treated in the trial’

The drug was found to be effective across all patients treated in the trial, including a group who had tumours with mutations in the AKT signalling pathway.

The phase III CAPItello-291 trial enrolled 708 women and men with an advanced form of ER-positive, HER-2 low or negative locally advanced or metastatic breast cancer.

Participants on the trial had seen their cancer recur or progress on standard hormone treatments, and the majority had also previously been treated with CDK4/6 inhibitors – drugs that block cancer cells from multiplying.

In current clinical practice, patients continue to receive fulvestrant hormone therapy, but this is often not effective, and many are left only with the option of chemotherapy, a treatment which can lead to debilitating side effects.

In the trial, adding capivasertib to fulvestrant hormone therapy doubled the median time to disease progression, from 3.6 months to 7.2 months. The treatment shrank tumours in 23% of patients, compared with 12% of patients who received fulvestrant hormone treatment plus a placebo.

Targeting the AKT pathway

The targeted drug was more effective for patients whose cancers had alterations to the AKT signalling pathway. Genetic alterations to the AKT pathway can drive both cancer’s development and treatment resistance.

Genetic alterations of the AKT pathway – revealed by tumour profiling – were present for 41% of patients on the trial. In this group treated with capivasertib and hormone therapy, it took an average of 7.3 months for the cancer to worsen compared with 3.1 months for those who received hormone therapy alone. Some 29% of patients with AKT pathway alterations who received capivasertib with hormone therapy saw their tumours shrink following treatment, compared with only 9.7% who received a placebo and hormone therapy.

Side effects from capivasertib with hormone therapy were manageable and consistent with previous studies.

More than two thirds of people with advanced breast cancer have ER-positive, HER-2 negative disease. ER-positive, HER-2 negative breast cancers have higher levels of the oestrogen receptor – allowing them to grow in the presence of oestrogen – but do not over-produce copies of the human epidermal growth factor.

Developing capivasertib

The development of capivasertib followed years of fundamental research at the Institute for Cancer Research (ICR), aimed at understanding how the AKT protein is regulated. In 2002, ICR scientists published the 3D structure of AKT and showed how the protein is activated.

Researchers then collaborated with Astex Pharmaceuticals to design small-inhibitors which would target AKT, based on its 3D structure.

In 2005, a series of prototype drug compounds discovered by the ICR and Astex was shown to have very promising activity against a range of human tumours grown in mice and was licensed to AstraZeneca. Then, in 2010, AstraZeneca announced its discovery of capivasertib, and began to develop the drug as a potential treatment for various forms of cancer.

The initial clinical development of capivasertib was centred on an early-stage trial which was led by the ICR and its partner hospital The Royal Marsden. Subsequently, phase II studies were completed in the UK in collaboration with the UK Cancer Research Network.

The trials used biomarkers that were developed at ICR to show proof of concept that the AKT protein was inhibited by capivasertib.

ICR researchers continue to study AKT biology to open up new ways of using treatments targeting the pathway.

Living well and longer with breast cancer

Trial leader Professor Nicholas Turner, Professor of Molecular Oncology at ICR London, and Consultant Medical Oncologist at The Royal Marsden NHS Foundation Trust, said:

“We are hopeful that capivasertib combined with hormone therapy will now become a new treatment option for patients whose cancer has progressed on hormone therapy plus a CDK4/6 inhibitor. We believe this new treatment could allow more women and men to live well and live longer with breast cancer.”

‘A landmark moment’

Professor Kristian Helin, Chief Executive at The Institute of Cancer Research, London, said:

“This is a landmark moment for the treatment of advanced forms of the most common type of breast cancer. It’s incredibly exciting to see a drug that was discovered following research conducted at the ICR now show remarkable benefits for patients in a phase III trial. Capivasertib could offer a completely new treatment option for these patients.

“I look forward to seeing further results from the CAPitello-291 trial, and I am hopeful that longer follow-up will show that capivasertib also extends the length of time that people survive with advanced breast cancer. But the existing findings are already strong enough for capivasertib to be submitted to regulators to be considered for approval as a new breast cancer treatment.”

Source: The Institute for Cancer Research

Metformin Ineffective in Most Breast Cancers

Breast cancer cells. Image source: National Cancer Institute on Unsplash

Researchers have found that the diabetes drug metformin, once hoped to hold enormous promise in treating breast cancer, does not prevent or stop the spread of the most common forms of the disease but may still have potential in HER2-positive breast cancer.

The randomised, double-blind trial enrolled 3600 patients who received two pills a day of either placebo or metformin. Overall, researchers found the addition of metformin to standard breast cancer treatments did not improve outcomes in the two most common types of breast cancer, hormone receptor-positive or negative.

“The results tell us that metformin is not effective against the most common types of breast cancer and any off-label use of this drug for the treatment of these common types of breast cancer should be stopped,” said Pamela Goodwin, a professor in the department of medicine at the University of Toronto’s Temerty Faculty of Medicine.

Prof Goodwin presented the findings at the 2021 San Antonio Breast Cancer Symposium.

While metformin was found not to be effective in treating the most common forms of breast cancer, there was evidence that use of metformin for five years might lead to a reduction in deaths from HER2-positive breast cancer, a less aggressive subtype which makes up about 20% of all breast cancers.

“Metformin is not beneficial for use in most common breast cancers, but in the cases of HER2 positive breast cancer, our findings suggest it may be beneficial,” said Prof Goodwin. “These results need to be replicated in future research before metformin is used as a breast cancer treatment, however, it could provide an additional treatment option for HER2-positive breast cancer,” she added

Previous studies suggested metformin may also reduce the risk of development and increase survival of some cancers, including breast cancer.

Metformin was theorised to slow breast cancer growth by improving patient metabolism, notably insulin levels, leading to reduced cancer cell growth, or that it might impact cancer cells directly.

Next steps would be to prospectively test the impact of metformin in patients with HER2-positive breast cancer in a randomised clinical trial. 

Source: University of Toronto