Tumor Molecular Profiling May Help Identify 'Exceptional Responders'

Roxanne Nelson, RN, BSN

May 20, 2020

Virtually all oncologists, at one time or another, have treated a patient who defied the odds and achieved an unexpectedly long-lasting response. These "exceptional responders" are patients who experience a unique response to therapies that have largely failed to be effective for others with similar cancers.

Genetic and molecular mechanisms may partly account for these responses and may offer clues about why the treatment works for only a few and not for others. To delve more deeply into that area of research, the National Cancer Institute (NCI) began the Exceptional Responders Initiative (ERI) with the goal of identifying potential biological processes that may be responsible, at least in part, for these unusual responses.

NCI researchers have now successfully completed a pilot study that analyzed tumor specimens from more than 100 cases, and the study has affirmed the feasibility of this approach.

Of these cases, six were identified as involving potentially clinically actionable germline mutations.

The findings were published online ahead of print in the Journal of the National Cancer Institute.

"Clearly, the analysis and validation of these results will prove critical to determining the success of this approach," write James M. Ford, MD, and Beverly S. Mitchell, MD, both of Stanford University School of Medicine, California, in an accompanying editorial. "Ultimately, prospective studies of tumors from exceptional responders, particularly to novel, genomically-targeted agents, may provide a powerful approach to cancer treatment discoveries."

A Special Case

Molecular profiling technology, including next-generation sequencing, has significantly changed the landscape of the development of cancer therapies, and clinical trials in early drug development are increasingly selecting patients on the basis of molecular alterations.

The ERI grew out of several meetings held by the NCI in 2013 and 2014. It was built on the ability to profile archived tumor material, explained study author S. Percy Ivy, PhD, associate chief of the Investigational Drug Branch in the Division of Cancer Treatment and Diagnosis of the NCI. "This made it possible to collect cases from participating clinicians from all over the country.

"Published cases included patients treated with a targeted therapy but not treated with knowledge of their tumor's genomics, who then later turned out to have genomic changes that made their tumor exquisitely sensitive to inhibition of a driving pathway," she said. "There have been published cases as well as cases in the experience of practicing oncologists that seem to do much better than expected.

"We wondered if we could find molecular reasons why tumors respond not only to targeted therapies but also to standard chemotherapy," said Percy. "If so, we could refine our choice of therapy to patients who are most likely to respond to it."'

On their website, the NCI writes that there was a particular case that triggered the interest in going ahead with this initiative. Mutations in the TSC1 and NF2 genes, which result in a loss of gene function, were detected in a patient with metastatic bladder cancer. In a clinical trial, the patient was treated with everolimus (Afinitor, Novartis), an inhibitor of the mammalian target of rapamycin (mTORC1), and achieved a complete response with a duration of more than 2 years.

In a separate analysis, researchers sequenced tumors from 96 other individuals with high-grade bladder cancer and identified five TSC1 gene mutations. Tumors were sequenced from 13 patients with bladder cancer who had received everolimus. Results showed that 3 of 4 patients with TSC1 gene mutations experienced some degree of tumor shrinkage after treatment; 8 of 9 patients who did not have the mutation experienced disease progression.

The NCI notes that in "subsequent workshops and discussions, it became obvious that all clinicians have seen a few exceptional responders."

Testing for Feasibility

The aim of the current study was to assess the feasibility and potential usefulness of sequencing DNA and RNA from clinical tumor specimens from patients who had experienced unusually profound or durable responses to systemic therapy.

Its main feasibility goal was to identify at least 100 cases involving exceptional responders whose cases could be analyzed in less than 3 years.

An exceptional patient was defined as one who had experienced a complete response to one or more drugs in which complete responses were seen in fewer than 10% of patients who received similar treatment; or a partial response lasting at least 6 months in which such a response is seen in fewer than 10% of patients who receive similar treatment; or a complete or partial response of a duration that is three times the median response duration represented in the literature for the treatment.

Studying exceptional responders presents many challenges, the first being to define what an exceptional response is and what it is not, explained Ivy. "This definition relies on the existence of data that a particular therapy will produce particular responses in groups of patients with similar tumors, as defined by organ of origin," she said.

Other challenges include obtaining tumor tissue and all the relevant clinical data, such as the number of prior treatments and the patient's response, as well as any known molecular characteristics (eg, HER2/NEU amplification, estrogen-receptor expression, germline mutations). "We also do not have data on other exposures, such as smoking or chemical exposure," she said. "In addition, when patients are not on clinical trial, the data are not uniformly obtained ― such as that scans may not be performed at particular intervals."

Importantly, the molecular tools used to analyze tumors were not available in the past, so many trials did not collect tumor tissue for subsequent research. "Even now, we are learning that there are characteristics beyond DNA and RNA that are potentially important to the ability of a tumor to respond, such as the immune system or epigenetic changes," she said.

From August 2014 to July 2017, a total of 520 cases were proposed by clinicians as possibly involving exceptional responders, and 222 cases met the criteria.

Analyzable tissue was available for 117 patients. Most of the responders (n = 80, 68.4%) had been treated with combination chemotherapy regimens; 34 patients (29.0%) had received one or more antiangiogenesis agents. In addition, six patients had an exceptional response following treatment with immune checkpoint inhibitors. The final analysis included 109 cases.

One exceptional responder was a woman with metastatic squamous lung cancer that was treated with paclitaxel and carboplatin. The patient achieved a 41-month complete response (expected rate, <10%). Another patient with esophageal adenocarcinoma who was treated with docetaxel and cisplatin experienced a partial response that lasted 128 months (reported median response duration, 24 months). After the patient's tumor recurred, he experienced for the second time a response to concurrent chemoradiation with the same drug regimen.

Overall, potentially clinically relevant germline mutations were identified in six tumors. Pathogenic BRCA1 or BRCA2 mutations were found in two breast cancer patients, one patient with non–small cell lung cancer, and one patient with rectal cancer. A breast cancer patient had a pathogenic BRCA1 germline mutation, and another had a likely germline mutation in CHEK2. A patient with poorly differentiated lung cancer and a history of breast cancer had a PALB2 mutation.

Future Steps

Molecular mechanisms are important, but other factors could also play a role in eliciting a response. One is the presence of comorbidities, which was not assessed in the study. Ivy noted that comorbidities could be very important to responses, along with medications that the patient is using for different types of ailments. In addition, the use of complementary and alternative medicines may also have an impact.

"As the field matures, we hope that others will collect these and other characteristics, so that all the data could be used to develop hypotheses about molecular and other factors that can better predict response or resistance," she said.

The results from this pilot study demonstrated feasibility. Ivy noted that "additional collaboration in similar studies would be welcome, as would methods to use data from various sources to improve our ability to correlate patient characteristics, tumor characteristics and response.

"We envision a larger national and international effort to collect more exceptional responder cases, including more from patients treated with targeted therapies," she added. "The NCI has been meeting with an interest group that focuses on ER cases in the UK, France, Italy, Canada, and Australia, and this collaborative effort is maturing, albeit slowly."

The project has been funded in whole or in part with federal funds from the NCI and NIH. Ivy has disclosed no relevant financial relationships. Several coauthors report relationships with industry. The editorialists have disclosed no relevant financial relationships.

J Natl Cancer Inst. Published online April 27, 2020. Abstract, Editorial

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