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Spaser can detect, kill circulating tumor cells to prevent cancer metastases, study finds

A nanolaser known as the spaser can serve as a super-bright, water-soluble, biocompatible probe capable of finding metastasized cancer cells in the blood stream and then killing these cells, according to a new research study.

The study found the spaser can be used as an optical probe and when released into the body (possibly through an injection or drinking a solution), it can find and go after circulating tumor cells (CTCs), stick to them and destroy these cells by breaking them apart to prevent cancer metastases. The spaser absorbs laser light, heats up, causes shock waves in the cell and destroys the cell membrane. The findings are published in the journal Nature Communications.

The spaser, which stands for surface plasmon amplification by stimulated emission of radiation, is a nanoparticle, about 20 nanometers in size or hundreds times smaller than human cells. It has folic acid attached to its surface, which allows selective molecular targeting of cancer cells. The folate receptor is commonly overexpressed on the surface of most human cancer cells and is weakly expressed in normal cells.

The discovery was made by researchers at Georgia State University, the University of Arkansas for Medical Sciences, the University of Arkansas at Little Rock and the Siberian Branch of the Russian Academy of Science.

“There is no other method to reliably detect and destroy CTCs,” said Dr. Mark Stockman, director of the Center for Nano-Optics and professor of physics at Georgia State. “This is the first. This biocompatible spaser can go after these cells and destroy them without killing or damaging healthy cells. Any other chemistry would damage and likely kill healthy cells. Our findings could play a pivotal role in providing a better, life-saving treatment option for cancer patients.”

Metastatic cancer occurs when cancer spreads to distant parts of the body, often to the bone, liver, lungs and brain, through a process called metastasis. Many types of cancers refer to this as stage IV cancer. Once cancer spreads, it can be difficult to control, and most metastatic cancer can’t be cured with current treatments, according to the National Institute of Health’s National Cancer Institute. One of the most dangerous ways metastasizing occurs is through the CTCs, which this study aims to detect and destroy using spasers.

The spasers used in this study measure just 22 nanometers, setting the record for the smallest nanolasers. A nanometer is one-billionth of a meter. Most results were obtained with a gold, spherical nanoparticle surrounded by a silica shell and covered with a uranine dye, which is widely used for tracing and biomedical diagnostics.

The researchers studied the spaser’s capabilities in vitro in human breast cancer cells with high folate receptor expression and endothelial cells with low folate receptor expression, as well as in mouse cells in vivo.

They found cells with spasers demonstrated high image contrasts with one or many individual “hot spots” at different laser energies above the spasing threshold. The presence of spasers was confirmed with several optical and electron microscopy techniques, which revealed an initial accumulation of individual spasers on the cell membrane followed by their entrance into the cell cytoplasm.

The study also found low toxicity of the spasers for human cells. At the same time, the spasers subjected to laser irradiation selectively killed the tumor cells without damaging the healthy ones.

Based on the study’s results, spaser-based therapeutic applications with high-contrast imaging is a promising field. The data suggest spasers have high potential as therapeutic and diagnostic agents that integrate optical diagnosis and photothermal-based cell killing, using just a few laser pulses to kill cancer cells.

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A new HER2 mutation, a clinical trial and a promising diagnostic tool for metastatic breast cancer

There is a group of metastatic breast cancers that has the HER2 gene amplified – the cells have many copies of it – which leads to enhanced activity of the product enzyme, a tyrosine kinase. HER2 has been established as a therapeutic target in breast cancer, and breast cancers in which the HER2 gene is not amplified do not, in general, respond to HER2-directed therapeutic approaches.

A few years ago, when the research teams of Dr. Matthew Ellis and others carried out a molecular characterization of breast cancer tumors, they found a new mutation in HER2 that was different from gene amplification but also resulted in tyrosine kinase being constantly activated.

“In this particular activation mechanism, the cells develop a subtle mutation within the functional part of the HER2 gene that activates the enzyme,” said Ellis, professor and director of the Lester and Sue Smith Breast Center, part of the National Cancer Institute-designated Dan L Duncan Comprehensive Cancer Center at Baylor College of Medicine. “The mutation locks the enzyme into an ‘on’ position.”

Ellis and his colleagues developed a preclinical model to study this new HER2 mutation and discovered that the enhanced enzymatic activity could trigger tumor formation. Furthermore, these tumor cells were sensitive to an experimental drug, neratinib. With this information in hand, the researchers took the next step.

“We launched a phase II clinical trial of neratinib in patients with metastatic breast cancer carrying a HER2 mutation,” Ellis said. “Finding patients that are positive for a HER2 mutation required a national collaboration because we had to screen hundreds of patients to identify the 2 to 3 percent that have a tumor driven by a HER2 mutation. The results of the clinical trial were encouraging in that about 30 percent of the 16 patients treated with neratinib had a meaningful clinical response showing significant disease stabilization or regression. Neratinib was well tolerated by most patients.”

“This is the first time we had a reasonable number of patients treated for HER2 mutations in whom we could estimate the response rate.”

The number of patients who could potentially benefit from this new treatment approach is estimated to be in the thousands. The researchers estimate that as many as 200,000 patients are likely to be living with metastatic breast cancer today in the United States. Based on the estimate that the new mutation is present in 2 to 3 percent of cases, the researchers calculated that approximately 4,000 to 6,000 patients with metastatic breast cancer carry a HER2 mutation and are therefore potential candidates for neratinib treatment.

Circulating tumor DNA analysis, a promising diagnostic tool

To identify the patients in this study who carried the new HER2 mutation, the researchers required tissue from the tumor, a biopsy, from which they could extract and sequence the genetic material to determine the presence of the HER2 mutation. This task turned out to be a major challenge because for 20 to 30 percent of the patients the researchers did not have sufficient material to make the diagnosis.

“To assist in our ability to identify patients with HER2 mutation-positive tumors, we conducted circulating tumor DNA analysis,” Ellis said. “The tumor’s DNA is released into the human bloodstream, and we were able to determine the presence of the mutation in blood samples from the patients. Importantly the circulating tumor DNA results were highly concordant with the tumor sequencing results, and they were much easier to determine. Notably, the blood test was sensitive enough that we could use it as a tool to determine eligibility for the clinical trial.”

In addition to bringing to the table a novel treatment for metastatic breast cancer carrying a HER2 mutation, the researchers have tested the value of the circulating tumor DNA as a disease-monitoring marker.

“A circulating tumor DNA-based blood test also could therefore be potentially used to monitor tumor progression and to determine whether patients are responding or not to treatment after just one month of therapy,” Ellis said.

Ellis also is a McNair Scholar at Baylor.

Read all the details of this study, the full list of contributors and their financial support in Clinical Cancer Research.

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A new HER2 mutation, a clinical trial and a promising diagnostic tool for metastatic breast cancer

There is a group of metastatic breast cancers that has the HER2 gene amplified – the cells have many copies of it – which leads to enhanced activity of the product enzyme, a tyrosine kinase. HER2 has been established as a therapeutic target in breast cancer, and breast cancers in which the HER2 gene is not amplified do not, in general, respond to HER2-directed therapeutic approaches.

A few years ago, when the research teams of Dr. Matthew Ellis and others carried out a molecular characterization of breast cancer tumors, they found a new mutation in HER2 that was different from gene amplification but also resulted in tyrosine kinase being constantly activated.

