Σάββατο, 15 Ιουλίου 2017

FIRST CAR-T CELL THERAPY APPROVED FOR ALL

A new dawn is breaking in the field of hematologic malignancies, as the first product based on chimeric antigen receptor (CAR) T cells was scrutinized today by a panel of experts and unanimously recommended for approval.
All 10 panel members at today's US Food and Drug Administration (FDA)  Oncology Drugs Advisory Committee meeting voted "yes" — there were no abstentions, and no one voted against recommending for approval.
The product is tisagenlecleucel-T (previously known as CTL019; developed by Novartis), and the "yes" vote was in answer to this question: "Considering the efficacy and safety results of Study B2202, is the benefit-risk profile of tisagenlecleucel favorable for treatment of pediatric and young adult patients (age 3-25 years) with relapsed (second or later relapse) or refractory (failed to achieve remission to initial induction or reinduction chemotherapy) B cell precursor acute lymphoblastic leukemia (ALL)? "
Commenting after the vote, panel members emphasized the "clear" efficacy of the product and the fact that there is a strong unmet need for new therapies for relapsed/refractory ALL. One panel member, Alan Rein, PhD, from the National Cancer Institute, Bethesda, Maryland, highlighted the "remarkable clinical successes." However, he also said that there are unanswered questions about long-term safety, so he was glad to see discussion of follow-up for 15 years.  

Similar Products Not Far Behind  

This product is made individually for each patient.
Blood is collected from the patient, and then autologous T cells are separated out and genetically engineered. The process involves inserting a CAR that targets CD19, an antigen expressed on B cells and tumors derived from B cells.  These CAR T cells are then infused back into the patient, who has undergone chemotherapy, and in the body the product homes in on B-cell leukemic cells and destroys them. 
Several similar products are in late stages of development. Coming up soon for review by the FDA is Kite Pharma's axicabtagene ciloleucel (KTE-C19) for lymphoma, while further back are CAR T-cell products from Juno.
Although they have been pitched as rivals in the race for the market, Kite's chief executive officer, Arie Belldegrun, said,  "I will be Novartis' biggest cheerleader today."
"I am amused by the horse-race metaphors that are used to frame the various companies developing CAR-T therapies," Dr Belldegrun wrote in a blog post. "Today is not about competition," he continued. "Today is about advancing an exciting technology that has the potential to transform cancer."
Today is about advancing an exciting technology that has the potential to transform cancer. Arie Belldegrun

Efficacy Data 

The main efficacy and safety data come from the phase 2 study CCTL019B2202 (B2202), which began on April 2015 and had data cutoff for efficacy analysis in November 2016.  
"This was the first global study of a CAR T cell therapy, and more importantly it was the first with a global supply chain of this product," commented principal investigator, Stephan Grubb, MD, PhD, from Children's Hospital in Philadelphia, Pennsylvania. He also ran some of the earlier trials with this product and treated the first pediatric patient with a CAR T cell. This was a 6-year old girl, who remains in remission 5 years later, he said. 
In the public part of the meeting, this patient, Emily Whitehead (now 12 years old), accompanied her father, who gave a moving account of how the therapy had saved her life. Another father also described the experience of his son, who underwent 6 years of chemotherapy for ALL, along with many procedures (including spinal taps and surgeries), before finally being treated with tisagenlecleucel and cured of the disease.
The B2202 study enrolled 88 patients (median age, 12 years; range, 3 to 27 years). These patients had received a median of three prior therapies, and just over half these patients had previously undergone stem cell transplantation.
However, 16 patients did not receive the product: 7 because of manufacturing failure, 6 because they died, and 3 because of adverse events.
The results show an overall remission rate of 82.5% (52 of 63 patients).
Of these 52 responders, 40 patients (63%) had a complete response within the first 3 months after infusion, and 12 (19%) had a complete remission with incomplete blood count recovery. All of these were associated with minimum residual disease–negative  status in the bone marrow.
In its briefing document, the FDA describes these results as representing  "clinically meaningful remission."
The median follow-up time for duration of response (DOR) was 4.8 months
(range, 1.2 to 14.1 months). The median DOR was not reached, and 75% of patients were relapse free at 6 months.
Seven patients went on to undergo hematological stem cell transplantation (HSCT) while they were in remission, and 14 went on to receive other chemotherapy without HSCT.
Eleven patients (17.5%) died after tisagenlecleucel infusion.
In the discussion period at the meeting, Novartis presented data to show that the overall survival seen with tisagenlecleucel is double that seen with other available therapies. The company noted that the 12-month survival rates in the B2202 study were 79% with tisagenlecleucel, compared with previous studies showing rates of 40% with blinatumomab and 20% with clofarabine monotherapy; the median overall survival durations were 16.6 months, 7.5 months, and 3 months, respectively.

Safety Data 

The safety analysis population consisted of 68 patients, the FDA noted.
The agency noted that the main serious adverse events include life-threatening cytokine release syndrome (CRS, which consists of fever, hypotension, acute kidney injury, and hypoxia) and hemophagocytic lymphohistiocytosis, as well as neurologic events that occurred with CRS or were delayed after the resolution of the CRS, coagulopathies with CRS, and life-threatening infections.
Grade 3 or 4 CRS occurred in 32 (47%) patients, but no patients died of CRS.
Neurologic toxicities, reported in 30 (44%) patients, included encephalopathy, delirium, hallucinations, somnolence, cognitive disorder, seizure, depressed level of consciousness, mental status changes, dysphagia, mental status changes, muscular weakness, and dysarthria.  All were reversible.
CRS is treated with the intereleukin-6 antagonist tocilizumab, and the neurologic symptoms are treated with corticosteroids, in addition to supportive measures.
These adverse reactions can be severe, and even life-threatening, but clinicians who have been involved in clinical trials with CAR T cells say that they are "manageable."
One of these clinicians is Elizabeth Budde, MD, PhD, assistant professor in the Department of Hematology and Hematopoietic Cell Transplantation at City of Hope Hospital in Duarte, California, who noted in a recent interview with Medscape Medical News that these patients need close monitoring with an experienced eye because " these patients can crash at any time."
Novartis said at the FDA meeting that the product would be restricted for use only by certified specialists, and only at certain selected treatment sites. In addition, it recommends that patients receiving this product stay close to the site for 3 to 4 weeks after receiving the infusion because of the risk for these severe adverse events. The company also proposed that the product have a Risk Evaluation and Mitigation Strategy for these two serious adverse events (CRS and neurologic toxicity).   
In summarizing the Novartis experience with tisagenlecleucel, head of the CAR T Cell Global Program, David Lebwohl, MD, said that he had been involved in hematologic drug development for 20 years but has "never seen anything like this before."
The product achieves a consistent high overall rate of remission and has "the potential to be a definitive therapy — many patients do not require further therapy…. This is truly a paradigm shift in a setting of enormous medical need," he told the meeting attendees.  

