Tag Archives: #breastcancer

Medicine

The Diagnosis That Will Save Millions Of Lives From Breast Cancer (Medicine)

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Detection of changes in lung tissue, indicating possible development of cancerous metastases, will allow diagnosis and preventive treatment

A new study from Tel Aviv University has revealed changes in healthy lung tissue, which are a preliminary sign of the possible development of cancer cell metastases. The changes were detected in an area known as the ‘microenvironment’ of the tumor, and found in connective tissue cells called fibroblasts. According to the researchers, understanding the metastatic process and diagnosing it at such an early stage may lead to life-saving preventive treatment.

Decipher the ‘black box’ of breast cancer

The study was led by Prof. Neta Erez, Head of the Department of Pathology at the Sackler Faculty of Medicine , along with a team of researchers in her laboratory, Dr. Ofir Shani and Dr. Yael Raz, as well as other researchers from Tel Aviv University, Tel Aviv Medical Center (Ichilov) , From the Sheba Medical Center and the Weizmann Institute The article was published in the journal eLife .

According to the researchers, in many cancers, including breast cancer, patients do not necessarily die from the primary tumor. The deadly cause, in the end, is the metastases, which reach vital organs and thrive there. Even in a patient who has undergone all the proposed treatments, including surgery to remove the primary tumor, followed by chemotherapy treatments and radiation designed to eliminate its remnants, metastases may appear several years later. In the follow-up methods used today, the metastases are detected when the disease is in an advanced stage, and medicine has no effective solutions.

For this reason, Prof. Erez’s group is researching the ‘black box’ – the same period of time between the apparent recovery and the appearance of the metastases, in order to understand the metastatic process and identify it already in the initial stages. The group’s research in recent years has shown that the target tissues in the organs to which the metastases are destined to reach ‘prepare the area’ for their absorption, and create a ‘friendly environment’ for them long before the metastases themselves appear. In the present study, the team looked for signs of these changes, which may be used in the future to identify the process at an early stage. They focused on connective tissue cells (fiber cells), called fibroblasts and found in, among other things, health.

What happens in the microenvironment of the metastases?

“In normal condition, fibroblasts play a key role in healing wounds and tissue damage, but recent studies have shown that cancer manages to recruit them and cause them to produce a supportive environment for it,” explains Prof. Erez.

The researchers performed sequencing of all expressed genes (transcriptomic sequencing) in fibroblast cells taken from the lungs of mice in a breast cancer model. They compared the results of the flooring in cells sampled from healthy lungs, lungs with micro-metastases (tiny metastases that cannot be detected by conventional clinical trials), and lungs with large metastases, in a state of advanced disease. Based on the changes identified from stage to stage, the researchers were able to characterize for the first time the process that takes place in the microenvironment of the cancer metastases, already in the early stages of preparing the surface for their absorption.

In addition, they specifically identified the proteins that drive the ‘rewiring’ processes in fibroblasts, and found that one of the key proteins in the process is Myc  , which is known as a driving factor in accelerating the division of cancer cells. It now turns out that this protein also plays an important role in the change that occurs in fibroblasts towards the absorption of metastases.

“We have been able to characterize processes that occur in seemingly healthy tissues in preparation for the absorption of cancerous metastases. We believe that in the future our findings could help identify the metastatic process before the metastases themselves reach and take root in the target organ. Of millions of people all over the world, “concludes Prof. Erez.

Featured image: Prof. Neta Erez © Tel Aviv University

Reference: Ophir Shani et al, Evolution of fibroblasts in the lung metastatic microenvironment is driven by stage-specific transcriptional plasticity, eLife (2021). DOI: 10.7554/eLife.60745

Provided by Tel Aviv University

Medicine

Study Identifies Biomarker For Breast Cancer Response To Immunotherapy (Medicine)

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A biomarker that has proven to be a predictor for response to immunotherapies in melanoma patients also has clinical relevance for breast cancer patients, according to a new study published in Clinical Cancer Research.

The study demonstrated that this biomarker, a molecule called the Major Histocompatibility Complex Class II protein (MHC-II), has the potential to be a predictor of immunotherapy benefit with two types of breast cancer—early-stage, triple negative breast cancer (TNBC) and high-risk, estrogen receptor-positive breast cancer (HR+) when expressed on breast cancer cells. Although immunotherapies are likely to soon be prescribed along with chemotherapies for these breast cancers before surgery, most patients don’t require the addition of immunotherapy to achieve treatment response. Without an optimal biomarker, clinicians don’t have a reliable way to discern which patients need immunotherapy and which ones don’t.

Clinical tests for MHC-II expression could shield breast cancer patients who don’t need the immunotherapy from possible treatment complications and additional costs. Immunotherapies are expensive and associated with significant toxicity.

