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Tuesday, May 4, 2021

Risk-reducing mastectomy saves lives of women who, because of hereditary or other risk factors, may have a very high lifetime risk of developing breast cancer, according to two new journal articles written to guide physicians and patients. All of these women should also discuss with their physicians nonsurgical options such as screening and medications to reach the best, customized treatment strategy, the essays mention.

Both articles, published May 4 in the Journal of the American Medical Association (JAMA), are by Ismail Jatoi, MD, PhD, of The University of Texas Health Science Center at San Antonio, and Zoe Kemp, MD, PhD, of the Royal Marsden Hospital in London (2021; doi: 10.1001/jama.2021.1647).

"Women who have a high-risk genetic mutation or have had previous chest wall radiation are potential candidates for surgery to prevent breast cancer," said Jatoi, Professor and Chief of the Division of Surgical Oncology and Endocrine Surgery. He performs cancer surgery at University Hospital and is a member of the tumor board at the Mays Cancer Center, home to UT Health San Antonio MD Anderson Cancer Center.

Most women who undergo risk-reducing mastectomy with breast reconstruction are ultimately relieved that they elected to go through with it. However, doctors and patients should consider all the benefits and risks, including potential quality-of-life issues, prior to any such surgery, Jatoi noted.

BRCA1 and BRCA2 gene mutations are the most common variants that put women at increased risk for breast cancer, but there are other high-risk mutations, as well, such as PTEN, TP53, STK11, CDH1 and PALB2.

"All of these mutations may give women a very high risk for developing breast cancer, a risk that exceeds 50 percent lifetime," Jatoi said. "Oncology teams may want to consider risk-reducing mastectomy for these patients. This surgery does not completely eliminate breast cancer risk, but it reduces it substantially." The risk isn't zero because surgeons can't remove all the breast cancer tissue, he said.

Other mutations, such as CHEK2 and ATM, put patients at moderate risk for developing breast cancer, and confer a risk that may range anywhere from 25 percent to 50 percent lifetime, Jatoi said.

"For those mutations, we don't usually recommend preventive mastectomy, although some women choose to have it done based on family history," he said. "Women with these mutations more often opt for screening or medicines to lower their risk."

Women who have cancer in one breast may have a very high risk for developing cancer in the opposite breast if they have a particular genetic mutation or have received previous radiotherapy treatments to the front of their chests during their childhood years.

"For those women, we do what is called contralateral risk-reducing mastectomy," Jatoi said. "That operation is generally not necessary unless women have a very high risk of developing cancer in the opposite breast."

Women who had chest wall radiation in the past should be carefully evaluated, he noted. "We put them in the same category as women with BRCA1 and BRCA2 mutations. These women had radiation for a different type of cancer, such as Hodgkin lymphoma, usually during childhood. They may be candidates for risk-reducing mastectomy."

The bottom line: A woman needs to weigh the benefits and the risks with her doctor, and decide what options are best for her. "It's not a decision the doctor makes alone," Jatoi concluded.​

Tuesday, May 4, 2021

Concerns about fertility often influence how young women with breast cancer approach treatment decisions and are a reason for forgoing or delaying hormone-blocking therapy, a new study by Dana-Farber Cancer Institute investigators shows.

The findings, published online by the journal Cancer, reinforce the need for physicians to talk with patients about their fertility-related priorities and address them in treatment plans, the study authors write (2021; Such conversations are important not only at the start of treatment, but during its entire course, as patients' goals and preferences may change over time.

"Young women with breast cancer face unique challenges, including issues surrounding fertility," noted the study's lead author Tal Sella, MD, Instructor of Medicine at Dana-Farber. "For many premenopausal women with hormone receptor-positive breast cancer, long-term endocrine therapy [which blocks hormones that feed the cancer's growth] may prevent patients from having children while treatment is under way. In this study, we explored the degree to which fertility concerns affect patients' decisions about receiving such therapy."

