New Findings on 'Exceptional Responders' to Cancer Therapies

Roxanne Nelson, RN, BSN

November 23, 2020

A small percentage of patients with cancer show exceptional responses to treatment and survive significantly longer than patients with clinically comparable tumors, despite having advanced disease.

An ongoing research project is studying why some patients have exceptional responses. The researchers have found particular molecular features in the tumors of about a quarter of these patients. In some cases, there are multiple rare genetic changes in the tumor genome. In other cases, the tumors are infiltrated with certain types of immune cells.

The findings were published online November 19 in Cancer Cell. They come from a genomic analysis of tumor biopsy specimens from 111 patients who were identified by the National Cancer Institute's (NCI's) Exceptional Responders Initiative, a national project launched in 2014.

An exceptional responder is defined as an individual who achieves a partial or complete response to a treatment that would be effective in fewer than 10% of similar patients. For exceptional response, the duration of response is at least three times longer than the usual median response time.

In this study of 111 such patients, about one quarter (24%, n = 26 patients) were found to have tumors in which there were molecular features that could potentially explain exceptional responses to treatment.

"We won't be able to identify, in every patient, which particular drugs will be beneficial," said Louis Staudt, MD, PhD, director of the NCI's Center for Cancer Genomics, who co-led the study. "We are nowhere near that. But what it does say is that we have identified particular mutations, some of which we knew about in some types of cancer but can also occur less commonly in other cancer types."

Staudt noted that these mutations can "illuminate" the path that the cancer will take — and potentially can be used to predict whether the cancer will be aggressive and will require treatment or could be managed with surveillance. This is why this research can be useful in the short term, he said.

"In the longer term, this is the kind of research that inspires future work," he told Medscape Medical News. "That would encompass clinical trials involving drugs that target some of the pathways we found to be genetically inactivated in some of these responders."

These results support the use of genetic testing in routine clinical care, he said.

Earlier this year, the NCI team published the results of a pilot study that affirmed the feasibility of this approach. Of the more than 100 cases that were analyzed, six were identified as involving potentially clinically actionable germline mutations.

"Curiosity Drove the Research"

"We had these wonderful and gratifying experiences with our patients, so we were immediately curious how that happened, so it was pretty much that curiosity that drove a lot of this work," said Staudt.

In the current study, Staudt and colleagues used multiple genomic methodologies to detect mutations, copy number changes, aberrant methylation, outlier gene expression, and the cellular makeup of the tumor microenvironment.

The hypothesized mechanisms for exceptional responses were broadly divided into the following four categories: DNA damage response (n = 15), intracellular signaling pathway (n = 9), prognostic genetics (n = 9), and immunologic engagement (n = 16). For many patients, two or more of these mechanisms were involved.

The authors note that the "predominance of plausible DNA damage response mechanisms parallels the frequent use of cytotoxic chemotherapy in routine cancer treatment reflected in this cohort."

Twenty-six patients were identified as exceptional responders. Among these patients, a variety of cancer types was represented: brain (8); gastrointestinal tract (6); breast (4); cholangiocarcinoma (2); lung (2); pancreas, endometrium, ovarian, and bladder (1 each). Many of these patients (65%, n = 17) were treated with chemotherapy that included DNA-damaging agents. For more than half (54%, n = 14), targeted therapies were used, and some patients received both.

The authors highlight several patients as examples of exceptional responders:

  • One patient with glioblastoma multiforme (GBM) was treated sequentially with surgery, localized carmustine, and radiotherapy. When the cancer recurred, temozolomide was administered. This induced a complete response that has lasted for more than a decade.

  • A patient with metastatic colon adenocarcinoma has had an ongoing and nearly complete response that has lasted 45 months (last follow-up) after receiving temozolomide in combination with the investigational drug TRC102 (methoxyamine, under development by Tracon) in a phase 1 clinical trial. TRC102 is an inhibitor of the DNA base excision repair pathway, which is a pathway that causes resistance to alkylating and antimetabolite chemotherapeutics.

  • A patient with metastatic, estrogen receptor–positive breast cancer received trastuzumab because of a high-level ERBB2 amplification, together with anastrozole (Arimidex). This resulted in an ongoing 2.4-year partial response.

    Although the patient was clinically HER2 positive, her tumor had exceedingly low expression of ERBB2 mRNA. Molecular profiling had classified the tumor as of the basal-like subtype rather than the HER2-enriched subtype. This meant that it was unlikely that trastuzumab contributed to the exceptional response, the authors note. Because the patient was estrogen-receptor positive, she received anastrozole, an inhibitor of aromatase (CYP19A), which converts testosterone into estradiol.

  • A patient with a gastrointestinal stromal tumor with a deletion of KIT exon 11 experienced relapsed after an initial response to imatinib, which targets KIT, but then achieved a complete response with sunitinib (Sutent). Gene expression profiling revealed high expression not only of KIT but also of genes encoding several tyrosine kinases that are targeted by sunitinib (KDR, FLT1, and FLT3). This may have accounted for the patient's response.

Favorable Genomic Characteristics

The authors defined a "prognostic genetics" category of tumors, characterized by genetic lesions that are now known to be associated with a favorable prognosis but that were not addressed through routine care that these patients received when they were first diagnosed. Although the patients experienced relapse after first-line treatment, their exceptional survival after salvage therapy could be linked to favorable genomic characteristics.

For example, several the patients with high-grade GBMs and astrocytomas had genetic lesions that are generally more common in low-grade glioma and that have been associated with an indolent clinical course following standard therapy.

The authors also assessed immune response. Examining immune cell infiltration in responder tumors in comparison with control cases, they found that signatures of B cells and activated (CD56dim) natural killer cells were higher in exceptional-responder tumors. In one patient with metastatic urothelial cancer who experienced disease progression after chemotherapy, radiotherapy, and surgery, treatment with nivolumab (Opdivo) produced a complete response that lasted 7 months. Such an outcome occurs in only about 3% of bladder cancer patients. The tumor expressed high mRNA levels of PDCD1, which encodes the nivolumab target PD-1, and CD274, which encodes the PD-1 ligand PD-L1. There was also a high level of amplification of IFNG, which encodes interferon-gamma, a cytokine that has been linked to favorable response to immune checkpoint blockade.

Moving to Precision Medicine

"It is very valuable to be tested up front and again when the disease progresses, because there may have been some genetic changes, and this may change the treatment," said co–lead author S. Percy Ivy, MD, of the NCI's Division of Cancer Treatment and Diagnosis.

"The goal of this study was to understand what was unique about these patients and their genetic makeup that led them to be classified as exceptional responders, and hopefully we will be able to tease that out," she added.

"As researchers, we have a lot to learn from these patients, and they have a lot to teach us," she added. "In the future, they will help us as we move closer to the goal of delivering precision oncology to all of our patients. We're not there yet, but every time we study more deeply and learn more, we are able to provide better care."

To encourage participation in this effort by investigators around the world, the NCI team and their colleagues have made their molecular profiling results and clinical information publicly available in the NCI Genomic Data Commons.

The study was supported by the NCI's Intramural Research Program, the National Institutes of Health, the Center for Cancer Research, and the NCI's Center for Cancer Genomics. Staudt and Ivy have disclosed no relevant financial relationships.

Cancer Cell. Published online November 19, 2020. Abstract

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