Justin Balko, PharmD, Ph.D., associate professor of Medicine and Pathology, Microbiology and Immunology, conceived and designed the study.

“These findings are particularly exciting for us, because if validated, they could provide a better way to personalize therapy for breast cancer patients. So far, the typical biomarkers like PD-L1 expression and the numbers of immune cells in the tumor have not done a good job of identifying patients who need immunotherapy,” said Balko, the study’s senior author.

Paula Gonzalez Ericsson, the study lead author, added, “the test can be easily performed on patient’s tissue samples obtained for diagnosis without the need of additional intervention.”

Balko and colleagues analyzed tissue samples donated by three cohorts of patients:

  • patients with non-immunotherapy-treated breast cancers
  • patients with TNBC treated with the immunotherapy durvalumab and standard chemotherapy
  • patients with HER2-negative breast cancer treated with either standard chemotherapy or the standard chemotherapy plus the immunotherapy pembrolizumab.

They determined that MHC-II is expressed in a subgroup of primary TNBC and HR+ breast cancers, and that tumor MHC-II expression is associated with response to standard chemotherapy plus durvalumab or pembrolizumab, but not to standard neoadjuvant chemotherapy alone.

“The findings of the association with response in early-stage high-risk HR+ patients suggests that MHC-II may be a useful tool in a broader context for breast cancer and this area would benefit from further study,” said co-senior author, Kim Blenman, Ph.D., MS, assistant professor of Medicine at Yale University.

The study is believed to be the first to evaluate and demonstrate the predictive capacity of tumor MHC-II for immunotherapy-specific benefit in patients with breast cancer. The researchers also noted that MHC-II has the potential to be a pan-cancer biomarker predictor for anti-PD-1 or anti-PD-L1 immunotherapies since its clinical relevance has been demonstrated with melanoma, breast cancer and Hodgkin’s lymphoma in this study and previous studies. However, they call for a large, randomized controlled trial to validate their findings with breast cancer, which was based on a retrospective tissue-based analysis.

Reference: Paula I Gonzalez-Ericsson et al, Tumor-specific major histocompatibility-II expression predicts benefit to anti-PD-1/L1 therapy in patients with HER2-negative primary breast cancer, Clinical Cancer Research (2021). DOI: 10.1158/1078-0432.CCR-21-0607

Provided by Vanderbilt University Medical Center

Medicine

This Newly Developed Drug Eradicates Breast Cancer In Mice (Medicine)

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Researchers discovered a small molecule, ErSO, that eradicates breast cancers in mice by targeting a pathway that protects cancer cells.

A new approach to treating breast cancer kills 95-100% of cancer cells in mouse models of human estrogen-receptor-positive breast cancers and their metastases in bone, brain, liver and lungs. The newly developed drug, called ErSO, quickly shrinks even large tumors to undetectable levels.

Led by scientists at the University of Illinois Urbana-Champaign, the research team reports the findings in the journal Science Translational Medicine.

“Even when a few breast cancer cells do survive, enabling tumors to regrow over several months, the tumors that regrow remain completely sensitive to retreatment with ErSO,” said U. of I. biochemistry professor David Shapiro, who led the research with Illinois chemistry professor Paul Hergenrother. “It is striking that ErSO caused the rapid destruction of most lung, bone and liver metastases and dramatic shrinkage of brain metastases, since tumors that have spread to other sites in the body are responsible for most breast cancer deaths,” Shapiro said.

The activity of ErSO depends on a protein called the estrogen receptor, which is present in a high percentage of breast tumors. When ErSO binds to the estrogen receptor, it upregulates a cellular pathway that prepares cancer cells for rapid growth and protects them from stress. This pathway, called the anticipatory Unfolded Protein Response, or a-UPR, spurs the production of proteins that protect the cell from harm.

“The a-UPR is already on, but running at a low level, in many breast cancer cells,” Shapiro said. “It turns out that this pathway shields cancer cells from being killed off by anti-cancer drugs.”

Illinois researchers on the study include, from front left, research scientist Chengjian Mao and graduate students Matthew Boudreau, Darjan Duraki and Ji Eun Kim. In the back row, from left, are molecular and integrative physiology professor Erik Nelson, chemistry professor Paul Hergenrother and biochemistry professor David Shapiro. © Photo by L. Brian Stauffer

Shapiro and former U. of I. medical scholar Neal Andruska first identified the a-UPR pathway in 2014 and reported the development of a compound that pushed the a-UPR pathway into overdrive to selectively kill estrogen-receptor-containing breast cancer cells.

“Because this pathway is already on in cancer cells, it’s easy for us to overactivate it, to switch the breast cancer cells into lethal mode,” said graduate student Darjan Duraki, who shares first-author status on the new report with graduate student Matthew Boudreau.