“In this particular activation mechanism, the cells develop a subtle mutation within the functional part of the HER2 gene that activates the enzyme,” said Ellis, professor and director of the Lester and Sue Smith Breast Center, part of the National Cancer Institute-designated Dan L Duncan Comprehensive Cancer Center at Baylor College of Medicine. “The mutation locks the enzyme into an ‘on’ position.”

Ellis and his colleagues developed a preclinical model to study this new HER2 mutation and discovered that the enhanced enzymatic activity could trigger tumor formation. Furthermore, these tumor cells were sensitive to an experimental drug, neratinib. With this information in hand, the researchers took the next step.

“We launched a phase II clinical trial of neratinib in patients with metastatic breast cancer carrying a HER2 mutation,” Ellis said. “Finding patients that are positive for a HER2 mutation required a national collaboration because we had to screen hundreds of patients to identify the 2 to 3 percent that have a tumor driven by a HER2 mutation. The results of the clinical trial were encouraging in that about 30 percent of the 16 patients treated with neratinib had a meaningful clinical response showing significant disease stabilization or regression. Neratinib was well tolerated by most patients.”

“This is the first time we had a reasonable number of patients treated for HER2 mutations in whom we could estimate the response rate.”

The number of patients who could potentially benefit from this new treatment approach is estimated to be in the thousands. The researchers estimate that as many as 200,000 patients are likely to be living with metastatic breast cancer today in the United States. Based on the estimate that the new mutation is present in 2 to 3 percent of cases, the researchers calculated that approximately 4,000 to 6,000 patients with metastatic breast cancer carry a HER2 mutation and are therefore potential candidates for neratinib treatment.

Circulating tumor DNA analysis, a promising diagnostic tool

To identify the patients in this study who carried the new HER2 mutation, the researchers required tissue from the tumor, a biopsy, from which they could extract and sequence the genetic material to determine the presence of the HER2 mutation. This task turned out to be a major challenge because for 20 to 30 percent of the patients the researchers did not have sufficient material to make the diagnosis.

“To assist in our ability to identify patients with HER2 mutation-positive tumors, we conducted circulating tumor DNA analysis,” Ellis said. “The tumor’s DNA is released into the human bloodstream, and we were able to determine the presence of the mutation in blood samples from the patients. Importantly the circulating tumor DNA results were highly concordant with the tumor sequencing results, and they were much easier to determine. Notably, the blood test was sensitive enough that we could use it as a tool to determine eligibility for the clinical trial.”

In addition to bringing to the table a novel treatment for metastatic breast cancer carrying a HER2 mutation, the researchers have tested the value of the circulating tumor DNA as a disease-monitoring marker.

“A circulating tumor DNA-based blood test also could therefore be potentially used to monitor tumor progression and to determine whether patients are responding or not to treatment after just one month of therapy,” Ellis said.

Ellis also is a McNair Scholar at Baylor.

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Radiation Therapy Prior to Surgery Reduces the Risk of Secondary Tumors in Early-Stage Breast Cancer Patients

Breast cancer patients receiving neoadjuvant radiation therapy have improved cancer-free survival over adjuvant radiation

Moffitt Cancer Center researchers launched a first of its kind study comparing the long-term benefits of radiation therapy in women with breast cancer either before surgery (neoadjuvant) or after surgery (adjuvant). Their study, published in the June 30 issue of Breast Cancer Research, found that patients who have neoadjuvant radiation therapy have a significantly lower risk of developing a second primary tumor at any site.

The majority of patients who have early stage breast cancer have surgery to remove their tumor or a complete mastectomy. Surgery is commonly followed by radiation therapy, which has been shown to increase relapse-free survival. However, in some cases, patients may require neoadjuvant radiation therapy to decrease the size of the tumor before surgery.  Currently, there are no studies that have analyzed the long-term effects of neoadjuvant radiation therapy on breast cancer patients.

Moffitt researchers compared the overall survival and the time to diagnosis of a second tumor, if any, of 250,195 breast cancer patients who received either neoadjuvant or adjuvant radiation therapy. They analyzed patient outcomes from a National Cancer Institute (NCI) registry database of cancer incidence and survival rates in the United States.  They included female patients in the analysis who were diagnosed between 1973 and 2011 with early-stage breast cancer. The analysis included 2,554 women who received localized neoadjuvant breast radiation therapy before surgery and 247,641 women who received localized adjuvant breast radiation therapy after surgery.

The researchers discovered that among the breast cancer patients who tested positive for the estrogen receptor (ER) biomarker, patients who had neoadjuvant radiation therapy had a significantly lower risk of developing a second primary tumor than patients who had adjuvant radiation therapy. This was true for patients who underwent both partial and complete mastectomies.  The researchers found that delaying surgery due to neoadjuvant radiation therapy was not a detriment to survival.

A number of recent studies have suggested that radiation therapy may re-educate and stimulate the immune system to target cancer cells. “The observed benefit of neoadjuvant radiation therapy aligns with the growing body of literature of the immune activation effects of radiation, including shrinking of untreated metastases outside the radiation field,” explained Heiko Enderling, Ph.D., associate member of Moffitt’s Integrated Mathematical Oncology Department.

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Study shows biomarkers can predict which ER-positive breast cancer patients respond best to first-line therapy

Two challenges in treating patients with estrogen-positive breast cancer (ER+) have been an inability to predict who will respond to standard therapies and adverse events leading to therapy discontinuation. A study at The University of Texas MD Anderson Cancer Center revealed new information about how the biomarkers retinoblastoma protein (Rb) and cytoplasmic cyclin E could indicate which patients will respond best to current first-line therapies.

The study also discovered that combining the current therapy with autophagy inhibitors will result in using one-fifth of the dosage of the standard treatment, which could significantly reduce side effects associated with this therapy. Findings were published in the June 27 issue of Nature Communications.

Standard treatment, consisting of palbociclib, often has adverse side effects and not all ER+ patients respond to the therapy. Palbociclib inhibits proteins called CDK4 and CDK6 (CDK4/6) and tumor cells escape this inhibition by activating autophagy, a process allowing cancer cells to thrive even when starved of nutrients. By combining palbocicilb with autophagy inhibitors in cells that express normal Rb and nuclear cyclin E, the dose of palbociclib was significantly reduced.

Khandan Keyomarsi, Ph.D., professor of Experimental Radiation Oncology, led a team that demonstrated how CDK4/6 and autophagy inhibitors synergistically induce cell senescence in Rb-positive cytoplasmic cyclin E-negative cancers. CDK4/6 inhibitors are approved by the Food and Drug Administration (FDA).

“Our findings could impact the majority of ER+ and HER2-negative breast cancers accounting for about 60 percent of advanced breast cancers,” said Keyomarsi. “We demonstrated for the first time evidence that Rb and cytoplasmic cyclin E status have a very strong effect on predicting response to the current standard first-line therapy for this population of patients, hormonal therapy plus palbociclib.We also discovered that by inhibiting the pathway such as autophagy that causes tumor cells to escape palbociclib growth inhibition, CDK4/6 inhibitor was more effective.”