Theoretical Long-term Toxicity Concerns 

In addition to the short-term safety issues mentioned above, the FDA noted in its briefing document that potential long-term safety concerns with tisagenlecleucel include the potential for generation of replication-competent retrovirus and the potential for insertional mutagenesis to cause new malignancies (genotoxicity).
However, these are theoretical concerns — the FDA also noted that clinical follow-up has not raised any concerns for tisagenlecleucel. The  B2202 study did not identify risks from clonal outgrowth and vector-mediated delayed adverse events (eg, secondary leukemias), the agency noted. "However, most study subjects have not been followed for very long, thus limiting the ability to assess the risk of delayed events," it added.
The FDA said that it requires 15 years of follow-up to monitor for subsequent malignant transformation.
Dr Grubb reports receiving research funding (institutional) from Novartis. 

BIOSIMILARS BEVACIZUMAB AND TRASTUZUMAB APPROVED BY FDA

On July 13, the U.S. Food and Drug Administration's (FDA) Oncologic Drugs Advisory Committee (ODAC) unanimously recommended approval of biosimilar versions of bevacizumab (Avastin) and trastuzumab (Herceptin).
In the morning session, ODAC members voted 17-0 in favor of approving Amgen's bevacizumab biosimilar candidate, ABP 215, for six of bevacizumab's indications. However, the committee did not consider whether Amgen's data would support approval for two of bevacizumab's indications for ovarian cancer, as they are covered by orphan drug exclusivity until 2021 and 2023.
In the afternoon session, ODAC members voted 16-0 in favor of approving Mylan's trastuzumab biosimilar candidate, MYL-1401O, for all of Herceptin's indications, including an indication for metastatic gastric cancer, which is protected by orphan drug exclusivity through October 20, 2017.


In both cases, ODAC and FDA reviewers found there were no clinically meaningful differences between the reference products and the biosimilars, though some panel members expressed concerns about extrapolating data from studies in a single disease to multiple indications. 

FIRST MULTI-TARGET TEST FOR NSCLC APPROVED BY FDA

On June 22, the U.S. Food and Drug Administration (FDA) granted premarket approval to Thermo Fisher Scientific for the first next-generation sequencing–based test that simultaneously screens tumor samples for biomarkers associated with three FDA-approved therapies for non–small cell lung cancer (NSCLC).
The Oncomine Dx Target Test simultaneously evaluates 23 genes clinically associated with NSCLC. Following FDA approval, results from analysis of three of these genes can now be used to identify patients who may be eligible for treatment with one of the following: the combined therapy of dabrafenib (Tafinlar) and trametinib (Mekinist); crizotinib (Xalkori); or gefitnib (Iressa). With this test, physicians can now match patients to these therapies in days instead of several weeks—the expected wait time when screening samples one biomarker at a time.
“For people battling non–small cell lung cancer, time is critical and days matter” said Joydeep Goswami, President of Clinical Next-Generation Sequencing and Oncology at Thermo Fisher. “The Oncomine Dx Target Test rapidly guides oncologists toward the right targeted therapy, with the goal of improving patient outcomes and the cost efficiency of treatments.”
LabCorp's Diagnostics and Covance Businesses, NeoGenomics Laboratories, and Cancer Genetics, Inc, are among the first laboratories that will offer the Oncomine Dx Target Test as a service to oncologists. All tests will be run on Thermo Fisher's Ion PGM Dx System, which received FDA 510(k) clearance in parallel for use on formalin-fixed, paraffin-embedded tissue samples.
Thermo Fisher developed the Oncomine Dx Target Test in collaboration with Novartis and Pfizer. It is based on Thermo Fisher's Ion AmpliSeq technology, which enables screening of tumor samples for multiple genetic markers with 10 nanograms of nucleic acid. Returning results using such a small amount of formalin-fixed, paraffin-embedded material is a critical advantage of the test, since samples from patients with NSCLC are often limited in quantity.
More information about the Oncomine Dx Target Test is available at www.thermofisher.com/oncomine-dxtarget.

SAFE TO DELAY SLNB IN MELANOMA

Postponing lymph node biopsy more than 30 days after melanoma diagnosis does not adversely impact long-term clinical outcomes, according to findings published by Nelson et al in the Journal of the American College of Surgeons.
Today, management of high-risk melanomas starts with surgical removal of the layers of skin cancer and a lymph node biopsy. Patients with a positive sentinel node biopsy may undergo complete lymph node dissection to lower the risk of recurrence.
In theory, postponing biopsy after a melanoma diagnosis could affect outcomes, either in a negative way (ie, allowing the growth and spread of cancerous cells to lymph nodes) or in a positive way (ie, allowing development of an antimelanoma immune response).
There have been small studies showing each of those scenarios, said study coauthor Mark Faries, MD, FACS, Codirector of the Melanoma Program at The Angeles Clinic and Research Institute. “We often get questions from patients as to whether or not they need to rush to have their operation performed when they are diagnosed with melanoma. So the question of whether waiting hurts or helps has never been clearly answered,” Dr. Faries said. “We wanted to settle that controversy by looking at two very large data sets to see if there was an actual difference.”
Study Details
In this study, the largest one to date, researchers analyzed the effect of delayed sentinel lymph node biopsy on survival of patients with melanoma.
Dr. Faries and colleagues from the John Wayne Cancer Institute and elsewhere examined the medical records of 2,483 patients who underwent wide local excision and sentinel lymph node biopsy for melanoma skin cancer between 1999 and 2015. They analyzed whether lymph nodes biopsied later were associated with different outcomes, either positive or negative, compared to lymph nodes biopsied earlier. The average follow-up time was 8 years.
Early and delayed sentinel lymph node biopsy were defined as less than 30 days and more than 30 days from diagnosis, respectively. Primary outcomes included disease-free survival and melanoma-specific survival.
Findings
Of those 2,483 patients, positive sentinel lymph nodes were identified in 432 patients (17%). A majority of patients (58%) underwent early sentinel lymph node biopsy. The study found no difference in melanoma-specific survival or disease-free survival in patients who underwent early or delayed sentinel lymph node biopsy.
An independent dataset from the first Multicenter Selective Lymphadenectomy Trial, a multicenter prospective randomized trial, was used to validate these findings. The exact same analysis showed similar results in survival outcomes.
A cancer diagnosis impacts not only the body, but also the mind and emotions. Approximately one-third of patients diagnosed with melanoma report emotional challenges such as fear of death, anxiety, and uncertainty. However, it is important for people to understand that if their biopsy needs to be postponed by several weeks, they are still safe.


“When we talk to patients diagnosed with melanoma, the main rationale is to get the surgical procedure over and done with and get the information and resources they need so that they can move on,” Dr. Faries said. “But people can be reassured that if they are in a situation where, for one reason or another, they need to wait to have an operation—that's okay too.”

UNPROVEN ROLE OF NEOADJUVANT TREATMENT OF PANCREATIC CANCER

Although good evidence supports adjuvant therapy after resection in patients with locally advanced pancreatic cancer, the role of neoadjuvant therapy in borderline resectable cases is less clear.
This was the conclusion from Jean-Luc Van Laethem, MD, PhD, Erasme University Hospital (ULB), Brussels, Belgium, who reviewed the subject here at the 19th World Congress on Gastrointestinal Cancer (WCGC).
Patients with resectable pancreatic ductal adenocarcinoma experience significant survival benefits with adjuvant chemotherapy, he said.
However, he continued, the use of neoadjuvant or induction therapy is not currently supported by the literature as a standard therapeutic option, apart from potentially in certain cases, and many questions over its use remain to be addressed.

