publication date: Jan. 8, 2021

Clinical Roundup

Study: Striking differences seen in COVID-19 responses in cancer patients

A study funded by Cancer Research UK shows that the immune response to COVID-19 is the same in people with solid tumors compared to those without cancer.

However, blood cancer patients varied in their ability to respond to the virus, with many unable to shake off the virus for up to 90 days after the first signs of infection—around five times longer than the average.

Due to the importance of sharing findings related to the pandemic, the publication has been fast-tracked online as a preprint in Cancer Cell. The study gives reassurance to many people with cancer, but also highlights that patients cannot be grouped together when it comes to delivering cancer care during the pandemic.

The COVID-19 pandemic has led to many challenges for people with cancer, including decisions around shielding and delaying treatment. There is also conflicting evidence around COVID-19 having a more detrimental effect on those with cancer, and there is little insight into how cancer patients’ immune systems respond to the virus.

Researchers led by Sheeba Irshad, a Cancer Research UK clinician scientist based at King’s College London, in collaboration with Professor Adrian Hayday and Piers Patten (consultant hematologist) wanted to address two key questions: 1) Does the immune response to COVID-19 in cancer patients differ to those without cancer; and 2) What is the long-term impact of COVID-19 on the immune system in people with cancer.

The study analysed the blood of 76 cancer patients: 41 of them had COVID-19, and 35 had not been exposed to the virus. The samples were compared to the blood of people who didn’t have cancer, and who had already been recruited to the previously published COVID-IP study led by Professor Adrian Hayday*. Of the 41 people with cancer, 23 had solid tumors, and 18 had blood cancer.

Immune responses to the virus in people with solid tumors were like those of people without cancer. This was the case even where patients were in the advanced stages of cancer and were undergoing active anti-cancer treatments. Both groups were able to mount a strong immune response to the initial COVID-19 infection, and subsequently developed high levels of antibodies to clear the virus from their systems.

This study was the first to show that high levels of COVID-19 antibodies are sustained long-term in patients with solid tumors—up to 78 days after exposure to the virus. The study also found that once patients had recovered from COVID-19, their immune systems returned to normal, pre-COVID functioning.

The immune response to COVID-19 in people with certain types of blood cancer was similar but milder in the active/early phases of the disease and became stronger over time resembling immune changes often seen in chronic infections. This was especially true for cancers affecting B cells: a type of immune cell that plays an important role in immune memory.

In patients with B cell-related blood cancers, the antibody response to the virus was more diverse compared to people with solid tumors and presented as three distinct groups: 1) those who developed antibodies and cleared the virus like the solid cancer patients and people without cancer; 2) those who never developed antibodies even >75 days after virus exposure and continued to fail to clear the virus; and finally, 3) those who despite having developed antibodies against the virus were unable to clear it.

The next phase of the SOAP study will monitor the immune responses of cancer patients to the COVID-19 vaccine.

 

American College of Surgeons study reports drop in lung cancer screening, rise in malignancy rates during spring COVID-19 surge

Researchers from the University of Cincinnati have identified a framework that could help people with serious health conditions keep up their lung cancer screening appointments during the current surge.

The study was selected for the 2020 Southern Surgical Association Program and published as an “article in press” on the Journal of the American College of Surgeons website in advance of print.

The researchers compared monthly visits for low-dose computed tomography screening for lung cancer during the three months in which COVID-19 restrictions were in place with the number of monthly visits from the three years before that. LDCT is an imaging modality known to reduce mortality from lung cancer by at least 20% in high-risk patients. The institution suspended LDCT on March 13 and began a phased reopening on May 5 with a full opening on June 1.

“We had 800 scans cancelled during that time and even during the resumed period, we had a decreased total volume of patients scanned and also noted a decreased number of new patients who were scanned for their lung cancer screening,” lead author Robert M. Van Haren, an assistant professor and thoracic surgeon at the University of Cincinnati College of Medicine and a member of Cincinnati Research in Outcomes and Safety in Surgery within the Department of Surgery, said in a statement.

The institution averaged 146 LDCT tests a month before COVID-19 compared with 39 in March to June this year (p<0.01), with new patient monthly averages falling from 56 to 15 (p <0.01).

“Also when we resumed our operations, we found that new patients were less likely to come back to our screening program,” he said. They reported that new patient monthly LDCT rates have remained low despite resuming full operations.