Deregulation of cell cycle checkpoint proteins, such as CDK4/6, is a key hallmark of cancer, resulting in uncontrolled cellular growth and tumor formation. Some CDK4/6 inhibitors, including palbociclib, ribociclib and abemaciclib, have shown potential in pre-clinical and clinical studies in numerous solid tumors. Palbociclib has demonstrated benefits in Phase II and III trials in advanced ER+ breast cancers, doubling progression-free survival compared to drugs such as letrozole or fulvestrant, and is currently being evaluated clinically in other solid tumors.

“Data provided through The Cancer Genome Atlas revealed alterations in the CDK4/6/cyclin D pathway in about 35 percent of the patients, making them an ideal population for targeting CDK4/6,” said Keyomarsi. “Our study revealed that inhibition of CDK4/6 and autophagy pathways cooperate to induce sustained growth inhibition and senescence in vitro and in vivo, in breast and other solid tumors and showed how autophagy inhibition can significantly decrease the dose of palbociclib required to treat breast cancer patients. We believe this new strategy can improve the efficacy of other CDK4/6 inhibitor treatments like ribociclib and abemaciclib.”

The team’s findings indicated how Rb and cyclin E status predicts response to a combination of CDK4/6 and autophagy inhibition in pre-clinical models and that autophagy blockade is successful in reversing resistance to palbociclib.

“Palbociclib resistance is a significant limitation of this treatment which is not curative and does not prolong survival even though transient responses and prolongation of response have formed the basis of FDA approval,” said Keyomarsi. “Our study provides evidence that models of hormone receptor-negative cancer and even non-breast cancer malignancies can respond to the combination of palbociclib and autophagy inhibition, when selected based on Rb and cyclin E isoform status, representing a completely new therapeutic opportunity for these cancers.”

Keyomarsi and colleagues anticipate future clinical studies based on this pre-clinical and clinical evidence with the aim of developing translational and clinical applications.

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Custom built molecule shows promise as anti-cancer therapy

Scientists at the University of Bath funded by Cancer Research UK have custom-built a molecule which stops breast cancer cells from multiplying in laboratory trials, and hope it will eventually lead to a treatment for the disease.

But perhaps even more importantly the method they used to create the molecule has potential to be applied to develop new treatments for a wide range of cancers and other diseases.

The team, from the Department of Biology & Biochemistry, working with colleagues at the University of Queensland in Australia and the University of Bristol, modified a protein which can interfere with cell multiplication in many cancers, including breast cancer, by binding with another protein and rendering it inactive.

They took a small piece of the protein, called a peptide, that is known to be important in binding, and modified it to retain the structure otherwise lost when cut out. The modification has the additional advantage of protecting the peptide from being broken down within cells. The resulting molecule still binds to its target protein and inhibits cancer cell multiplication, but crucially can travel across cell membranes to get at it. The full-sized proteins, which the peptides are taken from, are usually too large to protect from breakdown or to cross protective cell membranes so this removes a literal barrier to developing treatments.

The study is published in the journal ACS Chemical Biology

Dr Jody Mason, one of the lead researchers on the project, said: “Peptides have the potential to be incredibly potent drugs which are exquisitely specific for their target. However they are easily broken down in the body, much like when we eat a steak. We have modified the peptides so that they retain the structure they have within the full-size protein and can therefore bind to the target “

Professor David Fairlie, from the University of Queensland added “This is a particularly challenging cancer target involving intertwined proteins and large surfaces that must be blocked. International collaborations like this one have the potential to combine resources and scientific skills from multiple disciplines to conquer difficult problems in targeting human disease.”

Dr Justine Alford, Cancer Research UK’s senior science information officer, said: “This early study may have laid the groundwork for a potential new treatment for certain cancers by creating a sophisticated designer molecule that can effectively block a cancer-fuelling target in cells.

“Cancer survival is improving, but people still die from their disease, so we need to develop innovative ways such as this that could help more people survive in the future.” The team now intend to continue to work on the molecule to improve its stability, with a long-term view to it eventually becoming a cancer drug, although this is still years away.

They are also interested in finding other candidate peptides for similar trials.

The researchers believe that other small peptides are a promising avenue of research to create new treatments for different types of cancer, and potentially other diseases such as Alzheimer’s disease

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A patent study on the great new hope emerging from marine derived anticancer drugs

Microtubule dynamics govern crucial cellular functions and this is why microtubules are one of the most attractive anticancer drug targets. Microtubule targeting agents (MTAs) have the ability to treat a wide range of cancers. However, drug induced cytotoxicity and adverse side effects have hindered their development. Another major setback is multiple drug resistance in tumor cells. These limitations have prompted the need to develop novel MTAs from alternative sources, with better therapeutic efficacies. Recently, MTAs from marine sources have grabbed much attention due to their unique tubulin binding features and remarkable ability to reduce tumor progression.

The authors have summarized some of the most promising marine derived MTAs by systematically searching patent databases such as USPTO, Espacenet and WIPO for recent patents published from 2006 up to 2016. After a critical data analysis, only those patents focusing on the chemical synthesis and/or modifications of marine derived MTAs along with a significant demonstration of their in vitro and/or in vivo activity have been reviewed.

The survey of recent patents revealed that chemically modified versions of marine derived MTAs, overcoming drug resistance and their novel combination therapies increasing the overall efficacy, have positioned them as future anticancer blockbusters. Of particular interest are dolastatin, laulimalide, peloruside, hemiasterlin, halichondrin, eribulin mesylate, discodermolide, dictyostatin, cryptophycin and their analogs which have significant antiproliferative potency against a wide array of cancers and are also able to overcome multidrug resistance. A deeper understanding of the molecular mechanisms behind the specific drug interactions and of microtubule molecular biology in general, combined with innovative therapeutic regimen would lead to major advances in the field of cancer therapy.

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Talking Breast Cancer for Men’s Health Awareness Week

Males account for less than 1 percent of all breast cancer cases in the United States. In 2017, an estimated 2,470 American men will be diagnosed with the disease; 460 will die.

While rare among men, breast cancer symptoms, diagnosis and survival are similar for both genders. Men experience many of the same primary symptoms or signs of breast cancer: a lump or swelling in the chest area or new irregularities on the skin or nipples, such as redness, scaliness or puckering. Because male breasts generally have less tissue than female, it’s easier to detect lumps. However, some men with breast cancer never display obvious signs of the disease or fail to notice them.

“Both men and women benefit from being aware of their bodies and seeking care with their primary care providers for changes,” said Richard Schwab, MD, oncologist with Moores Cancer Center at UC San Diego Health.

The earlier breast cancer is detected, the better the chances of recovery and survival. In the earliest stages, the five-year survival rate (the percentage of people who live at least five years after diagnosis, excluding other causes of death) is 99 percent. If the cancer has spread to local lymph nodes, the 5-year survival rate drops to 85 percent. If the cancer metastasizes to more distant parts of the body, the rate falls to 27 percent.

As with women, men have a higher risk of developing cancer if they have a family history of breast disease or a mutation in a breast cancer risk gene, such as BRCA1 or BRCA2. In addition, age, high levels of radiation, elevated levels of estrogen (which can be caused by genetic conditions), other diseases, some kinds of medical treatment and lifestyle can increase a man’s risk of breast cancer.

