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Oncologists’ Guide to Genomics

Stay current on the latest trends in genomics and molecular diagnostics for oncology.

Tuesday, January 7, 2020

By Mark L. Fuerst

BOSTON—An investigational inhibitor of an enzyme that occurs in about 15 percent of human cancers shows signs of activity in select patients with solid tumors, according to a new study. The therapeutic AG-270 is a first-in-class, oral, potent, reversible inhibitor that targets the protein MAT2A. It was found to be safe and tolerable in patients who had solid tumors in which both copies of the MTAP gene were deleted. This gene encodes the metabolic enzyme methylthioadenosine phosphorylase.

"About 15 percent of all human cancers have both copies of the MTAP gene deleted," said Rebecca S. Heist, MD, a medical oncologist at Massachusetts General Hospital Cancer Center. "Research into the biology of these cancers led to the discovery that cancer cells with MTAP deletion are selectively vulnerable to inhibition of the MAT2A enzyme.

"MAT2A inhibition leads to the molecule S-adenosylmethionine (SAM) being produced at lower levels than normal," said Heist, who is also Associate Professor of Medicine at Harvard Medical School. "The reduction in SAM levels is sufficient to slow the growth of cancer cells with MTAP deletion, but does not affect healthy cells in which the MTAP gene is intact."

Heist presented the results of a phase I clinical trial at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics. The preliminary results are from the ongoing first-in-human phase I clinical trial of AG-270. The main goal of the trial was to determine the maximum tolerated dose of the investigational therapeutic.

Study Details

So far, Heist and colleagues have enrolled 39 patients who had an advanced solid tumor with MTAP deletion, or CDKN2A loss, which usually correlates with MTAP deletion. The most common cancers were bile duct cancer (seven patients), pancreatic cancer (seven patients), mesothelioma (four patients), and non-small cell lung cancer (four patients). The doses of AG-270 tested in the trial ranged from 50 mg once daily to 400 mg once daily and 200 mg twice daily.

One patient who had a high-grade neuroendocrine tumor of the lung had a partial response after treatment with 200 mg AG-270 once daily. Eight other patients, treated with doses ranging from 100 mg to 400 mg once daily, had stable disease. As of mid-August 2019, the partial response was ongoing 4.4 months after the patient started treatment. Stable disease was ongoing for two patients, including one patient who had a sex cord-stromal tumor, who had received treatment for more than 1 year.

"Importantly, the reduction in plasma SAM levels was similar across the entire range of doses we evaluated," noted Heist. "The 60-70 percent reduction achieved was in the same range that was associated with maximal inhibition of tumor growth in preclinical models."

The therapeutic was well-tolerated. Asymptomatic, exposure-dependent increases in unconjugated bilirubin were observed starting at 100 mg once daily, consistent with the known potential of AG-270 to inhibit the UGT1A1 gene. Three patients at 100 mg once daily, 150 mg once daily, and 200 mg twice daily doses developed grade 2 and 3 diffuse erythematous rashes during the second week of dosing that resolved within 1 week of stopping treatment. Exposure-dependent, reversible decreases in platelet counts were first observed at 200 mg once daily and were grade 3 and 4 in severity at 200 mg twice daily. Two patients treated at 200 mg twice daily developed reversible but dose-limiting grade 3 and 4 increases in liver enzymes. The maximum tolerated dose of AG-270 was determined to be 200 mg once daily.

"We are pleased that the study accomplished its main objective, which was to identify a safe AG-270 dose and schedule that would lower plasma SAM levels to the extent required for antitumor activity," stated Heist. "Although AG-270 demonstrated some evidence of single-agent activity, based on preclinical data, we believe that it will have its greatest benefit when combined with taxane-based chemotherapy. There are plans to test AG-270 in combination with taxanes in the clinic in the near future."

The main limitation of the study, she said, is that the trial enrolled patients with a wide range of advanced solid tumors, most of which are inherently resistant to standard treatments and had progressed despite standard treatments. This makes evaluating the single-agent activity of AG-270 in cancer treatment difficult in this study, Heist noted.

Mark L. Fuerst is a contributing writer.

Monday, November 25, 2019

By Mark L. Fuerst

BOSTON—An investigational bispecific HER2/HER3 antibody leads to clinical responses in patients who harbor fusions in the gene neuregulin 1 (NRG1), including those with metastatic pancreatic ductal adenocarcinoma (PDAC) or metastatic non-small cell lung cancer (NSCLC), according to a new study.