“We also found that patients were more likely not to show up for their CT appointments, and this rate was again significantly increased compared with baseline,” he said. The no-show rate went from 15% before the COVID-19 restrictions to 40% afterward (p<0.04).

When full operations resumed in June, 29% of patients were found to have lung nodules suspicious for malignancy compared with 8% in the pre-COVID-19 period (p<0.01). That meant more patients were referred to a specialist for either biopsy or surgery as their suspected cancer entered a more critical phase.

These poor rates of screening probably reflect patient fears about coming into the hospital during the pandemic, although the study did not look at that concern specifically, Van Haren said.

“We’ve done two things to try to deal with that situation,” he said. “One was that we made operational changes to ensure that screening is safe, and we made a big emphasis within our program and with our nurses and coordinators to educate patients about those changes and to really get the message out that screening is safe.”

The key operational change was shifting the setting for the LDCT from the hospital to an outpatient center, but other changes included enforcing social distancing in the waiting rooms and in the scanning areas, and spacing appointments farther apart to allow for appropriate cleaning of those areas.

“Our results are important and suggest that it’s critical to continue cancer screening operations, such as our lung cancer screening, during this pandemic,” he said. “It’s maybe more important now as we continue to undergo another surge of COVID-19 cases throughout the country.”

In an invited commentary, William B. Weir, and Andrew C. Chang, of Michigan Surgery, Ann Arbor, wrote, “We must find a way to continue routine oncologic care or the true COVID-19 mortality rate will begin to include advanced stages of lung cancer.”

 

Largest, most diverse ever study of prostate cancer genetics brings disparities into focus

Scientists at the USC Center for Genetic Epidemiology and the Institute for Cancer Research, London, led a study that brings together data from the majority of genomic prostate cancer studies globally.

Including more than 200,000 men of European, African, Asian and Hispanic ancestry from around the world, the study is the largest, most diverse genetic analysis ever conducted for prostate cancer. The study was published in Nature Genetics.

Risk for the disease is about 75% higher, and prostate cancer is more than twice as deadly, in Blacks compared to whites. Yet whites are often overrepresented as research participants, making these differences difficult to understand and, ultimately, address.

The study’s authors identified 86 new genetic variations that increase risk for prostate cancer, not previously discovered, bringing the total number of risk loci for prostate cancer to 269.

Applying a model for assessing prostate cancer risk based on the interplay of these genetic factors, the researchers showed that men of African ancestry inherit about twice the prostate cancer risk on average compared to men of European ancestry, while men of Asian ancestry inherit about three-quarter the risk of their white counterparts—evidence that genetics play some part in the differences in how often cancer occurs in different racial groups.

This research is also a step toward applying precision medicine to early detection.

“Our long-term objective is to develop a genetic risk score that can be used to determine a man’s risk of developing prostate cancer,” corresponding author Christopher Haiman, professor of preventive medicine at the Keck School of Medicine of USC and director of the USC Center for Genetic Epidemiology, said in a statement. “Men at higher risk may benefit from earlier and more frequent screening, so the disease can be identified when it’s more treatable.”

“[The Prostate Cancer Foundation] believes that Dr. Haiman’s research findings will lead to more effective prostate cancer precision screening strategies for men of West African ancestry,” Jonathan W. Simons, president and chief executive officer of the Prostate Cancer Foundation, said in a statement.

The foundation funds Haiman’s other work leading the RESPOND initiative exploring the disease among African American men.

Haiman and his colleagues used genomic datasets from the U.S., the UK, Sweden, Japan, and Ghana, to compare 107,247 men with prostate cancer to a control group comprising 127,006 men. By examining a spectrum of races and ethnicities, the study’s authors aim to make the genetic risk score more useful for more people.

“We not only found new markers of risk, but also demonstrated that, by combining genetic information across populations, we were able to identify a risk profile that can be applied across populations,” Haiman said. “This emphasizes the value of adding multiple racial and ethnic populations into genetic studies.”

Today’s screening guidelines for prostate cancer suggest that those 55 and older with average risk can choose to take the prostate-specific antigen test in consultation with their physicians. High PSA levels are associated with prostate cancer, but the PSA test tends to detect slow-growing tumors. With widespread use, it too often leads to unnecessary treatment.

The PSA test’s value as a screening tool would grow if it were deployed selectively to monitor people found to be at high risk for prostate cancer, which is where the genetic risk score could come into play. Those at particularly high risk might even begin screening before age 55.