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Study discovers proteins which suppress the growth of breast cancer tumors

Researchers at the University of Birmingham have found that a type of protein could hold the secret to suppressing the growth of breast cancer tumours.

The research, published today in Oncogenesis, examined the role Proline-Rich Homeodomain protein (PRH) can play in the progression of breast cancer tumours and could, in turn, help to better determine the prognosis for patients with the disease.

Dr Padma Sheela Jayaraman, of the University of Birmingham’s Institute of Cancer and Genomic Sciences, said: “PRH is a protein that controls and regulates when genes are switched on or off.

“However, prior to our research, the role of this protein in breast cancer has been poorly understood.

“Public databases show that, in a large number of breast cancer patients with a poor prognosis, the activity of the PRH gene had decreased.

“However, it was not known whether the amount of PRH protein was also lower in these patients as protein levels had not been recorded.”

The researchers used a special staining process on breast cancer tissue removed during biopsy to observe the levels and location of PRH proteins in breast cancer cells. They found that in a small study there were changes in PRH proteins in tumour cells compared to normal cells that were consistent with the decreased activity of the PRH gene in the public database.

Dr Jayaraman added: “In the laboratory, we found that when PRH protein levels are reduced in a breast tumour the cells are more able to divide, speeding up the progression of the tumour.

“Moreover, we identified some of the genes which are regulated by PRH and specifically contribute to the increased cell division.”

The researchers also carried out tests in a tumour model of mammary cancers, increasing PRH levels to observe the effect.

“We made the significant finding that high levels of PRH actually blocked the formation of the tumours, therefore our data suggests that PRH can block tumour formation in some breast cancers,” added Dr Jayaraman.

“We propose that monitoring PRH protein levels or activity in patients with breast cancer could be particularly important for assessing their prognosis.

“In addition, since PRH is known to be important in multiple cell types, this work has important implications for other types of cancer.

“We are now working to investigate the importance of PRH in prostate cancer and in cancer of the bile duct, a type of liver cancer.”

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Three-Week Radiation Therapy Treatment Given Post Mastectomy Is Safe and Effective

Rutgers Cancer Institute of New Jersey research shows low toxicity in shorter treatment course

A shorter course of radiation therapy given to breast cancer patients following mastectomy is safe and effective and cuts treatment time in half. That is according to data from a phase II clinical trial conducted by Rutgers Cancer Institute of New Jersey investigators and other colleagues who examined a hypofractionated regimen given over three weeks versus the traditional six week course of treatment. The work appears in the current online edition of the Journal of Clinical Oncology (http://ascopubs.org/doi/full/10.1200/JCO.2016.70.7158).

When there is a concern that cancer cells may remain in the chest wall and lymph node regions following a mastectomy, a patient may be given targeted radiation over a five to six week period to further treat the breast cancer. “Receiving radiation for that long of a period becomes a quality of life issue for many patients. This includes the inconvenience of frequent travel to the treatment facility, as well as fatigue and other common side effects that can cause lost time at work and other challenges,” notes the work’s senior investigator Bruce G. Haffty, MD, professor and chair, Department of Radiation Oncology at Rutgers Cancer Institute, Rutgers Robert Wood Johnson Medical School and Rutgers New Jersey Medical School.

Researchers explored an accelerated course of radiation that cut treatment time in half. Currently, there is limited data supporting this type of treatment in this patient population.

From 2010 to 2014, 67 eligible patients with stage II to IIIa breast cancer were enrolled at Rutgers Cancer Institute of New Jersey and Huntsman Cancer Institute at the University of Utah. A dose of 36.63 Gy (a unit of radiation measurement) was given in 11 fractions of 3.33 Gy each.  The fractions were delivered over a three-week period to the chest wall and area lymph nodes.  The treatment also allowed for an optional four fractions (3.33 Gy each) of radiation to the chest wall at the mastectomy scar area, resulting in a total of 15 treatments over three weeks.

The aim was to not have any reported treatment toxicities of grade three or above. After a median follow up of 32 months, no grade three toxicities or higher were reported. There were 29 grade two toxicities reported, with a majority being skin rash followed by fatigue, similar to what may be experienced with the longer five to six week course of treatment. The estimated three-year survival rate of the cancer not coming back to the breast area was 89.2 percent.  The estimated three-year survival rate for the cancer not coming back and spreading beyond the breast was 90.3 percent.

“While shorter courses of radiation therapy have been adopted in patients receiving radiation therapy to the breast alone after lumpectomy, there has not been adoption of shorter courses of treatment to the chest wall and lymph nodes after mastectomy. This trial demonstrated the safety of this shorter course approach in a prospective phase II study,” notes Dr. Haffty.

Based on this study, a larger post-mastectomy randomized trial has been developed through the Alliance Cooperative Group with Haffty and current study investigators Matt Poppe of the Huntsman Cancer Institute and Atif J. Khan of Memorial Sloan Kettering Cancer Center leading the effort.  In this phase III trial, a shorter course of radiation in the post-mastectomy, post-reconstruction setting will be compared to the more conventional five to six week course of treatment.

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For Women at Risk of Hereditary Breast Cancer, Multigene Test Could Help Extend Life Expectancy

Value in Health, the official journal of the International Society for Pharmacoeconomics and Outcomes Research (ISPOR), announced today the publication of new research indicating that testing for variants in 7 cancer-associated genes (versus the usual process of testing in just 2 genes) followed by risk-reduction management could cost-effectively improve life expectancy for women at risk of hereditary breast cancer. The report of these findings, A Multigene Test Could Cost-Effectively Help Extend Life Expectancy for Women at Risk of Hereditary Breast Cancer, was published in the April 2017 issue.

Using hypothetical cohorts of women at risk of hereditary breast cancer, the authors used a decision-analytic model to compare the relative cost and effectiveness of two test strategies for detecting pathogenic genetic variants: 1) the usual BRCA1/2 test strategy, and 2) a next-generation 7-gene strategy that tests for variants not only in BRCA1 and BRCA2, but also in TP53, PTEN, CDH1, STK11, and PALB2. The authors then used these test results to select appropriate breast cancer risk reduction treatments / therapies.

In the base-case scenario for 50- and 40-year-old women undergoing genetic testing, the incremental cost-effectiveness ratio (ICER) for the 7-gene test strategy compared with the BRCA1/2 test strategy was $42,067 and $23,734 per life-year gained, or $69,920 and $48,328 per quality-adjusted life-year gained, respectively. At these ICER levels, the 7-gene test strategy would be considered cost effective according to the World Health Organization guidelines.

“Pathogenic variants in the BRCA1 and BRCA2 genes explain only about 15% of the breast cancer familial relative risk,” said lead author Yonghong Li, PhD, Quest Diagnostics, USA, “while pathogenic variants in other genes, including TP53, PTEN, CDH1, and PALB2 contribute further to the familial relative risk. The results of this study,” Dr. Li added, “demonstrate the potential value of newer testing options that allow for the simultaneous analysis of expanded panels of additional genes whose pathogenic variants confer moderate to high risk for breast cancer.”

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Rogue Breast Tumor Proteins Point to Potential Drug Therapies

For patients with difficult-to-treat cancers, doctors increasingly rely on genomic testing of tumors to identify errors in the DNA that indicate a tumor can be targeted by existing therapies. But this approach overlooks another potential marker — rogue proteins — that may be driving cancer cells and also could be targeted with existing treatments.