NRG1 is a ligand that binds HER3, promoting HER2/HER3 heterodimerization and activation of PI3K/AKT/mTOR signaling. NRG1 fusions are rare oncogenic drivers found across numerous solid tumor types, with less than 1 percent incidence. MCLA-128 is a bispecific antibody that binds HER2, optimally positioning an anti-HER3 arm to block the HER3/ligand interaction. Preclinical experiments using NRG1-fusion-positive cancer cell lines and mouse xenograft models found that MCLA-128 effectively inhibited cell proliferation and caused tumors to shrink in mice.

Alison Schram, MD, a medical oncologist in the Early Drug Development Service at Memorial Sloan Kettering Cancer Center (MSKCC), presented clinical proof of concept of MCLA-128 to treat NRG1 fusion cancers at a press conference before the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics. 

"NRG1 fusions have recently been described in several cancer types and are enriched in diseases in desperate need of better therapy, including pancreatic and lung cancer," said Schram. "Identifying a new, effective treatment strategy for these patients could make a big impact in their lives."

Study Details

The MSKCC team performed next-generation sequencing of solid tumors from patients and identified 29 patients with tumors that were positive for NRG1 fusions, including those with pancreatic, lung, breast, prostate, and gallbladder cancers, as well as sarcoma and lymphoma, among others. Three of these patients were treated with 750 mg MCLA-128 intravenously every other week, and all three showed significant tumor shrinkage, said Schram.

One patient, a 52-year-old man with NRG1-fusion-positive advanced PDAC developed liver metastases, was put on additional chemotherapy, and developed side effects. His tumor was sequenced tumor, with no KRAS mutation found, and he was put on MCLA-128.

On MCLA-128 treatment, his levels of CA 19-9, a tumor biomarker for pancreatic cancer, dropped from 262 units/mL to 50 units/mL, which was close to the normal range of less than 40 units/mL. At 8 weeks, imaging revealed a 44 percent reduction in tumor diameter, which further decreased to a 54 percent reduction on his subsequent scan. The patient was considered to have a partial response by RECIST criteria and a complete response by PET response criteria. Importantly, within weeks of his first treatment his fatigue improved, and he started to gain back the weight he had unintentionally lost in previous months, noted Schram.

Another patient, a 34-year-old man with NRG1-fusion-positive advanced PDAC, took prolonged chemotherapy, progressed, and developed liver metastases. Treatment with MCLA-128 resulted in the reduction of CA 19-9 from 418 units/mL to 11 units/mL. Imaging at 6 weeks showed 22 percent reduction in tumor diameter, which further decreased to a 25 percent reduction at the next scan; PET imaging also revealed that the liver metastases were not metabolically active. The patient's tumor-related abdominal pain also subsided following treatment, she said.

"Both patients remain on therapy for more than 7 months, and have tolerated therapy extremely well," said Schram.

A third patient, a 54-year-old man with NRG1-fusion positive NSCLC with brain metastases, had previously progressed on six lines of therapy, including the tyrosine kinase inhibitor (TKI) afatinib, as well as two lines of radiation therapy. Upon treatment with MCLA-128, the patient's tumor shrank by 33 percent at 8 weeks, with improvement in his brain metastases, and by 41 percent at 16 weeks, confirming a partial response. "This emphasizes the potential superiority of this approach over TKIs," Schram said. "This patient says he continues to feel well on therapy.

"Treating these three patients with MCLA-128 was a rational decision based on our understanding of biology, and our data provide important proof-of-concept demonstrating the promise of targeting NRG1 fusions with this novel approach." 

Importantly, she noted that the patients feel well on treatment and report immediate improvement in their quality of life. Data from an ongoing clinical trial of 117 patients show MCLA-128 has a tolerable safety profile, with fewer than 5 percent of patients reporting presumed drug-related grade 3-4 adverse events, no reports of clinically significant cardiotoxicity or rash, and minimal gastrointestinal toxicity, she added. Minor infusion reactions have been managed by decreasing the dose.

"Initial data from these three patients suggests that it is important to look for NRG1 fusions in tumors, particularly in KRAS-negative pancreatic cancer and invasive mucinous adenocarcinoma of the lung, and when identified, patients should consider treatment in a clinical trial targeting this alteration," Schram said. Based on these data, a phase II trial of MCLA-128 is actively accruing and treating patients with NRG1 fusion-positive tumors (NCT02912949).

The three patients described here were treated through the FDA-approved single-patient investigational drug applications initiated by MSKCC as part of an expanded access program. This approach must continue to be tested in a larger patient population as part of a clinical trial for further validation, Schram noted. "From our preliminary experience, we feel this is a novel paradigm to target these alterations."