In order to translate the current research findings into better early detection, a large-scale clinical trial would be needed.

 

New NCCN resource for survivors helps guide life after cancer diagnosis and treatment

The National Comprehensive Cancer Network published two new Guidelines for Patients on healthy living and managing late and long-term side effects, and include appropriate ongoing screening for recurrence.

The books are available for free to view and print, or via the NCCN Patient Guides for Cancer App. The guidelines are Survivorship Care for Healthy Living and Survivorship Care for Cancer-Related Late and Long-Term Effects.

“These guidelines are applicable for survivors who are disease free as well as those living with cancer. They are far reaching across all cancer types, genders, and ages,” Crystal Denlinger, of Fox Chase Cancer Center, and chair of the NCCN Guidelines Panel for Survivorship, said in a statement.

“These guidelines include information on healthy living after a health crisis; which are good recommendations even for people who’ve never been diagnosed with cancer,” Tara Sanft, of Yale Cancer Center/Smilow Cancer Hospital, and vice-chair of the NCCN Guidelines Panel for Survivorship, said in a statement. “We want everyone to make a realistic plan to start moving more. It sounds simple, but we have really good data that exercise can reduce recurrence, even in people who didn’t exercise before diagnosis.”

The guidelines pay heightened attention to mitigating risks of cardiovascular disease. There is also information for primary care providers to appropriately advise survivors, in collaboration with oncologists, to help them stay up-to-date on evolving screening recommendations.

NCCN recognizes that the population of cancer survivors is growing rapidly, due to both an increase in diagnoses, and improving care methods that keep more people alive for longer.

This is resulting in a greater need for research into long-term effects from traditional and emerging therapies, with the latter including immune checkpoint inhibitors and chimeric antigen receptor T-cell therapy (side-effects from both immunotherapy types are covered in recently-published NCCN Guidelines for Patients).

 

Triple chemotherapy combination improves metastatic colorectal cancer outcomes

Researchers from SWOG Cancer Research Network have demonstrated that a triple drug combination—of irinotecan, cetuximab, and vemurafenib—is a more powerful tumor fighter and keeps people with metastatic colon cancer disease free for a significantly longer period of time compared with patients treated with irinotecan and cetuximab.

Results of the SWOG study, led by Scott Kopetz, of MD Anderson Cancer Center, are published in the Journal of Clinical Oncology.

The findings are expected to change the standard of care for patients with colorectal cancer that is metastatic and includes a mutation in the BRAF gene called V600E. This mutation is found in about 10% of metastatic colorectal cancers and tumors with the mutation rarely respond to treatment, resulting in a poor prognosis for patients.

Kopetz is an expert in the science of BRAF-mutated colorectal cancer and has tested a variety of combination therapies to treat it, including leading the BEACON trial. This phase III trial found that two targeted drugs, cetuximab and encorafenib, significantly shrank tumors and helped patients live longer compared with those who received standard treatment.

In his SWOG study, S1406, Kopetz and his team also pursued combination therapies to see what might work best. In this trial, they tested 106 patients whose metastatic colorectal cancer includes the deadly V600E mutation. All the patients had been previously treated with chemotherapy, and their cancer didn’t respond. The team randomly assigned study participants to one of two treatment groups – those who received irinotecan and cetuximab and those who received that combination with a third drug, vemurafenib.

The SWOG team found that patients who received the triple combination had better tumor response rates to the drugs, 17% compared to 4%, and stayed cancer-free longer.

On a molecular level, Kopetz said, here’s how the triplet works: Irinotecan, a traditional chemotherapy drug, kills cancer cells. Cetuximab, a monoclonal antibody, is a targeted drug that blocks cancer growth by blocking the action of a protein called epidermal growth factor receptor, or EGFR. Kopetz says vemurafenib, a BRAF inhibitor and another targeted therapy, attacks the BRAF protein directly, further slowing tumor growth.

“That 1-2-3 action, that triple threat, shuts off a powerful growth pathway in these cancers,” Kopetz said in a statement. “In this trial, unlike in BEACON, we added chemo and found that it makes for a more effective way to treat this aggressive form of colorectal cancer.”

Another intriguing finding: An 87% decline in circulating tumor DNA (ctDNA) of the BRAFV600E variant allele frequency in patients receiving all three drugs, compared with no ctDNA drop in patients receiving the two-drug combination.