If DNA can be described as the body’s genetic blueprint, proteins can be thought of as the construction workers who carry out the plan. Studying the blueprint can be vital to understanding genetic diseases, including cancer, but that focus also means that some problems arising with the workers may be missed.

Studying mice with breast tumors transplanted from patients, researchers at Washington University School of Medicine in St. Louis, The Broad Institute of MIT and Harvard, and Baylor College of Medicine have analyzed the proteins present in these tumors. The researchers demonstrated that some protein alterations can be used to identify drugs that may work against some cancers. The work is part of the National Cancer Institute’s (NCI) Clinical Proteomic Tumor Analysis Consortium efforts.

The study is published March 28 in Nature Communications.

“Proteins carry out most of the biological functions in the cell,” said senior author Li Ding, PhD, an associate professor of medicine at Washington University. “Knowing the DNA sequence does not automatically tell us everything about the proteins doing work in the cells. This is another layer of tumor complexity that we need to explore to identify new therapies.”

Ding said recent advances in a technology called mass spectrometry and in techniques to analyze massive quantities of data have made complex studies of the proteins in tumor cells possible. Another reason to prioritize the systematic study of proteins in tumors — cancer proteomics — is that the vast majority of cancer therapies developed from genetic studies actually target proteins.

“Identifying the rogue proteins of cancer is an important pathway toward developing new drugs,” said co-author R. Reid Townsend, MD, PhD, a professor of medicine and director of the Proteomics Shared Resource at Washington University.

“We can use proteomics to confirm and validate our genomics findings,” said Ding, also an assistant director of The McDonnell Genome Institute at Washington University School of Medicine. “In addition, it’s another tool to uncover additional events that drive cancer and are specific to individual patient tumors, including the amount of the ‘rogue’ protein, its specific form, or the type and extent of chemical modifications of the proteins that we know are treatable with approved or investigational drugs. We also can test these therapies in the mice before we evaluate them in patients.”

Steven A. Carr, PhD, of the Broad Institute, said the team analyzed a chemical modification called phosphorylation, which plays a central role in how healthy, as well as diseased, cells communicate.

“Disruption or enhancement in such signaling is often directly related to disease mechanism and can be targeted for therapy,” Carr said.

The researchers studied 24 tumor samples from breast cancer patients after the samples were transplanted into mice. Twenty-two of the transplanted samples retained their genetic and proteomic identities as specific types of breast cancer. A proteomic analysis of the tumors also identified multiple protein targets that have the potential to respond to drugs.

For example, the researchers showed dialed-up activity of multiple protein pathways that could be targeted with investigational drugs called PI3K inhibitors and mTOR inhibitors, separately and in combination, depending on the tumor. They also showed that drugs against a type of breast tumor called HER2 positive breast cancer — such as the dual ERBB2/EGFR inhibitor lapatinib — potentially could benefit more patients than currently receive them, if analysis of the tumor proteins is taken into consideration.

While most of these tumor models recapitulated specific types of breast cancer, Ding said the scientists were surprised to see that two of the 24 tumors evolved into a completely different type of cancer after transplantation into the mice. Instead of breast cancer, they resembled lymphoma and were driven by the cancer-causing virus Epstein-Barr, according to the researchers. Lymphomas are cancers of immune cells that may have arisen from lymphatic tissue present in the breast tumors transplanted into the mice.

The analysis of the lymphoma-like cancers was the first proteomic study of this type of tumor. Though unintentional, Ding said the analysis provides an explanation for why investigational drugs that inhibit a protein called BTK have been effective in treating patients with lymphoma.

“Since it is the proteins that interact directly with drugs, the strength of studying proteomics in patient-derived tumor models is the ability to test drug treatment in the mice,” Ding said. “With advances in cancer proteomics that increase the speed of measurement, we are moving toward a future that includes genomic and proteomic analyses of patient tumors.”

Co-author Matthew J. Ellis, MD, PhD, of Baylor, agreed. “The mouse work is promising enough to adapt these technologies for real time analysis of patient materials so that clinical trials can be designed to test this new diagnostic and drug selection approach,” he said.

Other key contributors to this project are Kuan-lin Huang, a PhD student in genomics and bioinformatics at Washington University; Shunqiang Li, PhD, an assistant professor of medicine at Washington University; Philipp Mertins, PhD, of The Broad Institute; and Sherri Davies, a senior scientist at Washington University.

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Scientists Find Possible Achilles Heel of Treatment Resistant Cancers

Scientists identify two signaling proteins in cancer cells that make them resistant to chemotherapy, and show that blocking the proteins along with chemotherapy eliminate human leukemia in mouse models.

Reporting results March 20 in Nature Medicine, researchers at Cincinnati Children’s Hospital Medical Center suggest that blocking the signaling proteins c-Fos and Dusp1 as part of combination therapy might cure several types of kinase-driven, treatment-resistant leukemia and solid tumor cancers.

These include acute myeloid leukemia (AML) fueled by the gene FLT3, lung cancers fueled by genes EGFR and PDGFR, HER2-driven breast cancers, and BCR-ABL-fueled chronic myeloid leukemia (CML), according to Mohammad Azam, PhD, lead investigator and a member of the Division of Experimental Hematology and Cancer Biology.

“We think that within the next five years our data will change the way people think about cancer development and targeted therapy,” Azam says. “This study identifies a potential Achilles heel of kinase-driven cancers and what we propose is intended to be curative, not just treatment.”

The weak spot is a common point of passage in cells (a signaling node) that appears to be required to generate cancer cells in both leukemia and solid tumors. The node is formed by the signaling proteins c-Fos and Dusp1, according to study authors. The researchers identified c-Fos and Dusp1 by conducting global gene expression analysis of mouse leukemia cells and human chronic myeloid leukemia (CML) cells donated by patients.

CML is a blood cancer driven by an enzyme called tyrosine kinase, which is formed by the fusion gene BCR-ABL. This fusion gene is the product of translocated chromosomes involving genes BCR (chromosome 22) and ABL (chromosome 9). Analysis of human CML cells revealed extremely high levels of c-FOS and DUSP1 in BCR-ABL-positive chemotherapy resistant cells.

Cancer sleeper cells

Cancer cells often become addicted to the mutated gene that causes them, such as BCR-ABL in kinase-driven chronic myeloid leukemia. Most chemotherapies work by blocking molecular pathways affected by the gene to shut down the disease process. In the case of CML, a chemotherapy called imatinib is used to block tyrosine kinase, which initially stops the disease. Unfortunately the therapeutic benefit is temporary and the leukemia comes back.

Azam and colleagues show in their CML models that signaling from tyrosine kinase – and growth factor proteins that support cell expansion (like interleukins IL3, IL6, etc.) – converge to dramatically elevate c-Fos and Dusp1 levels in the cancer cells.

Working together these molecules maintain the survival of cancer stem cells and minimal residual disease. The dormant cells wait around under the radar screen to rekindle the disease by acquiring additional genetic mutations after initially effective chemotherapy.