Current Clinical Landscape 

Dr Van Laethem started his review by highlighting that, in the current clinical landscape for pancreatic cancer, approximately 15% to 20% of cases are resectable, with an estimated survival with optimal therapy of up to 28 months.
A further 15% to 20% of pancreatic cancers are locally advanced, with an estimated survival of up to 15 months.
However, up to 70% of all pancreatic cancer cases are metastatic and are associated with a survival of up to 12 months.
"But there is a borderline between localized and locally advanced cases called borderline resectable diseases," he said, adding that choosing the optimal therapy for these cases is "a little bit confusing."
Dr Van Laethem emphasized that initial decision-making in these patients "of course should be multidisciplinary and rely on multislice CT [computed tomography] scanning to decide if we go to surgery or not, based on the resectability criteria."
He said that, for resectable cases, treatment can begin with neoadjuvant therapy before surgery and then adjuvant therapy or can proceed directly to surgery, followed by adjuvant therapy.
For borderline operable cases, in which a grade of R0 "is unlikely," patients can receive induction therapy before dissection of the tumor is attempted, or surgeons can go for upfront, or "risky," surgery, he said.
"The third situation is a tumor that will probably never be resectable and then we go for induction chemo and chemoradiation," Dr Van Laethem said. After this, surgeons can attempt "improbable" surgery.
He noted that the most recent practice guidelines for pancreatic cancer have concluded that high, grade I evidence supports the use of adjuvant chemotherapy, resulting in A or strong recommendations.
However, for neoadjuvant/induction therapy, only low, grade IV evidence is available, and any recommendations are B or moderate/borderline.

Numerous Trials of Adjuvant Therapy 

Dr Van Laethem highlighted the fact that numerous trials have studied adjuvant chemotherapy in pancreatic cancer, most of which have reported significant improvements in 2-year survival rates.
The most notable recent study was the European Study Group for Pancreatic Cancer (ESPAC) 4 trial, in which 722 patients with pancreatic ductal adenocarcinoma who had undergone curative resection were randomly assigned to gemcitabine or gemcitabine plus capecitabine. Survival significantly improved with combination therapy.
However, Dr Van Laethem pointed out that although the study met its primary endpoint, there were methodologic issues, overlapping confidence intervals for median overall survival, short follow-up of the last patients to be enrolled, and no differences in disease-free survival, among other problems.
Consequently, he said that mature data are " eagerly awaited" and that while gemcitabine plus capecitabine is a new treatment option in pancreatic cancer, it is "not a new standard."
To those ends, several ongoing phase 3 trials are studying adjuvant therapy in pancreatic cancer, including PACT-15PRODIGE 24/ACCORD 24RTOG 0848, and APACT.
Dr Van Laethem said that although surgery plus adjuvant chemotherapy is considered the standard in resectable pancreatic cancer, recent findings have indicated that around 25% of patients die within the first year of follow-up, 50% experience recurrence, and up to 40% do not complete adjuvant chemotherapy.
It is therefore clear that "better patient selection is needed," he said.

Neoadjuvant Therapy 

Neoadjuvant therapy given pre- or perioperatively aims to increase resectability, target occult disease, allow early intervention, and avoid treatment delays. This therapy also offers a "unique window" to allow patients with rapid progression to avoid ineffective surgery and permits the study of the effects of therapy on tumor biology.
However, Dr Van Laethem underlined that this relies on appropriate clinical selection, technical preparation of the patient, vascular staging, the assessment of molecular prognostic factors, and the appropriate selection of treatment based on such factors.
The meta-analyses available so far on the use of neoadjuvant therapy in pancreatic ductal adenocarcinoma have suggested that it is effective in only a minority of unresectable patients and that only patients with locally advanced disease are likely to benefit.
Dr Van Laethem said that nevertheless many potential confounding factors may have affected the results, including differences in both the regimens used and the types of studies included in the meta-analyses, the number of patients in individual trials, the resectability criteria used, and the lack of a control group in most trials.
Therefore, many questions remain over neoadjuvant/induction therapy, including the type of chemotherapy to be used, whether to combine it with radiation therapy, and the sequencing of treatments, particularly over whether to start with chemotherapy or chemoradiation.
Nevertheless, a study has shown that combining FOLFIRINOX (folinic acid, fluorouracil, irinotecan, oxaliplatin) with chemoradiation is both feasible and active in locally advanced pancreatic cancer and improves objective response rates and disease control rates.
To further explore whether chemoradiation is required after induction chemotherapy, patient selection, and the treatment modalities to be used, there are several ongoing and planned randomized controlled trials.
Emerging data from these trials suggest that nab-paclitaxel plus gemcitabine is as effective as neoadjuvant therapy in patients with resectable or borderline resectable pancreatic cancer. However, it is essential that tumor response, based on levels of circulating markers and imaging assessments, is evaluated early to differentiate between responders and nonresponders.

Best Available Evidence 

Dr Van Laethem concluded that the best available evidence indicates the current standard is to use adjuvant chemotherapy with gemcitabine after R0/R1 resection, while gemcitabine plus capecitabine remains "a new option."
In contrast, adjuvant chemoradiation is not standard therapy and should be used only in selected cases. He said that there is also no current standard adjuvant therapy for metastatic pancreatic ductal adenocarcinoma.
Although neoadjuvant/induction therapy is not standard treatment for potentially resectable tumors, Dr Van Laethem summarized, emerging evidence supports its use in "specific cases," such as patients suspected of having extrapancreatic disease and cases in which it is not clear that the patient can undergo surgery.
However, the overall evidence is low grade, and many questions remain, including the extent of the effect on survival outcomes and the role of chemoradiotherapy, which may be answered by ongoing trials.
After the presentation, session co-chair Thomas Seufferlein, MD, Department of Internal Medicine, Ulm University, German, thanked Dr Van Laethem for "this excellent, comprehensive overview."
He said, "One quick question from my side: You have a proportion of patients progressing under neoadjuvant treatment, maybe 20%.…They are not eligible for surgery anymore because they are progressing. Do you see that as a problem, or do you see it as a chance to learn the tumor biology and that maybe these patients would not have benefited? What is your view?"
Dr Van Laethem replied that he sees it as a chance to learn about the tumor biology because a patient with metastatic disease "is not a good candidate" for surgery.
No funding was reported. Dr Van Laethem has disclosed no relevant financial relationships.
19th World Congress on Gastrointestinal Cancer (WCGC). No abstract available. Presented June 28, 2017.