Kopetz said this is strong evidence that measuring the presence of ctDNA can be an effective way to measure short-term response to treatment. And it could be as easy as drawing blood using liquid biopsy.

 

Miami Cancer Institute launches new and expanded clinical trials for COVID-19 treatments

Miami Cancer Institute, part of Baptist Health South Florida, has initiated several clinical trials based on treatments from initial emergency and experimental COVID-19 therapies.

The institute is leading a trial using mesenchymal stem cells for critically ill patients with SARS-CoV-2 induced respiratory failure. It is also the location of the phase II, BLAZE-4 trial, which continues work on bamlanivimab, a monoclonal antibody recently awarded Emergency Use Authorization status by FDA for those with mild COVID-19 symptoms.

Early in the pandemic, Miami Cancer Institute received single-use emergency approval from the FDA to give mesenchymal stem cells to several COVID-19 patients who were critically ill. The patients recovered. The stem cells aid in healing by regenerating damaged lung tissue. The formal, phase I/IIa trial opening now is for hospitalized  patients who are receiving oxygen therapy or who are on ventilation support and are not showing improvement with other therapies.

The Florida Department of Health is allocating bamlanivimab for EUA use and Baptist Health has a limited supply. Miami Cancer Institute participated in the monoclonal antibody’s phase I study, BLAZE-1, which led to the EUA. Now the Institute is enrolling patients in the phase II study, BLAZE-4.

Bamlanivimab can be given as an IV infusion to COVID-19-positive patients who are not hospitalized and have mild symptoms. It must be administered within 72 hours of a positive test result. It works by prohibiting the virus from anchoring to ACE2 receptors, which are proteins on the surface of many cells that allow the SARS-CoV-2 virus to enter and infect cells. In the initial study, it showed a subsequent hospitalization rate of 1.7% among those who received the drug versus a 6% hospitalization rate among those who received a placebo.

The BLAZE-4 trial is a randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of bamlanivimab (also known as LY3819253) both on its own and in combination with another monoclonal antibody specific to target the spike protein of SARS-CoV-2 to prevent the virus from entering into the epithelial cells (LY3832479). There are five arms to the trial. Arm 1 is a placebo. Arms 2, 3 and 4 consist of bamlanivimab plus a second monoclonal antibody (both given in different dosages). Arm 5 is bamlanivimab alone.

The first trial showed that bamlanivimab may reduce viral load, symptoms and risk of hospitalizations and emergency room visits associated with COVID-19 and this trial may further improve the outcomes.

 

Phase III Keytruda + Lenvima study shows improved OS, PFS in advanced endometrial cancer

A combination of Keytruda (pembrolizumab) and Lenvima (lenvatinib) demonstrated statistically significant improvement in overall survival, progression-free survival and objective response rate versus chemotherapy in patients with advanced endometrial cancer.

Keytruda is sponsored by Merck, and Lenvima is sponsored by Eisai.

The phase III KEYNOTE-775/Study 309 trial evaluating the investigational use of Keytruda, an anti-PD-1 therapy, plus Lenvima, the orally available multiple receptor tyrosine kinase inhibitor, met its dual primary endpoints of OS and PFS, and its secondary efficacy endpoint of ORR in patients with advanced endometrial cancer following at least one prior platinum-based regimen.

These positive results were observed in the mismatch repair proficient subgroup and the intention-to-treat study population, which includes both patients with endometrial carcinoma that is pMMR as well as patients whose disease is microsatellite instability-high (MSI-H)/mismatch repair deficient.

Based on an analysis conducted by an independent data monitoring committee, Keytruda plus Lenvima demonstrated a statistically significant and clinically meaningful improvement in OS, PFS and ORR versus chemotherapy (treatment of physician’s choice [TPC] of doxorubicin or paclitaxel).

The safety profile of the Keytruda plus Lenvima combination was consistent with previously reported studies. Merck and Eisai will discuss these data with regulatory authorities worldwide, with the intent to submit marketing authorization applications based on these results, and plan to present these results at an upcoming medical meeting.

KEYNOTE-775/Study 309 is the confirmatory trial for KEYNOTE-146/Study 111, which supported FDA’s 2019 accelerated approval of the Keytruda plus Lenvima combination for the treatment of patients with advanced endometrial carcinoma that is not MSI-H or dMMR, who have disease progression following prior systemic therapy and are not candidates for curative surgery or radiation.