Young women with hormone receptor-positive breast cancer—which may grow in response to the hormones estrogen or progesterone—are usually treated with surgery followed by chemotherapy and at least 5 years of endocrine therapy to prevent the cancer from recurring. Endocrine therapy reduces the risk of recurrence by about 50 percent, research indicates, making it the most effective component of post-surgery (adjuvant) therapy.

Study Details
For this study, researchers surveyed 643 participants in the Young Women's Breast Cancer Study, a multi-institutional study of more than 1,300 women at or under the age of 40 when diagnosed with breast cancer from 2006 and 2016, led by principal investigator Ann Partridge, MD, MPH, of Dana-Farber. The participants, all of whom had hormone receptor-positive, stage I-III breast cancer, were asked at the time of diagnosis about their medical history, current medications, fertility concerns, and endocrine therapy decisions, among other subjects. Follow-up surveys were conducted every 6 months for the next 3 years and annually after that.

During the first 2 years after diagnosis, one-third of respondents indicated that fertility concerns affected their decisions regarding endocrine therapy. Forty percent of those who reported these concerns chose not to start, or to discontinue, such therapy, compared to 20 percent of those without such concerns. Of the women who expressed concerns and opted against or stopped endocrine therapy, 66 percent reported at least one pregnancy or pregnancy attempt during that 2-year period. Women who had had children before their diagnosis were less likely to express that concerns affected their endocrine therapy decisions than those who were childless.

These findings will be helpful in conjunction with those of the POSITIVE trial, which is examining whether it is safe for young women with breast cancer to take a break from endocrine therapy in order to have a child. Results of the trial are expected within the coming years.

Our findings shed new light on the dilemma facing many young women with hormone receptor-positive breast cancer: whether to optimize adjuvant treatment or fulfill their desire for children in the near term," said Dana-Farber's Shoshana Rosenberg, ScD, MPH, the new study's senior author. "Physicians can best help their patients by understanding their goals and developing treatment strategies that incorporate their needs."

Tuesday, May 4, 2021

By Warren Froelich

Combining a liquid biopsy with magnetic resonance imaging (MRI) significantly improved accuracy for predicting complete response among patients with locally advanced breast cancer who received neoadjuvant chemotherapy, according to a study presented during the AACR Annual Meeting 2021.

The improved accuracy may spare patients of a sentinel lymph nodes biopsy in the armpit, performed to confirm cancer has not spread to the axillary lymph nodes, the researchers said.

“Radiological procedures such as MRI can be potentially combined with the assessment of circulating biomarkers in order to advance overall accuracy," said Francesco Ravera, MD, PhD, a fellow in the Department of Internal Medicine at the University of Genoa in Italy. “This can bring effective advancements in the pursuit of a personalized and minimally invasive medicine."

Current standard of care to assess a breast cancer patient's response to chemotherapy prior to surgery, or neoadjuvant chemotherapy, includes radiological imaging of the tumor site, such as MRI. The procedure, designed to detect and measure tumor size and location, has an overall accuracy of about 80 percent in correctly assessing pathological complete response, defined as the absence of invasive cancer in breast and axillary nodes.

“Despite being the most accurate radiological procedure for this purpose, MRI does not allow to spare sentinel lymph node biopsy in patients assessed as complete responders, possibly exposing patients to collateral side effects and relevant discomfort," Ravera said in an interview.

Previous studies have demonstrated the potential efficacy of liquid biopsies, particularly plasma cell-free DNA (cfDNA) integrity, as a biomarker for the early diagnosis, recurrence, and response to therapy. Low cfDNA integrity, which corresponds to high cfDNA fragmentation, is a typical feature of neoplastic patients. When healthy cells die, they typically release similarly sized DNA fragments into the bloodstream. However, when cancer cells die, they release DNA fragments of varying sizes. By measuring the quantity of different fragmented sizes, clinicians can estimate the integrity of patients' cfDNA.