NEW TREATMENT FOR SICKLE CELL DISEASE

The US Food and Drug Administration (FDA) has approved L-glutamine oral powder (Endari, Emmaus Medical Inc) to reduce severe complications of sickle cell disease in patients aged 5 years and older with the disorder. This is the first approval for the rare disorder in almost 20 years.
"Endari is the first treatment approved for patients with sickle cell disease in almost 20 years," Richard Pazdur, MD, acting director of the Office of Hematology and Oncology Products in the FDA's Center for Drug Evaluation and Research and director of the FDA's Oncology Center of Excellence, said in an FDA news release. "Until now, only one other drug was approved for patients living with this serious, debilitating condition."
The decision follows consideration of data from a randomized trial of patients aged 5 to 58 years who had suffered two or more sickle cell pain crises within the 12 months before enrollment in the trial. The researchers randomly assigned patients to receive L-glutamine or placebo. Treatment was evaluated during a 48-week period.
Those who received L-glutamine experienced fewer hospital visits for pain crises that resulted in treatment with parenteral narcotics or ketorolac, on average, compared with those who received placebo (median three vs median four), fewer sickle cell pain hospitalizations (median two vs median three), and fewer hospitalized days (median 6.5 days vs median 11 days).
Those who were given L-glutamine also experienced fewer episodes of acute chest syndrome — a life-threatening sickle cell disease complication — compared with those who were given placebo (8.6% vs 23.1%).
Frequent adverse events include constipation, nausea, headache, abdominal pain, cough, extremity pain, back pain, and chest pain.
L-glutamine received orphan drug designation for sickle cell disease. The FDA's Office of Orphan Products Development (OOPD) is intended to incentivize the development of drugs for rare diseases. Development of this drug was supported in part by the OOPD Grants Program, which provides grants to conduct clinical studies on safety and effectiveness of treatments for rare diseases or conditions.
Approximately 100,000 people in the United States have sickle cell disease, according to the National Institutes of Health. The disease primarily affects African Americans, Latinos, and other minority groups. The average life expectancy for those with sickle cell disease in the United States is 40 to 60 years.

CANCER DIAGNOSIS MORE COMMON THAN MARRIAGE

It is now more common for an individual to be diagnosed with cancer than for an individual to get married, have a first child, or be awarded a degree from a university, says report by a leading cancer charity in the United Kingdom.
The report was published online July 10 by Macmillan Cancer Support to coincide with an advertising campaign by the charity Life With Cancer, which aims to reduce fear associated with a cancer diagnosis and to highlight the support that is available to help cancer survivors live as normally as possible.
Lynda Thomas, chief executive of Macmillan Cancer Support, said in a release: "Being told you have cancer changes your life, and it can leave people feeling as if they've been thrust into the unknown, bewildered and unprepared.
"But as more and more people are being diagnosed with cancer, it's important that we are all better informed about what to expect if we do one day we receive this shocking news."
The report gathers together data from a range of sources, including previously published research, surveys conducted by Macmillan Cancer Support, and official UK statistics, from which the charity derived an overview of the impact of cancer on a population level.
This overview showed that in 2015, approximately 360,000 people in the United Kingdom had been diagnosed with cancer.
Estimates suggest that that figure has already increased. Around 35% of cancer cases are diagnosed in people younger than 65 years, including more than 2000 children and teenagers every year.
The charity indicates that there were more than 70,000 new cancers cases per year than new marriages. There were approximately 50,000 more new cancer cases than there were women who gave birth to their first child or young people who were awarded undergraduate degrees.
The cancer diagnoses are divided almost equally among men (51%) and women (49%). Just more than half (53%) of all new cases are cancers of the breast, prostate, lung, and bowel.
Five-year survival rates range from more than 80% for breast cancer, prostate cancer, melanoma of the skin, Hodgkin's lymphoma, and thyroid and testicular cancer to fewer than 15% for lung and liver cancer and 6% to 7% for mesothelioma and pancreatic cancer.

Disease That Is Feared the Most

The report also shows that 37% of the general public say that cancer is the disease they fear the most, more than dementia (27%) and stroke or heart disease (11%).
Among those with cancer, 23% reported that they felt as if their life was effectively over when they were diagnosed. Furthermore, 64% were worried about the impact of the diagnosis on family and friends, and 21% were concerned that people would treat them differently.
However, 85% of people with cancer do not want the disease to define them, the report notes.
The impact of cancer on daily life also appears to be more manageable than people fear, with 90% of individuals with cancer saying they live their life as normally as possible, 52% saying that cancer has not changed who they are, and 75% reporting that they are no less able to support their friends than they were before.
No funding or relevant financial relationships have been disclosed. 
Macmillan Cancer Support. The C-Word: How We React to Cancer Today. Published online July 10, 2017. Full text

REDUCED ODDS OF PREGNANCY IN CANCER TREATED WOMEN

Treatment for most cancers in girls and women younger than 39 years significantly reduces the likelihood of subsequent pregnancy a large population study now shows.
Cancer survivors were 38% less likely to achieve a pregnancy compared to women in the general population, an impact of cancer treatment seen across almost all diagnostic groups and all ages, says a research group led by Richard Anderson, MD, PhD, from the MRC Center for Reproductive Health, Queen's Medical Research Institute at the University of Edinburgh, United Kingdom.
The study showed that 20.6% of cancer survivors achieved a first pregnancy after cancer diagnosis (2114 first pregnancies in 10,271 women), compared to 38.7% in control persons.
Women with cancer were about half as likely to achieve a first pregnancy after diagnosis as were controls. Dr Richard Anderson
"Thus, women with cancer were about half as likely to achieve a first pregnancy after diagnosis as were controls," said Dr Anderson. He presented the study on July 3 at the annual meeting of the European Society of Human Reproduction and Embryology in Geneva, Switzerland.
"This analysis provides robust, population-based evidence for the extent of the effect of cancer and its treatment on subsequent pregnancy across the reproductive age range," the study authors say. "The major impact on subsequent pregnancy in some common cancers highlights the need for enhanced strategies to preserve fertility in girls and young women."
Dr Anderson and colleagues note that the study findings are limited by the fact that they could not assess the impact of treatment on fertility because details about participants' treatment were not available. In addition, follow-up was limited for women diagnosed in the most recent period.
The impact of cancer therapy on subsequent pregnancy remains a significant issue, Dr Anderson commented to Medscape Medical News. With the increased number of young female cancer survivors and improved techniques for fertility restoration, such as cryopreservation of eggs and ovarian tissue, "there is a major need to improve access to fertility preservation and to identify those women [and girls] at risk," he said.
Approached for comment, Daniel M. Green, MD, of the Departments of Epidemiology and Cancer Control at St. Jude Children's Research Hospital in Memphis, Tennessee, told Medscape Medical News that the study "is confirmatory of several other population-based studies, primarily from the Nordic countries and one recently published from North Carolina." However, he noted that "the absence of exposure information is a significant weakness. This abstract does not add to our understanding of post-therapy fertility among survivors of childhood, adolescent, or young adult cancer."
Dr Green is coauthor of the Childhood Cancer Survivor Study, a multicenter research initiative that investigated long-term clinical outcomes in 14,000 5-year survivors of childhood and adolescent cancer diagnosed between 1970 and 1986.