This accelerated approval was based on tumor response rate and durability of response and was the first approval granted under Project Orbis. Under Project Orbis, Health Canada and Australia’s Therapeutic Goods Administration granted conditional and provisional approvals, respectively, for this indication.

Merck and Eisai are studying the Keytruda plus Lenvima combination through the LEAP (LEnvatinib And Pembrolizumab) clinical program in 13 different tumor types across 20 clinical trials, including a phase III trial evaluating the combination in the first-line setting for patients with advanced endometrial carcinoma (LEAP-001).

 

Cabometyx significantly improved PFS in phase III trial of previously treated radioiodine-refractory differentiated thyroid cancer

COSMIC-311, the phase III pivotal trial evaluating Cabometyx (cabozantinib) versus placebo in patients with radioiodine-refractory differentiated thyroid cancer who have progressed after up to two prior vascular endothelial growth factor receptor-targeted therapies, met the co-primary endpoint of demonstrating significant improvement in progression-free survival.

Cabometyx is sponsored by Exelixis.

Cabometyx reduced the risk of disease progression or death by 78% with a hazard ratio of 0.22 (96% CI 0.13 – 0.36; p<0.0001) at this planned interim analysis. The safety profile was consistent with that previously observed for Cabometyx.

Given these results, the independent data monitoring committee for the study recommended to stop enrollment and unblind sites and patients. Exelixis intends to discuss the study results, proposed changes to the study conduct, as well as plans for a regulatory filing with FDA in the near term.

COSMIC-311 is a multicenter, randomized, double-blind, placebo-controlled phase III pivotal trial that aimed to enroll approximately 300 patients at 150 sites globally. Patients were randomized in a 2:1 ratio to receive either cabozantinib 60 mg or placebo once daily. Detailed results will be submitted for presentation at a future medical conference.

 

Ohio State launches statewide study focused on breast cancer in Black women

The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute has launched its fourth statewide cancer research initiative focused on increasing breast cancer education, facilitating access to genetic counseling and ensuring appropriate screening, follow-up for abnormalities and treatment for Black women who are at an increased risk for breast cancer. 

The Turning the Page on Breast Cancer in Ohio program was launched with funding support from Pelotonia, the American Cancer Society and Pfizer and is a collaborative effort of experts from the OSUCCC – James, Ohio Association of Community Health Centers, Susan G. Komen and the North Central Region of the American Cancer Society.

Electra Paskett, co-leader of the OSUCCC – James Cancer Control Research Program, Marion N. Rowley Designated Chair in Cancer Research at the Ohio State College of Medicine, and Heather Hampel, a practicing genetic counselor with The James and professor/associate director of the Division of Human Genetics at the Ohio State College Medicine, are principal investigators of the study.

Hampel is also a member of the OSUCCC – James Molecular Carcinogenesis and Chemoprevention Program.

Hampel is a practicing genetic counselor with The James and professor/associate director of the Division of Human Genetics at the Ohio State College Medicine. She also is a member of the OSUCCC – James Molecular Carcinogenesis and Chemoprevention Program.

“Studies confirm that in the United States, Black women are 42% more likely to die of breast cancer than white women – and on average, Black women develop more aggressive breast cancer and die at younger ages than white women. Many factors, including insurance, socioeconomics and more frequent gene mutations, contribute to this disparity,” Paskett said in a statement.

“We are working to identify and directly break down those barriers to help women who are at the highest risk of developing breast cancer,” Paskett said. “Our goal is to help these women both understand their risk and get the medical guidance they need.”

The OSUCCC – James-led collaborative team will use a multi-level approach in 12 Ohio counties to provide breast cancer education and facilitate access to risk assessment, genetic counseling and testing, appropriate screening/surveillance, follow-up for abnormal tests, and prompt and appropriate treatment for Black women.

Researchers will use geographic predictors (county) of aggressive disease to identify and inform women who live in high-risk counties. Participating counties will include Franklin, Fairfield, Clark, Butler, Hamilton, Lake, Cuyahoga, Lorain, Trumbull, Summit, Stark and Mahoning.

Several strategies (e.g., Facebook ads, referral from providers or community organizations) will be used to direct interested women to a website where they can enter information about themselves and their family history of cancer to determine if they are at increased risk for breast cancer.