To estimate the accuracy of cfDNA integrity in assessing response of neoadjuvant therapy among breast cancer patients, Ravera and colleagues evaluated plasma taken from 38 patients who had completed an anthracycline/taxane-based treatment prior to surgery. Concentrations of different cfDNA fragments were assessed, with fragments ranging in size from 90-150 base pairs (bp), 150-220 bp, 221-320 bp, 100-300 bp, and 100-300 bp.
A score known as a cfDNA integrity index (DII) is typically expressed as the ratio of the concentration of long cDNA fragments to short cfDNA fragments. Fragment size ranges evaluated as the most informative indicators of response to neoadjuvant therapy were selected to calculate a measure of DNA integrity, expressed as a ratio of 321-1,000 bp concentration to 150-220 bp size fragments.

“The concentrations of 150-220 bp size fragments, typically derived from cellular apoptosis, significantly varied from pathological complete response patients and was therefore selected as a parameter to calculate cfDNA integrity index," Ravera said. “Fragments ranging from 321 to 1,000 bp presumably derived instead from non-apoptotic processes of cellular death.

“The cfDNA integrity index was therefore calculated as the ratio of the concentration of presumably necrotic cfDNA fragments to the one of fragments derived from cellular apoptosis."

Among the 38 patients evaluated, 11 experienced pathological responses following neoadjuvant chemotherapy, while 27 patients experienced an incomplete response, with residual disease either in the breast or axillary nodes following treatment. MRI had an accuracy of 77.1 percent, while the cfDNA integrity index of DII had an accuracy of 81.6 percent in predicting the achievement of a complete response at histopathological examination.

Ravera and colleagues then evaluated whether the cfDNA integrity index could be combined with MRI to improve prediction. The two concordant techniques yielded a combined prediction of complete response achieved with an accuracy of 92.6 percent, with a positive predictive value (accuracy in predicting a positive result) and a negative predictive value (accuracy in predicting a negative result) of 87.5 percent and 94.7 percent, respectively.

“Our work identifies a new parameter that is easily combinable with MRI to a more accurate prediction of response following neoadjuvant treatment, with possible implications for current protocols for the evaluation of nodal residual disease among patients with breast cancer undergoing neoadjuvant chemotherapy," Ravera noted.
Next steps include the confirmation of these results after the expansion of sample sizes, including evaluation of its use in prospective studies.

“In case of effective confirmation, the evaluation of the effective clinical validity of the combination of cfDNA integrity index and MRI would be of great interest," Ravera said. “This may be assessed by sparing sentinel lymph node biopsy in those patients assessed as complete responders by both techniques, comparing the rate of local recurrence with patients who undergo the usual clinical procedures."

Warren Froelich is a contributing writer.

Tuesday, April 27, 2021

A new Mayo Clinic study bolsters evidence that colorectal cancer is often imprinted in family genes and passed on from one generation to the next.

In the study, published in Clinical Gastroenterology and Hepatology, researchers within the Mayo Clinic Center for Individualized Medicine found 1 in 6 patients with colorectal cancer had an inherited cancer-related gene mutation, which likely predisposed them to the disease (2021; In addition, the researchers discovered that 60 percent of these cases would not have been detected if relying on a standard guideline-based approach.

"We found that 15.5 percent of the 361 patients with colorectal cancer had an inherited mutation in a gene associated with the development of their cancer," said Niloy Jewel Samadder, MD, a Mayo Clinic gastroenterologist and hepatologist, who is the study's senior author. "We also found that over 1 in 10 of these patients had modifications in their medical or surgical therapy based on the genetic findings."

The patients were tested with a sequencing panel that included more than 80 cancer-causing or predisposing genes. In comparison, standard panels for colorectal cancer only include 20 or fewer genes.