Mark L. Fuerst is a contributing writer.

Wednesday, October 23, 2019

By Catlin Nalley

A team of researchers have developed a bioinformatics-based approach for monitoring key changes in cancer cells. This new method, which identifies cancer-specific changes in metabolic pathways, can help distinguish patients more likely to respond to cancer therapies.

What prompted these efforts? "We had been studying the significance of the high rate of flux through the polyamine pathway in the prostate and prostate cancer, and we wanted to know if other disease sites had similar metabolic dysregulation," explained Dominic Smiraglia, PhD, Associate Professor of Oncology in the Department of Cancer Genetics and Genomics at Roswell Park Comprehensive Cancer Center.

"We also began questioning why this pathway was dysregulated in prostate cancer. From there, we began applying these questions to all metabolic pathways in all types of cancer so that we might identify metabolic pathways that were highly dysregulated in cancers, but not normal tissues," he continued. "By identifying these pathways, we could identify more tumor-specific therapeutic targets in different disease sites."

Study Details

The researchers, led by Smiraglia, examined the similarities and differences in cell metabolism among 10,704 tumors representing 26 major cancer types, including breast, prostate, colon, lung, liver, and skin cancer (Nat Commun 2018; doi:10.1038/s41467-018-07232-8).

Utilizing transcriptomic data from The Cancer Genome Atlas, cancerous tumors were differentiated from healthy tissue based on the expression patterns of genes within 114 metabolic pathways regulating various aspects of cell metabolism.

"We were able to look at the expression of genes from a particular pathway across all patients with a particular type of cancer and ask if some patients highly dysregulate this pathway, while others do not, and if this correlates with other clinical data such as molecular subtype of cancer or clinical outcomes," noted Smiraglia. "When we mapped transcripts onto these pathways, we were also able to successfully identify patterns of metabolic flux and, therefore, metabolites of interest that should be found to have increased or decreased expression.

"We could then enrich these patterns of transcriptional dysregulation for master metabolic transcriptional regulators, which could be responsible for the dysregulation of these pathways in multiple diseases sites, or in some disease sites as opposed to others," he continued. "Further, we were able to use these signatures of dysregulation to determine drugs they should and should not be responsive to, based on the DeSigN software, to determine potential inhibitors/stimulators of dysregulated pathways of interest, and showed with a significant amount of accuracy that we could specifically target not only a disease site, but a specific molecular subtype of a disease site with metabolic therapies."

This study highlighted the differences in metabolic reprogramming that not only occur in tumor as opposed to normal tissue, but also changes that exist between different tissues, according to Smiraglia. "It also highlights the enhanced susceptibility of different disease sites to different metabolism-targeted therapies and our ability to more specifically target these pathways in different disease sites," he told Oncology Times.

Based upon the transcriptomic data available across 26 different disease sites with matched normal tissue, the researchers demonstrated that they can:

  • identify highly dysregulated pathways in the tumor as compared to the normal tissue;
  • map the transcriptional reprogramming to better understand and predict patterns of metabolic flux;
  • attribute these transcriptional changes to master metabolic transcriptional regulators; and
  • predict and target these pathways with a high amount of specificity.

In addition, the research also identified metabolic pathways uniquely dysregulated among different subtypes of breast cancer. The findings suggest that metabolic-based therapies can be tailored to different subtypes of the disease.

Implications & Next Steps

This research supports the potential utilization of metabolic therapies in clinical practice.

"Traditionally, metabolism-targeted therapies have been avoided due to a high level of toxicity, given that cancer and normal tissues heavily rely on many of the same pathways," Smiraglia noted. "By identifying pathways that are more highly dysregulated in the tumor, as compared to the normal tissue, as well as those that are more specific to a particular disease site, you have the potential to more effectively use these metabolism-targeted therapies in the clinic with reduced toxicity.

"This bioinformatics pipeline also demonstrates that we can correctly map potential changes in metabolic flux, and thereby informs future metabolomics studies, as well as future basic research," he added.

What's next for Smiraglia and his team? Given the continued move towards personalized medicine, his lab is investigating the effects of targeting some of the uniquely dysregulated pathways in prostate cancer.

"Further, we are trying to better understand the role that these master metabolic transcriptional regulators play in the sensitivity to targeted therapies, and how this could be used to inform who should and should not be receiving these drugs in the clinic," he noted. "Our hope is to not only eventually have a clinical trial targeting a metabolic pathway, but to have the ability to stratify patients into those most or least likely to respond."

Catlin Nalley is a contributing writer.