High-risk women will be referred to genetic counseling, where they can receive a tailored risk assessment and genetic testing when appropriate. Women will then receive a personal prescription for breast health and be connected to experts who can help them navigate next steps.

All participating women will receive information about when to start breast cancer screening and what that screening should entail based on their risk stratification. Women will then be connected to local breast health specialists for their screening and follow-up. Efforts will be made at local health centers to ensure that women seen in those medical clinics have up-to-date screening and that women with abnormal screening tests receive proper and timely follow-up.

 

Roswell Park researchers: Aggressive breast cancers in Black patients are related to immune factors

A Roswell Park Comprehensive Cancer Center team led by Christine Ambrosone and Song Yao has found a distinct molecular signature in the tumor tissues of Black patients with breast cancer.

The study, published in the Journal of the National Cancer Institute, reports that an elevated number of exhausted,”nonfunctional T cells appears to be driving tumors in patients of African descent to be more aggressive and hard-to-treat — a finding that also opens the door to treatment interventions that could help to eliminate the striking disparities in survival between Black and white patients with breast cancer.

In the United States, rates of death from breast cancer are 40% higher among Black women than white women. Seeking new information about what is driving those unequal outcomes, the Roswell Park team used both pathological and gene-expression profiling to characterize infiltrating immune cells in the breast tumor microenvironments of 1,315 patients included in the Women’s Circle of Health Study.

The data the team compiled reveal distinct differences in the tumor immune responses among Black and white patients. While tumors from Black patients exhibited a stronger overall immune cell presence, the immune cells in Black patients appeared to have lower antitumor activities.

“We observed in the tumor microenvironment of breast cancer in patients of African descent a distinct signature of exhausted versus total CD8+ T cells, and noted further that this immune cell profile is associated with poorer breast cancer survival, particularly in the hormone receptor-positive subtype of breast cancer,” first author Yao, professor of oncology in the Department of Cancer Prevention and Control at Roswell Park, said in a statement.

The findings suggest that Black patients could have a higher response rate to immune checkpoint inhibitors. The potential of this approach is also supported by the stronger B-cell response in this patient population, a trait recently shown to regulate responses to immunotherapy, the researchers report.

“The activation of the immune system to eliminate and control cancer cells has become a clinical reality with recent breakthroughs in cancer immunotherapy,” senior author Ambrosone, chair of cancer prevention and control and senior vice president of population sciences at Roswell Park said in a statement. “We believe these findings may suggest an opportunity to enlist host immunity, part of the fundamental mechanism of human bodies to recognize and defend against the invasion of foreign agents, through immune checkpoint inhibitors in patients whose breast cancers fit this immune profile.”

In their new work, which was supported by the Breast Cancer Research Foundation, the Roswell Park team highlighted a lack of clinical trials on immune checkpoint inhibitors that have reported race-specific outcome data, emphasizing the need for enhanced recruitment of racial/ethnic minorities to lessen cancer disparities and to ensure that all patients have the opportunity to benefit from cutting-edge cancer treatment.

 

UCLA study: More women embracing ‘going flat’ after mastectomy

A growing number of women forgoing reconstruction after a mastectomy say they’re satisfied with their choice, even as some did not feel supported by their physician, according to a study led by researchers at the UCLA Jonsson Comprehensive Cancer Center.

The study, published in Annals of Surgical Oncology, surveyed 931 women who had a unilateral or bilateral mastectomy without current breast mound reconstruction to assess the motivating factors for forgoing the procedure and to measure whether surgeons provided adequate information and support for “going flat.”

Out of the women surveyed, 74% were satisfied with their outcome and 22% experienced “flat denial,” where the procedure was not initially offered, the surgeon did not support the patient decision, or intentionally left additional skin in case the patient changed her mind.

The team also explored reasons given for the choice and found women pointed to a desire for a faster recovery, avoidance of a foreign body placement and the belief that breast mound reconstruction was not important for their body image.

“Undergoing a mastectomy with or without reconstruction is often a very personal choice,” senior author Deanna Attai, an assistant clinical professor of surgery at the David Geffen School of Medicine at UCLA, said in a statement. “We found that for a subset of women, ‘going flat’ is a desired and intentional option, which should be supported by the treatment team and should not imply that women who forgo reconstruction are not concerned with their postoperative appearance.”