The patients with colorectal cancer were part of a larger cohort of 3,000 patients involved in the 2-year Interrogating Cancer Etiology Using Proactive Genetic Testing (INTERCEPT) study, and were newly diagnosed with various cancers at Mayo Clinic Cancer Center locations in Arizona, Florida, and Minnesota.

"Through the INTERCEPT study, the Center for Individualized Medicine has addressed a question of relevance to all cancer patients," noted Aleksandar Sekulic, MD, PhD, Associate Director of the Center. "The findings published by Dr. Samadder and colleagues shed a new light on the role our genes play in the development of colon cancer."

The colorectal cancer study emphasizes that uncovering hidden inherited genetic mutations using a universal testing approach and broader gene panels could lead to opportunities for cancer management in families and targeted cancer therapies that can save lives.

Study Details
In the study, Samadder and his team examined gene variants with which the patient was born and that predisposed them to developing cancer. Although many mutations that cause colorectal cancer happen by chance in a single cell—including from environmental factors, diet, smoking and alcohol use—the study confirms many are inherited mutations that set off a cycle of events that can lead to cancer.

"Though the most common mutations were found in genes typically associated with colorectal cancer, we found that a substantial number of mutations were present in genes typically associated with breast and ovarian cancer," Samadder explained. "This may lead to novel targeted therapies based on the cancer's unique genetic basis. For example, where a breast cancer drug can be used in a patient with colon cancer."

Equally important to the discovery of a patient's inherited cancer mutation is the potential for patients to share the heritable cause of their disease with their blood relatives, allowing family members to pursue care for earlier disease detection and cancer management.

"The power of genetics is that we can foresee the cancer that will develop in other family members," Samadder noted. "This can allow us to target cancer screening to those high-risk individuals and hopefully prevent cancer altogether in the next generation of the family."

In the study, all blood-related family members of patients found to have a genetic mutation were offered free genetic testing. Overall, just 16 percent of these family members underwent testing, which may suggest there are nonfinancial barriers to genetic testing.

Samadder said the next steps will be to incorporate the study findings into the care of all patients with cancer at Mayo Clinic.

"Steps are being taken to ensure all patients are offered genomic sequencing to better understand the genes that led to the development of their cancer, and how to precisely target treatment and improve survival," Samadder noted.

Tuesday, April 27, 2021

By Kurt Samson

A healthy lifestyle might offset the risk of developing a lethal form of prostate cancer, a researcher shared during the 2021 Annual Meeting of the American Association for Cancer Research (AACR) (Abstract 822).

Anna Plym, PhD, a postdoctoral research fellow at Brigham and Women's Hospital and Harvard T. H. Chan School of Public Health, noted that prostate cancer is the most common non-skin cancer detected in men, and the second-leading cause of cancer deaths in men, after lung cancer. Genetic factors account for approximately 58 percent of the variability in prostate cancer risk, she said.

Researchers looked at the genetic data of nearly 10,500 men—2,100 who developed prostate cancer over a median follow-up period of 18 years, and almost 240 whose prostate cancer proved lethal over a median follow-up of 22 years.

The study showed that men in the highest risk quartile, or lowest scores for healthy living according to their polygenic risk score, were 5.4 times more likely to develop prostate cancer and 3.5 times more likely to develop lethal prostate cancer than those in the lowest risk quartile.

“The decreased risk of aggressive disease in those with a favorable lifestyle may suggest that the excess genetic risk of lethal prostate cancer could be offset by adhering to a healthy lifestyle," said Plym.

“In our study, a healthy lifestyle did not attenuate genetic risk of overall prostate cancer. However, a healthy lifestyle did attenuate the genetic risk of lethal disease in men at highest genetic risk. While further studies are needed, this suggests that modifiable factors can mitigate the consequences of having a genetic susceptibility to prostate cancer," she noted. “While further studies are needed, this suggests that modifiable factors can mitigate the consequences of having a genetic susceptibility to prostate cancer."