While the original compound prevented breast cancer cells from growing, it did not rapidly kill them, and it had undesirable side effects. For the new research, Shapiro and Hergenrother worked together on a search for a much more potent small molecule that would target the a-UPR. Their analysis led to the discovery of ErSO, a small molecule that had powerful anticancer properties without detectable side effects in mice, further tests revealed.

“This anticipatory UPR is estrogen-receptor dependent,” Hergenrother said. “The unique thing about this compound is that it doesn’t touch cells that lack the estrogen receptor, and it doesn’t affect healthy cells – whether or not they have an estrogen receptor. But it’s super-potent against estrogen-receptor-positive cancer cells.”

ErSO is nothing like the drugs that are commonly used to treat estrogen-receptor-positive cancers, Shapiro said.

“This is not another version of tamoxifen or fulvestrant, which are therapeutically used to block estrogen signaling in breast cancer,” he said. Even though it binds to the same receptor that estrogen binds, it targets a different site on the estrogen receptor and attacks a protective cellular pathway that is already turned on in cancer cells, he said.

“Since about 75% of breast cancers are estrogen-receptor positive, ErSO has potential against the most common form of breast cancer,” Boudreau said. “The amount of estrogen receptor needed for ErSO to target a breast cancer is very low, so ErSO may also work against some breast cancers not traditionally considered to be ER-positive.”

Further studies in mice showed that exposure to the drug had no effect on their reproductive development. And the compound was well tolerated in mice, rats and dogs given doses much higher than required for therapeutic efficacy, the researchers found.

ErSO also worked quickly, even against advanced, human-derived breast cancer tumors in mice, the researchers report. Often within a week of exposure to ErSO, advanced human-derived breast cancers in mice shrank to undetectable levels.

“Many of these breast cancers shrink by more than 99% in just three days,” Shapiro said. “ErSO is fast-acting and its effects on breast cancers in mice are large and dramatic.”

The pharmaceutical company Bayer AG has licensed the new drug and will explore its potential for further study in human clinical trials targeting estrogen-receptor-positive breast cancers, the researchers said. The researchers will next explore whether ErSO is effective against other types of cancers that contain estrogen receptor.

Study co-authors at the U. of I. also include veterinary clinical medicine professor Timothy Fan, molecular and integrative physiology professor Erik Nelson, and professor emeritus of pathology Edward Roy. Fan, Hergenrother, Nelson, Shapiro and Roy are affiliates of the Cancer Center at Illinois. Fan, Hergenrother and Nelson also are affiliated with the Carl R. Woese Institute for Genomic Biology at Illinois and Hergenrother and Fan are faculty in the Carle Illinois College of Medicine at the U. of I.

Funders of this work include the University of Illinois, the U.S. Department of Defense, the National Institutes of Health, and Systems Oncology. The U. of I. has filed patents on some compounds described in the study.

The paper “A small-molecule activator of the unfolded protein response eradicates human breast tumors in mice” is available online and from the U. of I. News Bureau. DOI: 10.1126/scitranslmed.abf1383

Featured image: A small molecule, ErSO, that eradicates breast cancers in mice by targeting a pathway that protects cancer cells. © Photo by L. Brian Stauffer

Provided by University of Illinois

Medicine

Scientists Develop Intelligent Biodegradable Biomaterial for Breast Cancer Treatment (Medicine)

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Recently, a Chinese research team led by Prof. DONG Wenfei from the Suzhou Institute of Biomedical Engineering and Technology (SIBET) of the Chinese Academy of Sciences, in collaboration with Prof. SHAO Dan from the South China University of Technology and Prof. SUN Wen from the Dalian University of Technology, developed a coordination-responsive diselenide-bridged mesoporous organosilica nanoparticle (MON)-loaded with the ruthenium compound (KP1339) for breast cancer chemoimmunotherapy.  

KP1339-loaded MONs exhibited the glutathione (GSH) -stimulated coordination and redox dual-responsive drug release profile while induced intracellular GSH depletion and reactive oxygen species production in breast cancer cells.

Cancer chemoimmunotherapy has enjoyed significant clinical progress in recent years. Immunogenic cell death (ICD) is a particular form of cell death induced by various cancer therapeutics which elicit innate and adaptive immune responses. Although chemoimmunotherapy benefits treatment for solid tumors and inhibition of distant metastases, several studies have reported that anti-cancer drugs alone fail to promote sufficient ICD or elicit strong antitumor immunological responses. Further amplifying the chemotherapy-driven ICD in a natural or/and artificial manner is urgently warranted.

Amplification of chemotherapy-driven ICD has been achieved through nanoparticulate carriers with tumor targeting and controlled-drug release capable of responding to external or internal stimuli.  