The results challenge past studies showing that patients who chose not to undergo breast reconstruction tend to have a poorer quality of life compared with those who do have the surgery.

Attai and her team found that a majority of patients who elected to go flat were in fact satisfied with their surgical outcome. The authors believe that the survey tool commonly used for assessing outcomes was biased towards reconstruction. To avoid that bias, Attai partnered with patient advocates to develop a unique survey to assess reasons for going flat, satisfaction with their decision, and factors associated with satisfaction. They also identified concerns unique to these patients not captured by other validated surveys.

While a majority of the women surveyed reported they were satisfied with their surgical outcomes, 27% of patients surveyed reported not being satisfied with the appearance of their chest wall.

“Some patients were told that excess skin was intentionally left—despite a preoperative agreement to perform a flat chest wall closure—for use in future reconstruction, in case the patient changed her mind,” said Attai, who is also a member of the UCLA Jonsson Comprehensive Cancer Center. “We were surprised that some women had to struggle to receive the procedure that they desired.”

Surgeons may hesitate to recommend mastectomy without reconstruction surgeons due to being less confident that they can provide a cosmetically acceptable result for patients who desire a flat chest wall, she said.

“We hope that the results of this study will serve to inform general and breast surgeons that going flat is a valid option for patients, and one that needs to be offered as an option,” said Attai. “We also hope the results may help inform patients that going flat is an option, and to empower them to seek out surgeons who offer this option and respect their decision.”

 

New combination therapy could help fight difficult-to-treat cancers with common mutations

Scientists at the UCLA Jonsson Comprehensive Cancer Center describe a new combination therapy that suppresses the MAPK pathway by holding cancer-driving proteins in a death grip.

This combination of two small molecules has the potential to treat not only BRAF mutated melanoma, but also additional aggressive subtypes of cancers, including melanoma, lung, pancreatic and colon cancers that harbor common mutations in cancer genes called RAS or NF1.

The preclinical study, published in Cancer Discovery, a journal of the American Association for Cancer Research, found that a second-generation RAF inhibitor (type II RAFi) in combination with a standard MEK inhibitor could be effective in treating cancers with these mutations and could also help overcome acquired resistance to the current standard-of-care treatment targeting specific BRAF mutations.

“The idea behind this study was to develop a combination treatment that helps people with common lethal cancers by eliciting durable anti-tumor responses,” senior author Roger Lo, professor of medicine at the David Geffen School of Medicine at UCLA and member of the UCLA Jonsson Comprehensive Cancer Center, said in a statement. “Right now, MEK inhibitors by themselves provide limited clinical benefits, and the current MAPK pathway-targeted, combination therapy can help only certain patients with cancers harboring specific BRAF mutations.”

To test the effectiveness of the experimental combination, researchers used patient-derived models of melanoma, non-small cell lung cancer, pancreatic cancer and colon cancer as well as mouse tumors that mimic these human cancers. The team evaluated how the combination of type II RAFi plus MEKi impacts the MAPK pathway inside the cancer cells and the body’s cancer-fighting immune or T-cells over time in order to achieve long-term response by suppressing drug-resistant clones.   

The next-generation combination works by two unique mechanisms that can suppress drug-resistant clones. First, the two small molecules lock RAF and MEK proteins in the MAPK signaling pathway into a tight complex, which is unusual. Normally, molecules in this pathway touch and go in order to fire off growth-promoting signals. Keeping these molecules stuck together allows the drugs to effectively and durably block the MAPK pathway.

“It is quite remarkable that two drugs were able to bind to each of two proteins and sequester them from further propagating signals inside the cancer cells,” co-senior author Gatien Moriceau, assistant adjunct professor at the David Geffen School of Medicine at UCLA, said in a statement.

The combination prevented an attrition of killer T-cells inside the tumor and promoted T-cell clonal expansion.

“The combination unexpectedly preserves killer T-cells inside the tumors, which allows them to hunt down drug-resistant tumor clones,” Moriceau said. “This favorable impact on T-cells paves the way to combine MAPK-targeted therapies with anti-PD-1/L1 immune checkpoint therapy.”

The combination of type II RAFi plus MEKi is being tested in clinical trials in both melanoma and other solid cancers such as non-small cell lung cancer. 

The work was supported by NIH, the Melanoma Research Alliance and the V Foundation for Cancer Research.

Copyright (c) 2020 The Cancer Letter Inc.