Azam says Dusp1 and c-Fos support the survival of cancer stem cells by increasing the toxic threshold needed to kill them. This means conventional imatinib chemotherapy will not eliminate the residual disease stem cells. Doctors can’t just increase the dose of chemotherapy because it doesn’t target the Dusp1 and c-Fos proteins that regulate toxic threshold.

Targeting c-Fos and Dusp1

After identifying c-Fos and Dusp1, the authors tested different treatment combinations on mouse models of CML, human CML cells, and mice transplanted with human leukemia cells. They also tested treatments on B-cell acute lymphoblastic leukemia (B-ALL).

The treatment combinations included: 1) solo therapy with just the tyrosine kinase inhibitor, imatinib; 2) solo treatment with just inhibitors of c-Fos and Dusp1; 3) treatment with all three combined – imatinib along with molecular inhibitors of c-Fos and Dusp1.

As suspected, treatment with imatinib alone initially stopped CML progression but the leukemia relapsed with the continued presence of residual disease cells. Treatment with c-Fos and Dusp1 inhibitors alone significantly slowed CML progression and prolonged survival in a majority of mice but wasn’t curative. Treatment for one month with c-Fos/Dusp1 inhibitors and imatinib cured 90 percent of mice with CML, with no signs of residual disease cells.

Azam and his colleagues also point to an interesting finding involving solo treatment with just the deletion of c-Fos and Dusp1. This eliminated expression of the signaling proteins and was sufficient to block B-ALL development, eradicating the disease in mouse models.

Next steps

The authors stress that because the study was conducted in laboratory mouse models, additional research is needed before the therapeutic strategy can be tested in clinical trials.
They are following up the current study by testing c-Fos and Dusp1as treatment targets for different kinase-fueled cancers, including certain types of lung cancer, breast cancers and acute forms of leukemia.

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A Vulnerability in Triple-Negative Breast Cancer Could Improve Treatment Outcomes

Ludwig researchers have shown that triple-negative breast cancer cells ramp up production of a key component of DNA in response to chemotherapy and that targeting this pathway could undermine their resistance to such therapies.

A team of researchers led by Alex Toker of the Ludwig Center at Harvard has discovered a metabolic weakness in triple-negative breast cancer (TNBC) cells that may be exploited to quell their resistance to chemotherapy.

TNBC is notoriously aggressive and is difficult to treat because its cells lack the targetable receptors found in other forms of breast cancer. Only about 30 percent of TNBC patients achieve a pathologic complete response, or a complete eradication of active cancer cells, following chemotherapy. Those who do frequently relapse shortly afterward.

“Trying to understand the mechanisms that contribute to cancer’s resistance to therapy is a major mission here at the Ludwig Center at Harvard,” said Alex Toker.

In the new study, published online in the journal Cancer Discovery, Toker, an investigator at the Ludwig Center at Harvard Medical School, and his team including lead author Kristin Brown, formerly of the Ludwig Center at Harvard and now at Peter MacCallum Cancer Center in Melbourne, Australia, outline a newly discovered chink in the armor of TNBC cells. This “metabolic vulnerability” can be used to circumvent chemotherapy resistance.

The scientists demonstrated that chemotherapy effectively reprograms TNBC cells to ramp up production of the pyrimidine nucloetides, key building blocks of DNA. This heightens the cells’ DNA repair abilities and ultimately results in greater resistance to chemotherapies that work by damaging the DNA of rapidly dividing cells.

“This actually makes sense if you think about it, because if a tumor cell is going to repair DNA and therefore evade the death-inducing effects of chemotherapy, the only way they can really do that is by rebuilding DNA, and the only way to rebuild DNA is to make more nucleotides,” Toker said.

Toker and his team reasoned that blocking the pyrimidine synthesis pathway in TNBC cells would hinder their DNA repair abilities and make them more susceptible to the DNA-damaging effects of chemotherapy. To test this hypothesis, the team exposed TNBC cells in the lab to a drug combination of doxorubicin, a commonly used chemotherapy agent, and leflunomide, a known inhibitor of dihydroorotate dehydrogenase (DHODH), a crucial enzyme in the biochemical reactions that generate pyrimidines.

“One of the major reasons we chose leflunomide is because we wanted a rapid path to clinical impact, and leflunomide is already FDA-approved and widely used to treat autoimmune diseases such as rheumatoid arthritis,” Toker said.

Toker’s group found that leflunomide blocked the increase of pyrimidine nucleotides in TNBC cells, thus impairing their ability to repair the DNA damage dealt by doxorubicin, and resulting in increased cancer cell death.

The scientists then repeated the experiment in mice that had been transplanted with human TNBC cells. “We found that treating the mice with doxorubicin or leflunomide alone only slowed tumor growth, but that a combination therapy involving both drugs resulted in significant tumor regression,” Toker said.

Importantly, the combination therapy in mice did not cause any weight loss or gain in the animals – an indication that the drug regimen might be reasonably well-tolerated in humans.

“One of the things we would like to do is develop clinical trials in patients with this combination strategy, whether it be with leflunomide or some other drugs that are coming online that might have better pharmacological properties in patients,” Toker said.

In the meantime, Toker said his group is moving forward with plans to investigate the molecular basis of increased pyrimidine biosynthesis in TNBC cells.

“There is something about this pathway in triple negative breast cancer that is especially important,” Toker said. “We don’t know what the genetic basis underlying it is, but it’s something we would really like to find out.”

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Breast Cancer Patients with Dense Breast Tissue More Likely to Develop Contralateral Disease

Breast cancer patients with dense breast tissue have almost a two-fold increased risk of developing disease in the contralateral breast, according to new research from The University of Texas MD Anderson Cancer.

The study, published in the journal Cancer, is among the first to find the association between breast density (BD) and contralateral breast cancer (CBC).

According to study author Isabelle Bedrosian, M.D., a big challenge in the management of this patient population, especially as they are making surgical decisions, is trying to counsel women appropriately on their risk of developing breast cancer in the other breast.

“We know there are a number of well-established influences for developing both primary and secondary breast cancers, such as BRCA mutations, family history, and the tumor’s estrogen receptor status,” explained Bedrosian, associate professor, Breast Surgical Oncology. “We also know density is a risk factor for the development of primary breast cancer. However, no one has closely looked at it as a risk factor for developing contralateral disease.”

The estimated 10-year risk for women with breast cancer developing CBC can be as low as 2 percent, and as high 40 percent, said Bedrosian. The dramatic range is due in large part to the variability of risk factors across the patient population, she explained.

For the retrospective, case-controlled study, the researchers identified 680 stage I, II and III breast cancer patients, all treated at MD Anderson between 1997 and 2012. BRCA patients were excluded from the study, given their known increased risk of CBC.

Women with an additional diagnosis of metachronous CBC – defined as BC in the opposite breast diagnosed more than six months after the initial diagnosis – were the “cases,” and patients who had not developed CBC were the “controls.” Cases and controls were matched on a 1:2 ratio based on a number of factors, including age, year of diagnosis and hormone receptor status.

“With our research, we wanted to evaluate the relationship between the mammographic breast density of the original disease and the development of metachronous breast cancer,” said Carlos Barcenas, M.D., assistant professor, Breast Medical Oncology, and the study’s corresponding author.