MONs are excellent candidates for clinical application because of their tunable structure/chemistry and large surface area with controllable matrix degradation and responsive drug release. One of the scientific research subjects to be solved in cancer therapy is designing intelligent MONs that can be degraded and conduct controlled drug release in response to the tumor microenvironment characteristics, such as acidity, hypoxia, and high redox. 

According to the researchers, a high concentration of diselenide-bridged MON specifically evoked oxidative and ER stress to induce and amplify ICD. The cancer cell membrane coating strategy promoted the MON@KP1339-amplified ICD. It boosted robust antitumor immunity, which further demonstrated better regression of both primary and distant tumors, as well as metastasis inhibition in combination with a PD-L1 immune checkpoint inhibitor.  

This study suggests the design of biomimetic diselenide-bridged MON-based potential ICD nanoamplifier with a possibility of coordination and redox dual-responsive drug release and amplified ICD for efficient and safe cancer chemoimmunotherapy. 

The research article “Coordination and Redox Dual-Responsive Mesoporous Organosilica Nanoparticles Amplify Immunogenic Cell Death for Cancer Chemoimmunotherapy” has been published in Small. 

Featured image: Schematic of synthesis of diselenide-bridged MONs for coordination-responsive drug release and amplified ICD for efficient and safe cancer chemoimmunotherapy.(Image by SIBET)

Provided by Chinese Academy of Sciences

Medicine

Potential Drug Target For Difficult-to-treat Breast Cancer: RNA-binding Proteins (Medicine)

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Studies using human cell lines and tumors grown in mice provide early evidence that inhibiting RNA-binding proteins, a previously overlooked family of molecules, might provide a new approach for treating some cancers

In cancer research, it’s a common goal to find something about cancer cells — some sort of molecule — that drives their ability to survive, and determine if that molecule could be inhibited with a drug, halting tumor growth. Even better: The molecule isn’t present in healthy cells, so they remain untouched by the new therapy.

Plenty of progress has been made in this approach, known as molecular targeted cancer therapy. Some current cancer therapeutics inhibit enzymes that become overactive, allowing cells to proliferate, spread and survive beyond their norm. The challenge is that many known cancer-driving molecules are “undruggable,” meaning their type, shape or location prohibit drugs from binding to them.

University of California San Diego School of Medicine researchers are now exploring the therapeutic potential of RNA-binding proteins, a relatively untapped family of cancer-driving molecules. After genes (DNA) are transcribed into RNA, these proteins provide an extra layer of cellular control, determining which RNA copies get translated into other proteins and which don’t. Like many molecular systems that govern cell growth, RNA-binding proteins can contribute to tumor development when they malfunction.

In their latest study, publishing July 2, 2021 in Molecular Cell, the UC San Diego School of Medicine team discovered in human cells and mouse models that RNA-binding proteins represent a new class of drug targets for cancers, including triple-negative breast cancer, a particularly difficult-to-treat cancer because it lacks most other molecular drug targets.

One RNA-binding protein in particular stood out: YTHDF2. When the researchers genetically removed YTHDF2 from human triple-negative breast tumors transplanted into mice, the tumors shrank approximately 10-fold in volume.

“We’re excited that RNA-binding proteins look like they could be new class of drug targets for cancer,” said senior author Gene Yeo, PhD, professor of cellular and molecular medicine at UC San Diego School of Medicine. “We’re not yet sure how easily druggable they are in this context, but we’ve built a solid framework to begin exploring them.”

Yeo led the study with Jaclyn Einstein, PhD, a graduate student in his lab. Einstein will join a startup company spun out from the lab to explore YTHDF2’s druggability.

Yeo’s team has long studied the role of RNA-binding proteins in a number of other diseases. In 2016, for example, they discovered that mutations in one such protein contribute to ALS by scrambling crucial cellular messaging systems.

To begin exploring RNA-binding proteins as cancer drug targets, the researchers turned to an old philosophy known as synthetic lethality. In this one-two punch approach, they started with human breast cells engineered to over-produce another well-known cancer-driving molecule, and looked for additional vulnerabilities specific to those cells.

The researchers systematically silenced RNA-binding proteins in these cancer cells one-by-one using the CRISPR gene editing technique. They found 57 RNA-binding proteins that, when inhibited, kill cancer cells with the known hyperactive cancer-driver. The advantage of the synthetic lethal approach is that normal cells, which don’t produce that cancer-driving molecule, should be left untouched by the treatment. Of these 57 RNA-binding proteins, YTHDF2 appeared most promising.

Yeo’s team also recently developed a new laboratory technique called Surveying Targets by APOBEC-Mediated Profiling (STAMP), which allows them to measure what had previously been largely invisible: how RNA-binding proteins interact with RNA molecules within individual cells.