Study Details

For their cohort study, Dr Anderson and colleagues identified 23,201 female patients from the Scottish Cancer Registry who were first diagnosed between 1981 and 2012 and who subsequently became pregnant. All were 39 years of age or younger at the time of diagnosis. Pregnancies were included to the end of 2014.
The cancer registry records were cross-linked to hospital discharge records to calculate standardized incidence ratios (SIRs) for pregnancy. The calculations were standardized for age and year of diagnosis. A subgroup of cancer survivors who had not been pregnant prior to their cancer diagnosis was created for comparison with a matched control group of women from the general population. Additional analyses were performed for patients diagnosed with breast cancer, Hodgkin's lymphoma, and leukemia.
Cancer survivors achieved fewer pregnancies — 6627 observed compared to 10,736 expected pregnancies. A reduction in SIR was observed for women across almost all cancers. The SIR ranged from 0.34 in those with cervical cancer to 0.87 for women diagnosed with skin cancer. It was lowest in women from the most deprived quintile.
The reduced SIR in female cancer survivors was seen across all age groups, and it fell progressively with age at diagnosis.
The time frame in which diagnosis took place also had a strong impact on SIR. Women who were diagnosed with cancer in the period between 1981 and 1998 had an SIR of 0.47 compared to those diagnosed between 2005 and 2012, who had an SIR of 0.64 and higher pregnancy rates. This suggests that the impact on fertility of some cancer treatments is not as severe as it was previously, the study authors say.
The most significant reductions in pregnancy rates were seen in survivors of breast cancer (SIR, 0.44), leukemia (SIR, 0.30), and Hodgkin's lymphoma (SIR, 0.65). Pregnancy rates were favorably affected by more recent treatment for women with Hodgkin's lymphoma, but not for those with leukemia or breast cancer.
The proportion of first pregnancies that ended in termination was lower among women with previous cancer than among control persons (11.2% vs 14.7% of pregnancies), but no differences were observed in the risk for either miscarriage or stillbirth.
"This study provides further evidence that cancer and cancer treatment are associated with achieving fewer pregnancies," said Jessica R. Gorman, PhD, MPH, of the School of Social and Behavioral Health Sciences at Oregon State University College of Public Health and Human Sciences, in Corvallis. "It is interesting to note that this was the case for all age groups and most cancers." However, she added in an email, "more research is needed to explore the reasons for this outcome."
Dr Gorman is coauthor of a 2016 study of young female cancer survivors and their use of fertility care after completing cancer treatment. Results showed that many of the women did not feel they had received enough information about fertility care, despite the fact that they wanted to have children.
"To improve fertility outcomes for female cancer survivors, it is important to offer fertility consultation both at the time of cancer diagnosis and after completing treatment, when survivors may be more prepared to discuss family building options," Dr Gorman told Medscape Medical News. In addition to information about fertility and parenthood options, women treated for cancer need guidance and support from healthcare providers to navigate "both the emotional and practical issues that arise when considering their family building options," she said.
These conversations can be difficult, acknowledged Nancy Baxter, MD, PhD, chief of the General Surgery Department at St. Michael's Hospital and professor of surgery at the University of Toronto, Canada. Dr Baxter is lead author of a 2013 Canadian population-based study showing that recurrence-free survivors of nongynecologic malignancies who were 20 to 34 years of age were less likely than control persons to experience childbirth after diagnosis. Although the overall effect was small, it was influenced by prediagnosis childbirth and malignancy type.
These conversations have to occur when patients may already be feeling overwhelmed by their diagnosis and their pending treatment, Dr Baxter told Medscape Medical News. "Although fertility preservation is not a guarantee, the options can increase the chances of future fertility and do not need to result in major delays in treatment, so are possible for most women at risk."
To make things easier, she pointed out, a decision aid called BEFORE is being developed to help women understand their risks and options. It will point to resources and help guide patient-doctor conversations. A version for women with breast cancer is almost ready for use.
Clinicians also need to find out whether individual patients want to pursue fertility preservation, Dr Baxter said, adding, "Not every woman wants to have children.
"As doctors, we need to be looking further ahead and focusing not only on curing our patients but also on how we can help their lives after cancer be as normal as possible," Dr Baxter told Medscape Medical News. "We have made great strides, but there is definitely more work to be done."
No funding has been disclosed. The study authors, Dr Green, and Dr Gorman have disclosed no relevant financial relationships. Dr Baxter has a relationship with Servier Canada Inc.
European Society of Human Reproduction and Embryology. Abstract O-082, presented July 3, 2017.