Of the selected patients, 229 were cases and 451 were controls. The MD Anderson researchers categorized each patient’s breast density by mammogram reading, assessed at the time of first diagnosis, as “nondense” or “dense,” using the categorizations from the American College of Radiology.

Among the cases, 39.3 percent were classified as having nondense breast tissue and 60.7 percent as having dense breast tissue, compared to 48.3 percent and 51.7 percent, respectively, in the controls.

After adjusting for known breast cancer risk factors, the researchers found almost a two-fold increased risk of developing CBC in breast cancer survivors with dense breasts.

“Our findings have valuable implications for both newly diagnosed patients with dense breasts and for breast cancer survivors as we manage their long-term risk of a secondary diagnosis,” said Barcenas. “Our future goal is to develop a risk model incorporating breast density to best assess a breast cancer survivor’s risk of developing CBC.”

In the long-term, the researchers hope to use this tool to counsel patients on their personal risk and their options for treatment and surveillance, if their risk is sufficiently high.

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Tucatinib (ONT-380) Progressing in Pivotal Trial Against HER2+ Breast Cancer

Phase 1 clinical trial data published this week in the journal Clinical Cancer Research show early promise of the investigational anti-cancer agent tucatinib (formerly ONT-380) against HER2+ breast cancer. The 50 women treated had progressed despite a median 5 previous treatment regimens. Twenty-seven percent of these heavily pretreated patients saw clinical benefit from the drug, with at least “stable disease” at 24 or more weeks after the start of treatment. These data led to two subsequent Phase Ib studies, resulting in tucatinib earning FDA fast-track status and the expansion of this study once meant only to demonstrate drug safety into the “pivotal” trial that will determine approval.

“Usually we expect the results of a phase 1 clinical trial to give us data that we can use to guide the results of future treatments. This is a great case in which, for many of these patients, the results were immediate. There are women who are alive today because of this drug,” says Virginia Borges, MD, MMSc, director of the Breast Cancer Research Program and Young Women’s Breast Cancer Translational Program at the University of Colorado Cancer Center. Borges has been a major driver of the drug’s development from its invention at Array Biopharm in Boulder, CO and now through clinical trials of the drug, which is licensed to Cascadian Therapeutics of Seattle, WA.

Tucatinib is a small molecule inhibitor of the HER2 growth factor receptor. The drug works by targeting the HER2 “tyrosine kinase” – a link in the chain of communication that allows HER2 receptors to signal the growth of the cell. The fact that it is a small molecule means the drug is able to pass through the blood-brain barrier to act against brain metastases of the disease. HER2+ breast cancer is more likely to affect younger women and also more likely than other breast cancers to metastasize specifically to the brain.

Working with Borges’s Young Women’s Breast Cancer Translational Program at CU Cancer Center, young investigator Elena Shagisultanova, MD, PhD, recently earned a $1.4m competitive ASPIRE grant from Pfizer, Inc., to conduct a clinical trial exploring the use of tucatinib against so-called “triple positive” breast cancer – those cancers driven by both estrogen and progesterone receptors and the HER2/neu oncogene.

“When both [estrogen and HER2] are positive, they counteract the therapy aimed at one or the other, playing off each other like kids splitting parents,” Borges says. More specifically, when both avenues are present, the crosstalk leads to tumors being resistant to treatment, as either avenue can allow the cancer to survive therapy. Previous trials concurrently targeting estrogen and HER2 have been, according to Borges, “lackluster,” resulting in no changes to the standard of care.

The forthcoming trial lead by Shagisultanova will be a multi-center clinical trial with CU Cancer Center as the lead site, testing the combination of three drugs – tucatinib plus the anti-estrogen receptor drug letrozole and the cell cycle inhibitor palbociclib – against breast cancers positive for both HER2 and estrogen receptors.
“Tucatinib could be a substantially practice-changing drug,” Borges says, meaning that in addition to the drug’s current investigations as a third-, fourth-, or more-than-fifth-line treatment, she envisions its use sooner in the arc of breast cancer treatment and with far more patients.

“I think this drug has an extremely high likelihood of being approved for women with HER2+ breast cancer for use after previous treatments,” Borges says. “And it’s going to be an especially important drug due to its ability to control brain metastases. The opportunity to study it as a front-line drug for recurrent triple positive breast cancer could even someday help us prevent or delay these brain metastases.”

Because the drug is taken in pill form and has a very favorable side effect profile, Borges points out that it is relatively patient-friendly, allowing women to avoid treatments in infusion centers and also many of the side-effects associated with chemotherapies.

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Researchers Find Key Genetic Driver for Rare Type of Triple-Negative Breast Cancer

Researchers find key genetic driver for rare type of triple-negative breast cancer

New mouse model leads to surprising discovery that sheds light on metaplastic breast cancer

For more than a decade, Celina Kleer, M.D., has been studying how a poorly understood protein called CCN6 affects breast cancer. To learn more about its role in breast cancer development, Kleer’s lab designed a special mouse model – which led to something unexpected.

They deleted CCN6 from the mammary gland in the mice. This type of model allows researchers to study effects specific to the loss of the protein. As Kleer and her team checked in at different ages, they found delayed development and mammary glands that did not develop properly.

“After a year, the mice started to form mammary gland tumors. These tumors looked identical to human metaplastic breast cancer, with the same characteristics. That was very exciting,” says Kleer, Harold A. Oberman Collegiate Professor of Pathology and director of the Breast Pathology Program at the University of Michigan Comprehensive Cancer Center.

Metaplastic breast cancer is a very rare and aggressive subtype of triple-negative breast cancer – a type considered rare and aggressive of its own. Up to 20 percent of all breast cancers are triple-negative. Only 1 percent are metaplastic.

“Metaplastic breast cancers are challenging to diagnose and treat. In part, the difficulties stem from the lack of mouse models to study this disease,” Kleer says.

So not only did Kleer gain a better understanding of CCN6, but her lab’s findings open the door to a better understanding of this very challenging subtype of breast cancer. The study is published in Oncogene.

“Our hypothesis, based on years of experiments in our lab, was that knocking out this gene would induce breast cancer. But we didn’t know if knocking out CCN6 would be enough to unleash tumors, and if so, when, or what kind,” Kleer says. “Now we have a new mouse model, and a new way of studying metaplastic carcinomas, for which there’s no other model.”

One of the hallmarks of metaplastic breast cancer is that the cells are more mesenchymal, a cell state that enables them to move and invade. Likewise, researchers saw this in their mouse model: knocking down CCN6 induced the process known as the epithelial to mesenchymal transition.

“This process is hard to see in tumors under a microscope. It’s exciting that we see this in the mouse model as well as in patient samples and cell lines,” Kleer says.

The researchers looked at the tumors developed by mice in their new model and identified several potential genes to target with therapeutics. Some of the options, such as p38, already have antibodies or inhibitors against them.

The team’s next steps will be to test these potential therapeutics in the lab, in combination with existing chemotherapies. They will also use the mouse model to gain a better understanding of metaplastic breast cancer and discover new genes that play a role it its development.

“Understanding the disease may lead us to better ways to attack it,” Kleer says. “For patients with metaplastic breast cancer, it doesn’t matter that it’s rare. They want – and they deserve – better treatments.”