The researchers used STAMP in this study to get a detailed look at how the various cells that make up a breast tumor behave without YTHDF2. The approach revealed that YTHDF2-deficient cancer cells die by stress-induced apoptosis, a carefully controlled mechanism cells use to destroy themselves. Apoptosis is supposed to shut down malfunctioning cells so tumors don’t arise, but it doesn’t always work. By removing YTHDF2, they managed to re-activate this cell death signal.

To test how safe it might be to treat cancer by inhibiting YTHDF2, the researchers engineered mice that lack YTHDF2 in every cell of the adult body, not just transplanted breast cancer cells. The mice appeared completely normal — not only did they not have tumors, there were no changes in body weight or behavior.

“Those otherwise healthy mice tell us that we might expect minimal adverse side effects of potential therapies that work by targeting YTHDF2,” Einstein said.

Co-authors of the study also include: Mark Perelis, Isaac A. Chaim, Julia K. Nussbacher, Alexandra T. Tankka, Brian A. Yee, Assael A. Madrigal, Archana Shankar, all at UC San Diego; Jitendra K. Meena, Heyuan Li, Nicholas J. Neill, Siddhartha Tyagi, Thomas F. Westbrook, all at Baylor College of Medicine.

Disclosure: Gene Yeo and Jaclyn Einstein are inventors on a patent disclosure at UC San Diego related to this work. Yeo is co-founder, member of the Board of Directors, equity holder, on the Scientific Advisory Board and paid consultant for Locanabio and Eclipse BioInnovations. Yeo is a visiting faculty at the National University of Singapore. The terms of these arrangements have been reviewed and approved by the University of California San Diego in accordance with its conflict-of-interest policies.

Featured image: Triple-negative breast cancer cells are shown on the left. Without the RNA-binding protein YTHDF2 (right), fewer cancer cells survived. © UC San Diego Health Sciences

Reference: Jaclyn M. Einstein, Mark Perelis, Isaac A. Chaim, Jitendra K. Meena, Julia K. Nussbacher, Alexandra T. Tankka, Brian A. Yee, Heyuan Li, Assael A. Madrigal, Nicholas J. Neill, Archana Shankar, Siddhartha Tyagi, Thomas F. Westbrook, Gene W. Yeo, Inhibition of YTHDF2 triggers proteotoxic cell death in MYC-driven breast cancer, Molecular Cell, 2021, , ISSN 1097-2765, https://doi.org/10.1016/j.molcel.2021.06.014. (https://www.sciencedirect.com/science/article/pii/S1097276521004937)

Provided by UCSD

Medicine

Using Targeted Therapy to Treat Breast Cancer (Medicine)

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Proton therapy is a newer type of radiation therapy that uses energy from positively charged particles called protons. Studies have suggested that proton therapy may cause fewer side effects than traditional radiation, since doctors can better control where the proton beams deposit their energy.

In this Mayo Clinic Minute, Dr. Robert Mutter, a Mayo Clinic radiation oncologist, explains potential long-term advantages of using targeted therapy to treat breast cancer.

Watch: The Mayo Clinic Minute.

Journalists: Broadcast-quality video (1:03) is in the downloads at the end of this post. Please courtesy: “Mayo Clinic News Network.” Read the script.

Unlike traditional X-ray radiation, proton beam therapy can more precisely target tumors, sparing more normal tissue.

“The main advantage is this idea of sparing normal tissues and reducing late side effects of treatment. This is especially important in breast cancer,” says Dr. Mutter.

Dr. Mutter says because the heart sits right behind breast tissue, using protons to target breast cancer tumors can reduce the radiation dose to the heart and lungs, and may offer better outcomes for patients.

“We think that that’s going to lead to less risk of heart disease, and less risk of lung disease or second cancers in the future,” says Dr. Mutter.

In recent years, Dr. Mutter says studies have shown the potential to safely shorten the course of radiation treatment for breast cancer.

“We think that protons may be a way that we can do this even more effectively because protons expose less normal tissues. If we can reduce the number of daily treatments, that means that my patients are able to be back with their families, or back at their work or the things that they love to do, and not coming in for their treatment,” he says.

Provided by Mayo Clinic

Medicine

Breast Cancer’s Response to Tumor Stiffness May Predict Bone Metastasis (Medicine)

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In cases of breast cancer, bone metastasis – when cancer cells spread to new sites in the bone – causes the most breast cancer-related harm and is often incurable in advanced disease. A new study by University of Arizona Health Sciences researchers found that cancer cells become more aggressive when exposed to tissue stiffening and that these changes persist over time. 