Also of note is that, among the men maintaining a healthy lifestyle at study entry who had the highest genetic risk, there was a 3 percent lifetime cumulative occurrence of lethal prostate cancer. This was half of the 6 percent lifetime cumulative incidence for men with the least healthy lifestyle. It is also comparable to the 3 percent population average.

It is unclear however if the increased genetic risk of prostate cancer, including progression to lethal disease, can be offset by adherence to a healthy lifestyle, Plym noted.

Study Methodology

The investigators used a validated risk score based on polygenics—those traits with contribution of more than one gene—for overall prostate cancer. They quantified the genetic risk of prostate cancer in 10,443 men in the Health Professionals Follow-up Study for whom genotype data was available.

Next, they applied a validated lifestyle score for lethal prostate cancer which encompassed healthy weight; vigorous physical activity; not smoking; and high consumption of tomatoes, fatty fish, and reduced intake of processed meat. They then examined the incidence of overall and lethal (metastatic disease or prostate cancer-specific death) prostate cancer from the date of blood (1993-1999) or cheek collection (2005-2006) through 2014 (2016 for lethal disease).

In a median follow-up period of 18 years for overall prostate cancer and 22 years for lethal prostate cancer, the researchers identified 2,111 overall prostate cancer cases and 238 lethal prostate cancer cases.

Multivariable Cox proportional-hazards models were used to estimate the risk of overall and lethal prostate cancer by joint categories of genetic risk (PRS quartiles) and a time-varying lifestyle score (1-2: least healthy, 3: moderate healthy, and 4-6: most healthy).

Both unweighted and inverse probability weighted (IPW) models (to account for possible bias arising from the genotype sampling design) were applied. Lifetime cumulative incidence was estimated using regression standardization.

The PRS enabled risk stratification for both overall and lethal prostate cancer, with men in the highest genetic risk quartile having a 5.4-fold increased risk of overall prostate cancer and a 3.5-fold increased risk of lethal prostate cancer compared with men in the lowest genetic risk quartile.

Among men in the highest genetic risk quartile, adhering to a healthy lifestyle was significantly associated with a decreased risk of lethal prostate cancer (HRipw=0.54, 95% CI=0.31- 0.94) compared with the least healthy lifestyle. However, adhering to healthy lifestyle was not associated with a decreased risk of overall prostate cancer (HR=1.01, 95% CI=0.84-1.22).

The researchers then measured the effect of adhering to a healthy lifestyle, and found that among men in the highest-risk quartile, those with the highest healthy lifestyle scores had about half the risk of developing lethal prostate cancer compared with those with the least healthy lifestyle.

In the high-risk group, having a healthy lifestyle at the time of study entry was associated with a lifetime cumulative lethal prostate cancer incidence of 3 percent, compared with 6 percent for high-risk men having the least healthy lifestyle and 3 percent for the study population as a whole.

Adhering to a healthy lifestyle was not associated with a decreased risk of overall prostate cancer, nor did it affect men in the lower genetic risk quartiles, Plym said, adding that further research is necessary to determine why the benefit was limited to lethal prostate cancer risk in men with the highest genetic risk.

One possible explanation for the findings is that the genetic variants that contribute to a high polygenic risk score are also the variants with the strongest interaction with lifestyle factors, according to Plym.

“The study adds to a wide body of cancer prevention research that shows the benefit of a healthy lifestyle, including not smoking, maintaining a healthy weight, getting regular exercise, and eating a healthy diet," she noted, adding that the results of this study underscore the importance of surveillance for those with a genetic predisposition to develop prostate cancer.

“Our findings add to current evidence suggesting that men with a high genetic risk may benefit from a targeted prostate cancer screening program, aiming at detecting a potentially lethal prostate cancer while it is still curable."

Plym noted that the study was observational, and therefore the association between healthy lifestyles and prostate cancer may not be a causal link.

Kurt Samson is a contributing writer.​