NO BENEFIT OF FIRST LINE NIVOLUMAB IN NSCLC

In CheckMate 026 study, nivolumab was not associated with significantly longer progression-free survival (PFS) than chemotherapy among patients with previously untreated stage IV or recurrent non–small cell lung cancer (NSCLC) with a PD-L1 expression level of 5% or more. The overall survival (OS) was similar between the groups. Nivolumab had a favourable safety profile, as compared with chemotherapy, with no new or unexpected safety signals, the study investigators reported in 22 June 2017 issue of The New England Journal of Medicine (NEJM). 
In a background, the authors explained that in two phase III trials, nivolumab resulted in significantly longer OS than docetaxel among patients with metastatic NSCLC who had disease progression during or after platinum-based chemotherapy. Benefit was seen regardless of the PD-L1 expression level but was enhanced in patients with non-squamous NSCLC with increased PD-L1 expression.
In an international, randomised, open-label phase III trial, CheckMate 026 (ClinicalTrials.gov number, NCT02041533) the study investigators compared first-line nivolumab with chemotherapy in patients with PD-L1–positive NSCLC.
In the NEJM paper, they reported the efficacy and safety of nivolumab compared to platinum-based chemotherapy as first-line therapy in patients with stage IV or recurrent NSCLC with a PD-L1 expression level of 5% or more (primary efficacy analysis population) and those with a PD-L1 expression level of 1% or more (secondary efficacy analysis population). Furthermore, they reported an exploratory analysis to assess the effects of the tumour-mutation burden on treatment outcomes.
The study investigators assigned, in a 1:1 ratio, patients to receive nivolumab (administered intravenously at a dose of 3 mg per kilogram of body weight once every 2 weeks) or platinum-based chemotherapy (administered once every 3 weeks for up to six cycles). Patients receiving chemotherapy could cross over to receive nivolumab at the time of disease progression.
The primary endpoint was PFS, as assessed by blinded independent central review, among patients with a PD-L1 expression level of 5% or more.
Of 1325 patients enrolled in the trial, 541 (41%) underwent randomisation, with 271 assigned to receive nivolumab and 270 assigned to receive chemotherapy. A total of 784 patients (59%) did not undergo randomisation because their PD-L1 samples could not be evaluated, because the PD-L1 expression level was less than 1%, or because they did not meet other trial criteria. During screening, 71% of patients who had PD-L1 results that could be evaluated had a PD-L1 expression of 1% or more. Overall, 530 patients (98% of all the patients who had undergone randomisation) received treatment.
Among the 423 patients with a PD-L1 expression level of 5% or more, the median PFS was 4.2 months with nivolumab versus 5.9 months with chemotherapy (hazard ratio [HR] for disease progression or death, 1.15; 95% confidence interval [CI], 0.91 to 1.45; p = 0.25), and the median OS was 14.4 months versus 13.2 months (HR for death, 1.02; 95% CI, 0.80 to 1.30).
An exploratory analysis was conducted in 312 patients (58% of the patients who had undergone randomisation) to assess the effect of the tumour-mutation burden on outcomes. The percentage of patients with a high tumour-mutation burden was imbalanced between the treatment groups (30% in the nivolumab group vs. 39% in the chemotherapy group).
Among the patients with a high tumour-mutation burden, the response rate was higher in the nivolumab group than in the chemotherapy group (47% vs. 28%), and PFS was longer (median, 9.7 vs. 5.8 months; hazard ratio for disease progression or death, 0.62; 95% CI, 0.38 to 1.00). The OS was similar between groups regardless of the tumour-mutation burden. However, 68% of the patients with a high tumour-mutation burden in the chemotherapy group received subsequent nivolumab because of treatment crossover, access to nivolumab after the trial, or both. There was no significant association between tumour-mutation burden and PD-L1 expression level. However, in the nivolumab group, patients with both a high tumour-mutation burden and a PD-L1 expression level of 50% or more had a higher response rate (75%) than those with only one of these factors (32% among patients with a high tumour-mutation burden only and 34% among those with a PD-L1 expression level of ≥50% only) or neither factor (16%). However, this comparison was not powered for statistical analysis.
In term of findings related to high tumour-mutation observations, the authors wrote that it was an exploratory analysis that was not prespecified, the data are hypothesis-generating and require further prospective validation.
Treatment crossover 
A total of 128 of 212 patients (60%) in the chemotherapy group received nivolumab as subsequent therapy.
The authors commented that “given that nivolumab therapy prolongs survival among previously treated patients with advanced NSCLC, the high frequency of subsequent nivolumab treatment may have contributed to the favorable overall survival in the chemotherapy group. In addition, imbalances in the characteristics of the patients at baseline may have favored the chemotherapy group, including disease characteristics that are associated with a better prognosis (i.e., slightly fewer liver metastases, smaller tumor burden, and a higher proportion of women). Two factors that appear in retrospect to have had an influence on the response to nivolumab (i.e., a PD-L1 expression level of ≥50% and a high tumor-mutation burden) also disfavored the nivolumab group, which had lower proportions of such patients than did the chemotherapy group.
Two additional observations worth noting are the high percentage of patients in this trial who had received radiotherapy previously (39%) and the median time from diagnosis to randomization of approximately 2 months.”
Side effects
Treatment-related adverse events of any grade occurred in 71% of the patients who received nivolumab and in 92% of those who received chemotherapy. Treatment-related adverse events of grade 3 or 4 occurred in 18% of the patients who received nivolumab and in 51% of those who received chemotherapy.
Differences between CheckMate 026 and KEYNOTE-024
The KEYNOTE-024 trial established a role for pembrolizumab as first-line treatment in patients with NSCLC with a PD-L1 expression level of 50% or more as determined by the Dako 22C3 PD-L1 test in a prospectively designed trial. The median PFS was 10.3 months in the pembrolizumab group and 6.0 months in the chemotherapy group. The response rate was 45% in the pembrolizumab group and 28% in the chemotherapy group.
Analyses comparing treatment efficacy in patients with a PD-L1 expression level of 50% or more were not prespecified in CheckMate 026. Other differences between these two trials include different assays to assess PD-L1 tumour expression, the criteria related to previous radiotherapy and glucocorticoid use during the trials, and imbalances between groups in the characteristics of the patients (e.g., sex in CheckMate 026 and the lower percentage of patients who had never smoked in the immunotherapy group in KEYNOTE-024 [3%] than in CheckMate 026 [11%]).
The CheckMate 026 was supported by Bristol-Myers Squibb, ONO Pharmaceutical, a Cancer Center Support Grant (CA016672, to MD Anderson Cancer Center [Dr Blumenschein]) from the US National Institutes of Health, and a Hollings Cancer Center K12 Paul Calabresi Career Development Grant (K12 CA157688, to Dr Wrangle). The study team thank the staff of Dako for collaborative development of the PD-L1 IHC 28-8 pharmDx assay.

NO SURVIVAL BENEFIT OF NIVOLUMAB IN IPILIMUMAB PRETREATED MELANOMA PATIENTS

As reported in the Journal of Clinical Oncology by Larkin et al, the phase III CheckMate 037 trial has shown no difference in overall survival with nivolumab (Opdivo) vs investigator’s choice of chemotherapy in ipilimumab (Yervoy)-refractory advanced melanoma. More chemotherapy patients never received study treatment and more received programmed cell death protein 1 (PD-1) inhibitors after assigned treatment. The finding of durable responses in the first 120 nivolumab patients enrolled in the trial supported the accelerated approval of nivolumab in this setting in December 2014.
Study Details
In the open-label trial, 405 patients with unresectable or metastatic melanoma from 90 sites in 14 countries were randomized 2:1 between December 2010 and January 2014 to receive nivolumab at 3 mg/kg every 2 weeks (n = 272) or investigator’s choice of dacarbazine or carboplatin plus paclitaxel (n = 133). Patients had to have progressed after treatment with ipilimumab or with ipilimumab and a BRAF inhibitor if they were BRAF V600–mutation positive. Chemotherapy consisted of dacarbazine at 1,000 mg/mevery 3 weeks or carboplatin AUC = 6 plus paclitaxel at 175 mg/m2 every 3 weeks. Patients were treated until disease progression or unacceptable toxicity; nivolumab patients could continue to receive nivolumab beyond disease progression. The co-primary endpoints were objective response rate and overall survival.
Of patients randomized to receive nivolumab, 99% received study treatment. Of those patients randomized to receive chemotherapy, 77% received treatment, with 16 patients withdrawing consent and 13 not receiving treatment by patient request. More nivolumab patients had brain metastases (20% vs 14%) and elevated lactate dehydrogenase levels at baseline (52% vs 38%).
Overall Survival
At database lock in March 2016, median follow-up was approximately 2 years. Among all randomized patients, median overall survival was 15.7 months in the nivolumab group vs 14.4 months in the chemotherapy group (hazard ratio [HR] = 0.95, P = .716). Median progression-free survival was 3.1 months vs 3.7 months (HR = 1.0, 95.1% confidence interval [CI] = 0.78–1.436), reduced from medians of 4.7 vs 4.2 months in an earlier analysis. Overall response rates were 27% vs 10%, and median durations of response were 32 months vs 13 months.
Overall, more patients in the chemotherapy group received systemic therapy after assigned therapy (62% vs 40%) and more received anti–PD-1 or anti–programmed cell death ligand 1 treatment (41% vs 11%). In an analysis among patients who received study treatment that censored patients at the start of PD-1 inhibitor treatment after assigned therapy in the chemotherapy group, median overall survival was 16.4 months in the nivolumab group vs 11.8 months in the chemotherapy group (HR = 0.81, 95.54% CI = 0.59–1.11).
Adverse Events
Grade 3 or 4 treatment-related adverse events occurred in 14% of the nivolumab group vs 34% of the chemotherapy group. Treatment-related adverse events led to treatment discontinuation in 5% vs 11%. The most common treatment-related adverse events of any grade with a potential immunologic cause in the nivolumab group were skin (38%), gastrointestinal (18%), and hepatic (11%) adverse events.
The investigators concluded: “Nivolumab demonstrated higher, more durable responses but no difference in survival compared with [investigator’s choice chemotherapy]. [Overall survival] should be interpreted with caution, as it was likely impacted by an increased dropout rate before treatment, which led to crossover therapy in the [investigator’s choice chemotherapy] group, and by an increased proportion of patients in the nivolumab group with poor prognostic factors.”
The study was supported by Bristol-Myers Squibb.