Tumor stiffening, which develops as diseased breast tissue becomes fibrotic, plays a major role in how breast cancer cells spread throughout the body. The paper, “Breast tumor stiffness instructs bone metastasis via maintenance of mechanical conditioning,” published today in the journal Cell Reports, found that the stiffness of the breast tumor microenvironment can cause changes to cancer cells that make them more aggressively spread to the bone. The resulting changes are maintained as “mechanical memory,” which instructs the cancer cells to send signals that lead to the breakdown of bone. Once this happens, patients often suffer debilitating complications like spontaneous fractures.

Casey Romanoski, PhD, is one of the researchers who helped develop the MeCo score.
Casey Romanoski, PhD, is one of the researchers who helped develop the MeCo score. © UAHS

“Unfortunately, bone metastasis is normally not identified until an advanced state when it’s not reversible,” said senior author Ghassan Mouneimne, PhD, associate professor of cellular and molecular medicine and cancer biology in the UArizona College of Medicine – Tucson. “What’s really exciting is one day being able to take a sample from the patient’s primary tumor and predict who is at high risk for bone metastasis. Then we could intervene with a prevention strategy that we are now validating in the lab.” 

The study, which is the first to demonstrate the concept of mechanical memory during cancer metastasis, developed a novel mechanical conditioning, or “MeCo,” score, to quantify the cellular changes. Eventually, researchers hope the MeCo score can be used to help identify breast cancer patients who might benefit from repurposed antifibrotic treatments to prevent bone metastasis. 

“The higher the patient’s breast tumor MeCo score, the higher the likelihood they would go on to have bone metastasis and poorer outcomes,” said Casey Romanoski, PhD, assistant professor of cellular and molecular medicine and a member of the BIO5 Institute and UArizona Cancer Center. “This stiffness signature could have incredible clinical utility.”

To further explore the clinical application, Dr. Mouneimne and Adam Watson, PhD, a former graduate student and postdoctoral fellow at the UArizona Cancer Center, worked with Tech Launch Arizona, the office of the university that commercializes inventions stemming from research, to launch a startup, MeCo Diagnostics, LLC. The company is working toward maturing the technology and bringing it to the marketplace where it can impact the lives of breast cancer patients everywhere. 

It was previously known that tumor stiffness induces cellular changes that lead to a more aggressive cancer, but according to Dr. Watson, lead author on the paper, the concept of “stiffness” was misleading. 

“Most early-stage breast tumors are stiffer than surrounding tissue, yet most don’t spread to bone,” he said. “It’s not about tumor stiffness but rather stiffness responsiveness of the cancer cells, which we call mechanical conditioning.” 

To study this phenomenon, the team created a laboratory environment that mimicked the stiff or soft tumor environments encountered in the body and assessed how breast cancer cells responded. They found that cells grown in a stiff environment had a “mechanoresponse” characterized by cell spreading, invasion and turning on genes linked with both bone development and disease. And these gene changes endured even after the cells were moved to a soft environment.  

Next, researchers looked at what genes were turned on and off in breast cancer cells in response to the stiff environments. Based on these gene expression changes, they developed the MeCo score, which was validated and refined using data from thousands of patients with breast cancer.

“This is the culmination of a lot of work by researchers from many different fields,” Dr. Mouneimne said. “It highlights the environment we have at the University of Arizona Health Sciences, and how working together can make progress in this challenging area of breast cancer metastasis.”

Future investigations could focus on how cancer cells maintain the gene expression changes that drive metastasis, based on additional findings that identified a transcription factor called RUNX2 that was activated by fibrotic-like stiffness. RUNX2 stays attached to the DNA as the cell divides and “bookmarks” which genes remain turned on, which includes the genes that drive bone metastasis and the breakdown of bone.

Featured image: Ghassan Mouneimne, PhD, hopes the findings of a recently concluded study will lead to a way to predict which breast cancer patients are at high risk for bone metastasis. © UAHS

Provided by University of Arizona Health Sciences

Medicine

PARPi Prevents Disease Recurrence in BRCA-mutated High-risk, Early Stage Breast Cancer (Medicine)

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  • Full results from the OlympiA Phase III, multicenter trial promise to extend the use of PARPi olaparib as adjuvant therapy for patients with early-stage, high-risk breast cancer with a germline BRCA mutation.
  • Reflecting the relevance of this potentially practice-changing study, these data were selected to first outing during a Plenary Session at the American Society of Clinical Oncology’s (ASCO), 2021 Virtual Annual Meeting, 04 – 08 June.
  • Driven through a global academic and industry partnership, including VHIO, OlympiA opens up a new treatment avenue to prevent disease recurrence for these patients.