Friday, September 20, 2019

By Michelle Perron

TP53, the tumor suppressor gene known as the "guardian of the genome," can mount a potent defense against cancers. When this gene is mutated, that defense collapses, potentially leading to tumor development.

Researchers have been studying TP53 for years and their work has led to greater understanding of TP53 activity. A comprehensive study published recently in Cell Reports (2019; https://doi.org/10.1016/j.celrep.2019.07.001) provides new information about the gene's expression and the clinical outlook associated with its mutation.

Background

The p53 tumor suppressor protein is a transcription factor that inhibits cell division or survival in response to stresses. As multiple authors have described, TP53 acts as a fail-safe mechanism of cellular defenses against cancer. For many cancers, mutations in TP53 have been linked to a poorer prognosis. However, many variables can affect outcomes in patients with a TP53 mutation. Researchers in this new study sought to identify a more accurate readout of p53 function in human cancers that would not be based strictly on mutation of the TP53 gene and might lead to more accurate prognostic predictions.

The team, led by Larry Donehower, PhD, incorporated an approach similar to that of The Cancer Genome Atlas (TCGA) network, which has simultaneously examined tumors of many cancer types on five independent data platforms. Donehower is Professor of Molecular Virology and Microbiology at Baylor College of Medicine in Houston and a member of the faculty of the Human Genome Sequencing Center at Baylor College of Medicine. The TCGA network contributed to the acquisition of patient samples and the generation of data underlying the study.

Study Findings

The team at Baylor analyzed TP53 mutations in whole exome sequences of 10,225 TCGA patients across 32 cancer types. In this group, they identified 3,786 patients with TP53 mutations. Patients with some cancer types had high frequencies of TP53 mutation (>90%) while other cancer types exhibited few or no TP53 mutations.

The Baylor team's study integrated two data platforms (TCGA exome sequencing and copy number determination) to analyze individual TP53 alleles in both wild-type and mutant TP53 tumors. They found that more than 91 percent of tumors with TP53 mutations had structural loss of both functional TP53 alleles. These results indicate that a strong selection for loss of function of both TP53 alleles exists, Donehower said. "This is further confirmation of TP53 as a classic recessive tumor suppressor."

Another important determination in this study is in the area of genomic stability. Genomic instability is a central characteristic of most cancers, and TP53 is believed to prevent this instability. The Baylor team's analysis confirmed that TP53 mutation does affect genomic stability, global RNA, miRNA, and protein expression across most cancer types.

"Our examination of TCGA cancer types revealed that 19 of 23 examined cancer types had significantly enhanced copy number instability in the mutant TP53 cohort relative to their wild-type TP53 counterparts," the researchers wrote. "This global copy number instability was closely associated with increased amplification of known oncogenes and deep depletion of known tumor suppressors." Increased changes in cancer driver gene copy number are likely to be one mechanism by which TP53 mutation may result in cancers with poorer prognosis.

The final conclusion of the study is perhaps the most impactful because it is related to prognosis. Analysis of the mutant TP53 cancers across the RNA, miRNA, and protein expression data platforms consistently showed strong enhancement of pathways regulating cell-cycle progression, the authors wrote. They found that TP53 mutation status was only weakly predictive of overall survival across most cancers, but a p53 signature based on relative RNA expression of four genes consistently upregulated in mutant TP53 cancers was much more prognostically predictive. They found that 11 of 24 TCGA cancers showed significantly poorer survival with the high p53 signature, and that no cancer types showed poorer survival with a low p53 signature.

"We developed a normalization approach for each of 11 cancer types that would facilitate prognostic predictions on samples from individual patients entering the clinic," the authors wrote. "Thus, we believe this four-gene RNA expression signature could serve as an improved prognostic marker and a better indicator of the absence of p53 functionality in some cancer types."

Implications

While the authors conceded that many of their discoveries on TP53 mutation status in human cancers have been reported previously, Donehower noted that earlier studies were performed in a single cancer type with one or two data collection methods. The authors pointed out that the massive dataset provided by TCGA, along with collection of data by five distinct data platforms, has provided a richer, more comprehensive look at the genes and pathways affected in cancers with TP53 mutations.

Donehower said this research may also contribute to prognostic predictions. "This paper is mostly reinforcing what we already know, but we believe in a much more comprehensive way," he explained. "One contribution is that we have enhanced our understanding of mechanisms for how p53 is mutated and what cell signaling pathways are activated when this occurs. More importantly, and perhaps more helpful from an oncologist's point of view, we can look at the expression signature of a cancer and predict prognosis better than that obtained merely from TP53 mutation status."