James Larkin, PhD, FRCP, of the Royal Marsden NHS Foundation Trust, is the corresponding author of the Journal of Clinical Oncology article.

GENOMIC TESTING FOR EVERY CANCER PATIENT? NOT YET

In a provocative new report, the chief medical officer (CMO) of England has called for all patients with cancer, as well as those with rare diseases, to undergo full genomic sequencing.
In fact, genomic sequencing should become part of routine medical practice for these patients and be as standard as blood tests and biopsies.
"Please, can we move from talking and experimenting about genomes and move it into practice for patients," said CMO Dame Sally Claire Davies, DBE, FMedSci, FRS, in an interview with The Telegraph.
In her report, which is compiled independently and without government input, Dr Davies says that genomic medicine has the potential to "save costs and improve quality of care by targeting treatment, maximizing benefit and reducing side effects."
This is particularly true for patients with rare diseases, who often undergo a lengthy "diagnostic odyssey."  Genomic sequencing can potentially provide a more rapid diagnosis, identify therapeutic options faster, and improve outcomes.
"By moving from a cottage industry and into modern science, not only do we bring it much closer to  patients, but we will get more bang for our buck," said Dr Davies. "We need to develop a genomic literate set of professionals, both doctors and nurses and even managers, so that they walk with us into this new era."
Every patient gets their genome done if they've got cancer. Dr Sally Claire Davies
Dr Davies emphasized that she would like all "appropriate patients to get the opportunity. My dream is in the end that every patient gets their genome done if they've got cancer."
The leading UK cancer charity, Cancer Research UK, reacted with enthusiasm to the announcement. Sir Harpal Kumar, chief executive of Cancer Research UK, statedthat "This timely report from the chief medical officer showcases just how much is now possible in genomics research and care within the NHS [National Health Service]."
However, two US experts approached for comment were both critical of the proposal.
Widespread genomic tests of patients with cancer offers up the promise of "precision oncology" of matching treatments to specific mutations, with the premise that this will be a more effective therapy and improve response and outcomes.
But thus far, precision oncology has not been shown to work, and the data are just not there, commented Vinay Prasad, MD, MPH, a hematologist-oncologist at the Knight Cancer Institute, Oregon Health and Science University, Portland.
It's a very foolish thing to suggest testing all patients at this juncture, because it is abundantly clear we are not there yet," Dr Prasad told Medscape Medical News. "It's not even being done at tertiary cancer centers in the US, which are often on the cutting edge."
For them to go ahead with this seems a little bit reckless. Dr Vinay Prasad
In contrast, the United Kingdom is generally far more thoughtful and careful as to how they fund cancer care, he pointed out. "For them to go ahead with this seems a little bit reckless."
Dr. Prasad emphasized that to date, there is a lack of data from phase 3 randomized trials comparing patients who undergo genomic testing and then receive tailored treatment based on those results vs patients who receive standard therapy.
"And then we would need to see a survival benefit in the patients who did receive the tailored treatment," he said.

Lackluster Results

Dr Prasad pointed to the MOSCATO trial, which used genomic testing to select treatment for patients. Although this was not a randomized trial, the results showed the limitations of testing.
After patients received a targeted therapy based on genetic testing, the overall response rate was 11%, with 2 patients achieving a complete response and 20 patients showing a partial response. In addition, 100 had stable disease and 33 had progressive disease. The median overall survival duration was 11.9 months.
An actionable molecular alteration was identified in 411 of 843 patients, but only 7% actually benefited from this strategy, Dr Prasad pointed out.
A similar trial, the ProfiLER study, presented at this year's annual meeting of the American Society of Clinical Oncology (ASCO) and reported by Medscape Medical News at that time, also showed limited results.
Among patients who had at least one "actionable" alteration (52% of 2676 enrolled) and who received recommended targeted therapy, 53.7% were alive after 3 years, as compared with 46.1% of patients who did not.
The 5-year survival rate was also higher for patients who were treated with a targeted agent (34.8% vs 28.1%).
Richard Schilsky, MD, chief medical officer at ASCO, found the study to be somewhat "disappointing."
"This study is similar to what many other studies are showing ― the researchers found an actionable mutation in about 50% of patients, which is similar to what other groups have reported in the same ballpark, and then targeted therapy available for about 35% of them," he commented during the meeting.
This translated to only about 100 patients who were able to receive the targeted therapy, with a median progression-free survival duration of 2.8 months, he pointed out. "So your view of these results depends on whether you are a glass-half-full or a glass-half-empty person — 5% to 10% of patients who get the drug respond, but these responses are relatively short-lived," he said.

"Little More Than a Lottery"

Dr Prasad also noted that next-generation sequencing is very expensive and could cost hundreds of millions of dollars to test every patient with cancer in the United Kingdom. "And it is not clear that this information will necessarily lead to better choices," he said.
It is particular interesting that England should go for this because the health system has refused to pay for cancer drugs that are effective but now appears to be willing to shoulder the cost for widespread genomic testing.
I consider this an inappropriate recommendation. Dr Jack West
Another US expert agrees. "Based on the absence of prospective population data, I consider this an inappropriate recommendation, and ironic that it is coming from a system that has decided it cannot cover interventions with a proven survival benefit because of concerns that they are not sufficiently cost-effective," commented Jack West, MD, medical oncologist and chair of the Outreach, Education, and Telemedicine Workgroup at Providence/Swedish Health & Services, Seattle, Washington.
"It is unfortunate to forgo treatments with a proven benefit in favor of interventions with no proven improvement in population-based cancer outcomes, seemingly based more on newsworthiness than proven benefit," Dr West told Medscape Medical News
"I also think it's likely to prove very frustrating to have a large number of patients for whom a potentially or known effective treatment is identified but will not be covered in the UK," he added. 
Dr West pointed out that it could be a great opportunity to facilitate targeted therapy research if patients with an identified marker for which there is an investigational agent have access to clinical trials with those agents. "If such research opportunities are not available, however, I fear it is likely that a policy of broad genomic testing is more likely to escalate only frustration and costs, without a demonstrable improvement in outcomes for cancer patients," he said.
Given the current level of data, which consist primarily of retrospective data and anecdotal reports of "remarkable results" for selected patients with uncommon to rare mutations, a policy of favoring "broad molecular testing for all cancer patients is little more than a lottery, with highly visible winners, but far more who end up losing," Dr West added.