In the quest to establish more potent treatment strategies that target vulnerabilities in BRCA1/2-associated cancers, PARP inhibitor (PARPi) olaparib (Lynparza®) continues to drive more precise and personalized therapeutic approaches. By prolonging survival and reducing risk of disease progression, this anti-cancer therapy has been approved for the treatment of both BRCA1/2 mutated advanced breast and ovarian cancers, and is also licensed as maintenance therapy after response to platinum-based chemotherapy for the latter.

Over the past two decades, the development and regulatory approval of an array of more personalized and targeted therapies against breast cancer continue to significantly improve outcomes for patients. However, an estimated 2.3 million women were diagnosed with this disease worldwide in 2020 (1). As the most common cancer among women globally, the vast majority of breast cancer cases are diagnosed at an early stage.

BRCA mutations are found in approximately 5% of breast cancer patients. Around 55-65% of women with a BRCA1 mutation, and approximately 45% with a BRCA2 mutation will develop breast cancer before the age of 70 (2). Despite advances in treatment, many patients with high-risk disease will unfortunately develop a recurrence.

Responding to these trends, the OlympiA interventional Phase III study (3), directed by Andrew Tutt, Institute of Cancer Research and Kings College London (UK), aimed at extending the personalized and targeted promise of olaparib to patients with early-stage, primary, high-risk HER2-negative breast cancer and a germline BRCA1/2 mutation (gBRCAm), to improve clinical outcomes as well as prevent disease recurrence.

OlympiA is an active, double-blind, randomized trial (1:1) which enrolled 1836 patients with high-risk HER2-negative breast cancer and gBRCAm to receive adjuvant therapy with olaparib or placebo for 12 months. Randomisation was stratified by hormone receptor status (ER and/or PgR positive/HER2 negative versus TNBC), prior neoadjuvant versus adjuvant chemotherapy, and prior platinum use for breast cancer.

Selected to first outing during a Plenary Session (4) at the American Society of Clinical Oncology’s (ASCO), 2021 Virtual Annual Meeting, 04 – 08 June, and publish simultaneously in The New England Journal of Medicine (5), data showed that targeted treatment with olaparib achieved a superior 40% reduced risk of disease recurrence compared with the control group. Efficacy assessment of results obtained upon 3.5 years’ follow-up showed a 7% absolute risk reduction of distant relapse in patients treated with olaparib, compared with placebo.

Judith Balmaña, Principal Investigator of VHIO’s Hereditary Cancer Genetics Group, member of the SOLTI academic research group, an OlympiA Steering Committee member, investigator and co-author of this present study observed, “Regarding the recurrence of invasive disease, analysis at three years revealed that 77% of patients in the placebo arm and 86% of those receiving olaparib showed no relapse. Furthermore, as an orally administered therapy with low-level toxicity, this agent promises an improved quality of life for these patients.”  She continued, “Showing that patients with early-stage high-risk breast cancer with a germline BRCA1/2 mutation can be more effectively treated with targeted therapy, and also signposting greater opportunities for cure, these results are potentially practice-changing.”

“Previous results presented during last year’s ASCO 2020 Virtual Annual Meeting (6), also co-authored by Judith Balmaña, evidenced the efficacy and safety of olaparib as monotherapy in HER2-negative gBRCA-mutated metastatic breast cancer. Data from this present, major International study point to a new, more effective treatment strategy using olaparib for patients with early-stage disease towards cure,” concluded Cristina Saura, Principal Investigator of VHIO’s Breast Cancer Group.

Supported by NRG Oncology and AstraZeneca, the OlympiA trial is powered by a major   global academic and industry collaborative partnership between the Breast International Group, NRG Oncology, the US National Cancer Institute (NCI), Frontier Science & Technology Research Foundation (FSTRF), Astra Zeneca, Myriad Genetics Laboratories, Inc., Br.E.A.S.T. – Data Center & Operational Office at the Institut Jules Bordet, and Merck Sharp & Dohme Inc.

Featured image: Dr. Judith Balmana © VHIO

References

  1. GLOBOCAN. Breast Cancer. December 2020: https://gco.iarc.fr/today/data/factsheets/cancers/20-Breast-fact-sheet.pdf.
  2. National Breast Cancer Foundation. BRCA: The Breast Cancer Gene. Available at https://www.nationalbreastcancer.org/what-is-brca.
  3. Randomised, Double-blind, Parallel Group, Placebo-controlled Multi-centre Phase III Study to Assess the Efficacy and Safety of Olaparib Versus Placebo as Adjuvant Treatment in Patients With gBRCA1/2 Mutations and High Risk HER2 Negative Primary Breast Cancer Who Have Completed Definitive Local Treatment and Neoadjuvant or Adjuvant Chemotherapy. NCT02032823.
  4. Virtual 2021 ASCO Annual Meeting, 04-08 June: Plenary Session, Sunday, June 06, 19:00h – 22:00h CEST. LBA1: OlympiA: A phase III, multicenter, randomized, placebo-controlled trial of adjuvant olaparib after (neo)adjuvant chemotherapy in patients with germline BRCA1/2 mutations and high-risk HER2-negative early breast cancer.
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Medicine

Better Choice Of Contraceptives Can Prevent Breast Cancer (Medicine)

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An EPFL study into the distinct biological effects of different progestins on the breast shows that contraceptive-related breast cancer can be prevented by more informed choices about the composition of contraceptives.