Michelle Perron is a contributing writer.

Tuesday, August 27, 2019

By Kurt Samson

Combining classic clinical tumor characteristics with the 21-gene breast cancer recurrence score (RS) more accurately predicts which premenopausal patients may safely forego adjuvant therapy than the gene assay alone, researchers have found. Results from a pre-specified secondary endpoint analysis of data from the landmark Trial Assigning IndividuaLized Options for Treatment (Rx), or TAILORx—the largest breast cancer treatment trial to date—were first reported at the 2019 ASCO Annual Meeting and published in the New England Journal of Medicine (2019;380:2395-2405).

The primary endpoint findings of the TAILORx trial, published in 2018, showed that about 70 percent of women with hormone receptor (HR)-positive, HER2-negative, axillary lymph node–negative breast cancer, the most common form of the disease, have a low enough distant relapse risk that, when guided by the RS assay, they may not require chemotherapy.

In the new analysis, hazard ratios for distant recurrence among women at high clinical risk were about 2.5-3 times higher than for those at low clinical risk, regardless of endocrine therapy, either alone or with chemotherapy. Combining classic clinical features could also be used to identify which younger patients will most likely benefit from more effective anti-estrogen therapy, the researchers said.

"With this new analysis, it is clear that women ages 50 or younger with a RS result between 16 and 20, and at low risk clinically, do not need chemotherapy," said lead author Joseph A. Sparano, MD, Associate Director for Clinical Research at Albert Einstein Cancer Center and Montefiore Health System in New York City.

"Integration of the RS with clinical risk information could also help identify premenopausal women at higher clinical risk who may benefit from ovarian function suppression and more aggressive anti-estrogen therapy."

Supported by the NCI, the trial was designed and led by the ECOG-ACRIN Cancer Research Group, of which Sparano serves as Vice Chair.

Study Details

Out of a total of 9,427 women with RS and clinical risk information, 70 percent were found to be at low risk if they had a low-grade tumor no larger than 3 cm, ≤2 cm and intermediate grade, or ≤1 cm and high grade. The other women were determined to be at high clinical risk of distant recurrence. Most of the patients were being treated with tamoxifen alone.

Clinical risk features were prognostic in women with an intermediate RS of 11-25 who were randomly assigned to endocrine monotherapy or combined with chemotherapy for women with higher recurrence scores.

After 9 years, the estimated rate of distant recurrence was less than 5 percent for patients 50 years of age or younger who received endocrine therapy alone and had an RS of 10 or less, regardless of clinical risk, and around 4.7 percent of low clinical risk and an intermediate RS. The estimated 9-year recurrence rate was above 10 percent among patients with high clinical risk features treated with endocrine monotherapy, and in women with a high RS who received both chemo and endocrine therapy.

Although clinical risk features added prognostic value across all groups, disease-free survival and distant recurrence-free interval rates were similar with or without chemotherapy in the entire RS 11-25 group, regardless of clinical risk. However, clinical risk alone was not predictive of chemotherapy benefits, and this proved true for two-thirds of the subjects over age 50 or older.

Editorial

"Readers may be surprised to learn that the classic prognostic markers were not directly analyzed in the 2018 article, unsurprised to learn that they contribute prognostic information, and curious as to why it took two articles in the Journal, published almost a year apart, to impart this information," wrote NEJM Deputy Editor Dan L. Longo, MD, Dana-Farber Cancer Institute, and statistician David J. Hunter, MB, BS, University of Oxford, U.K. (N Engl J Med 2019;380:2472-2474)

The answers lie in how clinical trials are conducted and reported, and affirm the need to incorporate new research findings into practice, they explained.

On the basis of previous studies, they observed, the authors indicate that adding ovarian suppression and an aromatase inhibitor might reduce risk equivalent to that of adjuvant chemotherapy.

"Thus, practice-changing suggestions are being made on the basis of a subgroup analysis of a secondary objective in the trial, published as a follow-up to the report of the primary objective."

"The promise of 'precision' medicine has collided with the rather messier world of using all available evidence to try and make educated guesses to improve patient outcomes," according to the editorial.

"To then view this data set as the test of a single hypothesis would be wasteful of the opportunity to incorporate secondary objectives or even post hoc analyses…The presentation of additional analyses from important data sets will remain a fundamental component of evidence synthesis," according to the commentary.

The reporting of findings beyond prespecified and primary objectives is important, and "judicious use of these data should continue to inform clinical practice," they wrote.

Kurt Samson is a contributing writer.