Report Urges Widespread Genomic Testing 

The report outlines a lengthy list of goals and recommendations for making widespread genomic testing a reality, while at the same time making sure that patient privacy is protected.
One recommendation is to centralize genetic testing of patients in the NHS and set up a national network. This would make the process more standardized and ensure that all patients had equal access to testing. Currently, genetic testing is conducted at 25 regional laboratories and several smaller centers.
Another is to set up a new National Genomics Board, which would oversee the expansion and development of genomic services.
The establishment of genetic testing would likely make cancer screening programs more effective by targeting the screening at individuals who are most likely to benefit and least likely to be harmed, the report suggests. Screening for breast, prostate, colorectal, and lung cancer provides the most immediate opportunities, it adds.
Dr Davies does acknowledge that patients will have concerns about privacy and the protection of their personal data and that they may struggle to grasp the full concept of what genetic testing can accomplish. "The field of genomics is complex, and we cannot expect patients to understand it readily," she writes. "As members of clinical teams we must engage patients and the public and develop real partnerships."
Key to this process is having a short, simple, understandable, and workable consent process for patients to choose how confidential genomic data about them are used.
The report also highlights gaps in infrastructure, public engagement, organization of research, and provision of services that need to be addressed in order to implement the proposed policies.

MAMMAPRINT TEST ADDED TO ASCO GUIDELINES

In an update to its 2016 clinical practice guideline on the use of biomarkers in early invasive breast cancer, the American Society of Clinical Oncology (ASCO) has outlined  specific recommendations for using the MammaPrint (Agendia) genomic test to identify patients who can safely skip adjuvant chemotherapy.
The new paper, titled "Use of Biomarkers to Guide Decisions on Adjuvant Systemic Therapy for Women With Early-Stage Invasive Breast Cancer: American Society of Clinical Oncology Clinical Practice Guideline Focused Update" was published onlineJuly 10 in the Journal of Clinical Oncology. Only the MammPrint test was reviewed for this update.
"Some women with breast cancer are more likely to have a recurrence of cancer and need to receive chemotherapy to lower this risk," Vered Stearns, MD, co-chair of the ASCO expert panel that developed the guideline update, said in a statment.
"The MammaPrint test can now be added to the list of tests that help clinicians identify women who need chemotherapy and those who do not," said Dr Stearns, who is co-director of the Breast Cancer Program at The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland.
The recommendations are based on findings from MINDACT (Microarray for Node-Negative Disease May Avoid Chemotherapy Trial). It showed that in more than 6500 women with early-stage breast cancer who had undergone surgery, the 70-gene assay was associated with a 46% reduction in chemotherapy prescription.
As previously reported by Medscape Medical News, the MINDACT results were initially presented at the American Association for Cancer Research 2016 Annual Meeting in New Orleans, Louisiana, and were then publishedin the New England Journal of Medicine.
"The MINDACT trial results provide level 1A evidence that using MammaPrint could change clinical practice by substantially de-escalating the use of adjuvant chemotherapy and sparing many patients an aggressive treatment they will not benefit from," said principal investigator, Martine Piccart, MD, PhD, head of the Department of Medicine at the Jules Bordet Institute in Brussels, Belgium, and cofounder and chair of the Breast International Group.
However, the test isn't suitable in all women with early breast cancer, said Ian Krop, MD, PhD, ASCO expert panel co-chair, in the statement. "We do not recommend it for women with HER2 [human epidermal growth factor receptor 2]-positive tumors or those with triple-negative breast tumors," said Dr Krop, a medical oncologist at Dana-Farber Cancer Institute in Boston, Massachusetts.
Commenting to Medscape Medical News, Dr Krop said, "It is important that patients be informed that while the MammaPrint assay may be able to determine that their prognosis is relatively favorable, it cannot rule out that chemotherapy may still provide a small benefit."
"In addition, patients should understand that no biomarker test is perfect, and that some patients with favorable test results still have recurrence and that many patients with high-risk assay results remain disease free," Dr Krop added.  

Other Genomic Assays 

Other biomarker genomic assays that measure the expression of a relatively small number of genes in breast tumor tissue can also provide important prognostic and possibly predictive information and were included in the 2016 ASCO clinical practice guideline, the update authors point out.  The genomic signatures identified as being useful in patients with node-negative estrogen receptor/progesterone receptor–positive cancers include Oncotype DX (Genomic Health Inc), EndoPredict (Myriad Genetics), PAM50 risk of recurrence score, and the Breast Cancer Index.
"None of these assays are perfect," the update authors acknowledge. Available data show that some patients developed recurrent disease despite favorable assay results, and many others with poor-prognosis genomic scores remain disease free without chemotherapy. "Thus, improvements are needed in the assays to additionally reduce overtreatment but minimize risk of recurrence," they conclude.

Recommended Use of the Test 

The update of the 2016 clinical practice guideline recommends that MammaPrint be considered in women with estrogen receptor–positive or progesterone receptor–positive, HER2-negative, node-negative breast cancer who are at a high clinical risk for recurrence in order to determine whether adjuvant systemic chemotherapy would be beneficial.
It should also be considered in women with estrogen receptor–positive or progesterone receptor–positive, HER2-negative breast cancer with one to three positive lymph nodes who are at a high clinical risk for recurrence. "However, such patients should be informed that a benefit from chemotherapy cannot be excluded, particularly in patients with greater than one involved lymph node," the update authors point out.
In any patients who meet these criteria and have a low MammaPrint score, hormone therapy alone is recommended because it is unlikely that chemotherapy will provide substantial additional benefits, they say.
It is not recommended that MammaPrint be used in women with a low clinical risk for recurrence. Thus, clinicians should not use MammaPrint to guide decisions on adjuvant systemic therapy in patients with hormone receptor–positive, HER2-negative, node-positive breast cancer at low clinical risk, or any patient with HER2-positive or triple-negative breast cancer.
MINDACT results showed that women in the low clinical risk category did not benefit from chemotherapy "regardless of genomic MammaPrint risk," the update authors note. "Therefore, the MammaPrint assay does not have clinical utility in such patients," they add.
In addition, only a small number of patients with triple-negative breast cancer were included in MINDACT, and most of these patients were classified as high risk. As a result, most received chemotherapy and were not analyzed separately.
"Given that no other therapies (eg, endocrine therapy or HER2-targeted therapy) are recommended for these patients, the Panel felt strongly that until data from larger data sets are available, the MammaPrint assay should not be used to guide clinical decisions in patients with triple-negative breast cancer," the update authors write.

Another Use for the Test? 

Recent results from a long-term follow-up study of patients with "ultralow-risk" breast cancers indicate the assay may also be helpful in identifying postmenopausal patients who can forgo standard endocrine treatment after surgery, although this particular use is not currently recommended by ASCO. The study was published online June 29 in JAMA Oncology .
As reported in Medscape Medical News, the study showed that patients with tumors that scored under the ultralow-risk threshold on MammaPrint and who did not receive tamoxifen had an "exceedingly low" risk for death from breast cancer during 20 years of follow-up.
"This is an exciting advance because approximately 20% to 25% of tumors diagnosed today may be ultralow risk," said lead investigator of that study, Laura Esserman, MD, from the Helen Diller Family Comprehensive Cancer Center at the University of California, San Francisco, in a press statement.
Dr Krop is an employee of  AMAG Pharmaceuticals and also has relationships with Genentech and Novartis. Dr Stearns reports relationships with AbbVie, Merck, Pfizer, MedImmune, Novartis, Celgene, and Puma Biotechnology. Several other members of the expert panel also disclose potential conflicts of interest, which are available at jco.org .
J Clin Oncol. Published online July 10, 2017. Abstract