Hormonal contraceptives, e.g. the pill, the patch, and the vaginal ring, contain synthetic hormones that prevent pregnancy by either stopping ovulation, changing the cervical mucus to stop sperm from passing through the cervix and finding an egg, or changing the womb’s lining to prevent a fertilized egg from being implanted in it.

Despite their widespread use, hormonal contraceptives are known to increase the risk of breast cancer, which is the most common cause of cancer-related death among women worldwide, and also topped the list of most commonly diagnosed cancers in 2020.

The main component of hormonal contraceptives are progestins, which, mimic the female sex hormone progesterone. Progesterone is involved in a number of biological processes, including the menstrual cycle, pregnancy, and various aspects of fetal development, like brain programming.

Now, a team of scientists led by Professor Cathrin Brisken at EPFL’s School of Life Sciences, have taken a thorough and close look at the different biological effects that different progestins in hormonal contraceptives have on the breast tissue – the mammary epithelium. The work is published in EMBO Molecular Medicine.

“Although we know how different contraceptive formulations affect the cardiovascular system, we know little about their effects on the breast,” says Brisken. “So we developed new approaches to compare the most commonly used progestins in different hormonal contraceptives and were surprised to find that some of them stimulate cell proliferation in the breast – while others do not.”

The researchers tested the effects of prolonged exposure to different progestins on human breast epithelial cells or HBECs, which line the inner layer of the breast. To do this, they developed “humanized” mouse mammary glands by grafting breast epithelial cells from donated human breast tissue from reduction mammoplasty samples into the animals’ milk ducts and monitoring their growth in vivo.

“We found that HBECs engraft and proliferate in mouse milk ducts, maintaining hormone receptor expression and hormone responsiveness, which are crucial factors for establishing a relevant preclinical model and thereby to foster translational research,” says Brisken.

The team realized that what distinguished the stimulatory and the innocuous progestins were their “androgenic properties” – a technical term for substances that trigger the development of male characteristics, such as body hair, muscle mass etc. This isn’t as strange as it sounds: progesterone, mostly known as a female hormone, is used for the production of the famous male hormone testosterone in both women and men.

Some progestins have androgenic properties, acting like testosterone; some actually block them. The key is a protein known as the androgen receptor, which, when activated by an androgenic progestin, travels into the cell’s nucleus where it regulates the expression of certain genes.

Working with the epithelial cells in a mouse model, the researchers found that androgenic progestins act through the androgen receptor to induce the expression of the protein Rankl, which plays an important role in cell proliferation in the mammary epithelium. This effect was not seen with anti-androgenic progestins.

The study showed that androgenic – but not anti-androgenic – progestins promote cell proliferation. “Exposing human breast epithelia to androgenic progestins for prolonged periods of time caused hyperproliferation and changes in the cells that are associated with early, pre-malignant lesions – at least in xenografted human breast epithelia,” says De Martino.

“Hormonal contraception exposes women to different progestins with or without estrogen,” says Brisken. “The androgenic properties of progestins determine their biological activity in the breast epithelium, and reveal an unexpected role for androgen receptor activity in the proliferation of breast epithelial cells.”

The crucial insight of the study is that progestins with anti-androgenic activity may be a safer option with regards to breast cancer risk than testosterone-related compounds, e.g. the widely used contraceptive levonorgestrel (“Plan B”). “It might be possible to prevent breast cancer associated with contraception by making more informed choices taking the molecular composition of a contraceptive into account,” concludes Brisken.

Other contributors

  • University Hospital of Lausanne (CHUV)
  • International Cancer Prevention Institute

Funding

  • Swiss National Science Foundation
  • Swiss Cancer League
  • Biltema ISREC Foundation Cancera Stiftelsen
  • Mats Paulssons Stiftelse
  • Stitelsen Stefan Paulssons Cancerfond
  • Joint Action and Learning Initiative (JALI)

Featured image: Fluorescence stereo micrograph of a mouse mammary gland intraductally injected with normal human breast epithelial cells. Credit: Marie Shamseddin (EPFL).

Reference: Marie Shamseddin […] Cathrin Brisken, “Contraceptive progestins with androgenic properties stimulate breast epithelial cell proliferation”, EMBO Mol Med (2021)e14314. https://doi.org/10.15252/emmm.202114314

Provided by EPFL