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The Role of Common Risk Factors in ER-Positive, ER-Negative Breast Cancer

Karla Kerlikowske, MD, and team recently published a paper in the Journal of the National Cancer Institute that examined the role of common risk factors in the development of ER-positive and ER-negative breast cancers. The study sheds new light on how a woman’s age, weight, and menopausal status affect her risk for breast cancer. Dr. Kerlikowske discusses the findings below.


What was the aim of the study?
The goal of the study was to examine how common breast cancer risk factors play a role in the development of estrogen receptor (ER)-positive versus ER-negative invasive breast cancer. Some breast cancer cells contain receptors that attach to the hormone estrogen that can fuel the growth of breast cancer cells. ER-positive tumors have receptors that attach to the hormone estrogen, whereas ER-negative breast cancers do not.

What led you to pursue this question?
Primary prevention with hormone therapy (selective estrogen receptor modulators or aromatase inhibitors) blocks the effects of estrogen in the breast tissue so cells don’t receive the hormone estrogen’s signals to grow and multiply. Hormone therapy leads to a decrease in the risk of estrogen receptor positive- but not estrogen receptor negative breast cancer.
It is important to know which women are at increased risk for each cancer subtype so women at increased risk of ER-positive cancer can discuss with their provider hormone therapy as an option for prevention.

Does the study address gaps in existing research?
Most studies examining the role of risk factors in the development of breast cancer have examined risk of breast cancer overall, rather than by ER cancer subtype. Studies that have examined risk factors for ER cancer subtype have been small and inconsistent in their results.
Our large prospective Breast Cancer Surveillance Consortium (BCSC) cohort study was able to examine risk for ER-positive and ER-negative invasive cancer with strong, prevalent risk factors according to a woman’s age and menopausal status.

What are your chief findings?
We found family history of breast cancer in a first degree relative, benign breast disease, and breast density increased the risk for both ER-positive and ER-negative invasive breast cancer, but the level of risk varied by age. We also found postmenopausal women who were overweight or obese were similarly at increased risk of ER-positive and ER-negative cancer while peri/premenopausal women who were overweight or obese were at increased risk of ER-negative cancer to a greater extent than ER-positive cancer.
Women at highest risk in our study had benign breast lesions with proliferative changes (overgrowth of the cells that line the ducts or the milk glands). These women were at high risk of ER-positive cancer.

Why is this new information? And why is it significant?
Prior studies show premenopausal women who are overweight or obese are not at increased risk of ‘premenopausal’ breast cancer because assessment of weight is measured close to the time of diagnosis.
We found premenopausal women who are overweight or obese are at increased risk of breast cancer in the next ten years, and at greatest risk of ER-negative breast cancer which is more difficult to treat than ER-positive breast cancer.

Premenopausal covers a huge age variance — is there heightened risk for overweight women in their 20s, 30s?
Premenopausal was defined as women who reported a menstrual period within the last 180 days, were under age 40, or birth control hormone users. Perimenopausal women were not sure if their periods had stopped; or their last menstrual period was 180-364 days ago.

What is the link between extra weight and increased risk?
Postmenopausal women who are overweight or obese have elevated circulating estrogens to promote breast tumor growth. Premenopausal women who are overweight or obese have high blood levels of insulin and insulin-like growth factor and chronic low-grade inflammation. It has been hypothesized that they are possible mechanisms by which obesity increases breast cancer risk in these women.

What are the implications of the findings?
These findings provide new information for women and providers about which women are at increased risk of ER-positive versus ER-negative breast cancer. This will aid discussions about preventive measures such as losing weight or the option of preventive hormone therapy.

Can the findings be incorporated into clinical practice?
Peri/premenopausal and postmenopausal women who are overweight or obese should be encouraged to lose weight to decrease breast cancer risk.
Women with benign lesions that show proliferative changes on breast biopsies are at increased risk of ER-positive breast cancer and should calculate their 5-year risk of breast cancer using the BCSC risk calculator (https://tools.bcsc-scc.org/BC5yearRisk/). If risk is >3%, women should be counseled on preventive measures such as taking hormone therapy.

How much do premenopausal women have to be overweight to have higher risk? Can it be just 5 or 10 lbs. or does it have to be significant, say, 30 or more lbs.?
Overweight is six to seven pounds or more above what is considered ideal body weight for a woman’s height.

What should women do to lower their risk?
Maintain ideal body weight for their height and exercise regularly.

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Moffitt Cancer Center Researchers Report Promising Clinical Activity and Minimal Toxicities for HER2-Targeted Dendritic Cell Vaccines in Early-Stage Breast Cancer Patients

HER2-Targeted Dendritic Cell Vaccines Stimulate Immune Responses and Regression of HER2-Expressing Early-Stage Breast Tumors

Deregulation and inhibition of the immune system contributes to cancer development. Many therapeutic strategies aim to restimulate the immune system to recognize cancer cells and target them for destruction. Researchers from Moffitt Cancer Center report that a dendritic cell vaccine that targets the HER2 protein on breast cancer cells is safe and effectively stimulates the immune system leading to regression of early-stage breast cancer.

The HER2 protein is overexpressed in 20-25% of all breast cancer tumors and is associated with aggressive disease and poor prognosis. Moffitt researchers have previously shown that immune cells are less able to recognize and target cancer cells that express HER2 as breast cancer progresses into a more advanced and invasive stage. This suggests that strategies that can restimulate the immune system to recognize and target HER2 early during cancer development may be effective treatment options.

The Moffitt researchers previously developed a vaccine that helps the immune system recognize the HER2 protein on breast cancer cells. Their approach involves creating the vaccine from immune cells called dendritic cells that are harvested from each individual patient to create a personalized vaccine.

In order to determine if the HER2-dendritic cell vaccine is safe and effective, the Moffitt researchers performed a clinical trial in 54 women who have HER2-expressing early-stage breast cancer. The dendritic cell vaccines were prepared by isolating dendritic cells from each patients’ blood and exposing them to fragments of the HER2 protein. Patients were injected with a dose of their personal dendritic cell vaccine once a week for 6 weeks into either a lymph node, the breast tumor, or into both sites.

The researchers report that the dendritic cell vaccines were well-tolerated and patients only experienced low-grade toxicities. The most common adverse events were fatigue, injection site reactions, and chills. They also show that the vaccine was able to stimulate an immune response in the majority of the patients. Approximately 80% of evaluable patients had a detectable immune response in their peripheral blood and/or in their sentinel lymph node wherein their cancer is most likely to spread to first. Importantly, the immune responses among the patients were similar, regardless of the route of vaccine administration.

The Moffitt researchers assessed the effectiveness of the vaccine by determining the percentage of patients who had detectable disease within surgical specimens after resection. The absence of disease is termed a pathological complete response (pCR). They report that 13 patients achieved a pCR and patients who had early non-invasive disease called ductal carcinoma in situ (DCIS) achieved a higher rate of pCR than patients who had early-stage invasive disease. Interestingly, patients who achieved a pCR had a higher immune response within their local sentinel lymph nodes.

“These results suggest that vaccines are more effective in DCIS, thereby warranting further evaluation in DCIS or other minimal disease settings, and the local regional sentinel lymph node may serve as a more meaningful immunologic endpoint,” said Brian J. Czerniecki, MD, PhD, Chair of the Department of Breast Oncology at Moffitt Cancer Center.