What Is an EXCEPTIONAL RESPONDER to Cancer Treatment? Significance, Biology, and Genetics

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

An ongoing research project is investigating why some patients have exceptional responses. Researchers found specific molecular features in tumors from approximately a quarter of these patients. In some cases, the tumor genome contained many rare genetic alterations. In others, the tumors were infiltrated by particular types of immune cells.

The findings, published online on November 19 in Cancer Cell, come from the analysis of tumor biopsy samples from 111 patients identified by the US National Cancer Institute (NCI) Exceptional Responders Initiative, a national project launched in 2014. This was a genomic analysis.

What is an exceptional responder in cancer?

An exceptional responder is defined as an individual who responds to a treatment effective in fewer than 10% of similar patients, with a partial or complete response to that treatment. For this exceptional situation, the duration of response is at least 3 times longer than the normal median response duration.

In this study of 111 exceptional responders, approximately a quarter of patients (24%, 26 patients) had tumors with molecular features that could potentially explain their exceptionally favorable responses to treatment.

Dr. Louis Staudt, director of the NCI Center for Cancer Genomics, who led the study, said, "We will not immediately be able to determine which medications will benefit each patient. We are not close to that. But what this study says is that we have identified certain mutations that may occur in cancer types with exceptional responders."

Staudt noted that these mutations could "illuminate" the course cancer will take and might potentially be used to predict whether a cancer will be aggressive and require treatment, or could be managed with surveillance. He therefore said this research might be useful in the short term.

"In the longer term, this is the kind of research that inspires future studies. Clinical trials will begin involving medications that target some of the cellular pathways we found to be genetically inactivated in some exceptional responders."

The study’s graphical abstract is shown below:

Explanation of the graphic: In this study, the tumor microenvironment as well as genetic and epigenetic changes were characterized by analyzing tumor biopsies from 111 exceptional responders. The integrative analysis revealed plausible mechanisms for treatment response in approximately a quarter of patients. The mechanisms fell into four broad categories: DNA damage response, intracellular signaling, immune involvement, and genetic alterations associated with favorable prognosis — many tumors belonged to multiple categories. These analyses reveal rare genetic lesions supporting treatment success and also provide numerous testable hypotheses about oncogenic mechanisms that may affect cancer treatment response.

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

In early 2020, the NCI team published the results of a pilot study confirming the feasibility of this approach. Six of more than 100 analyzed cases were found to contain potentially clinically actionable germline (inherited) mutations.

Curiosity drove the research

Staudt said, "We have had this wonderful and rewarding experience of an exceptional response with our patients, so we immediately wondered how it happened. It was essentially this curiosity that drove a large part of this study".

In the current study, Staudt and colleagues used multiple genomic methods to detect mutations, copy-number changes, abnormal methylation, outlier gene expression, and the cellular composition of the tumor microenvironment.

The hypothesized mechanisms of exceptional responses were broadly divided into the following four categories:

1. DNA damage response (15 patients),
2. intracellular signaling pathway (9 patients),
3. prognostic genetic interaction (9 patients), and
4. immunological interaction (16 patients).

For many patients, two or more of these mechanisms were involved.

The authors note that "cytotoxic chemotherapies were frequently used, paralleling the generation of DNA damage and the response to DNA damage." A predominance of the DNA damage response may be described in these patients.

26 patients were identified as exceptional responders. Their cancers included brain tumors (8 patients); gastrointestinal cancers (6 patients); breast cancer (4 patients); cholangiocarcinoma (2 patients); lung cancer (2 patients); and pancreatic, endometrial (uterine), ovarian, and bladder cancer (1 each).

Most of these patients (65%, 17 patients) received chemotherapy containing DNA-damaging agents. More than half (54%, 14 patients) received targeted therapies, and some patients received both.

Examples of exceptional patients

• A patient with the brain tumor glioblastoma multiforme (GBM) was treated sequentially with surgery, localized carmustine, and radiotherapy. When the cancer recurred, temozolomide was given. This produced a complete response lasting more than 10 years.
• Metastatic colon cancer in one patient showed an ongoing, nearly complete response lasting 45 months (at last follow-up) after temozolomide combined with the investigational drug TRC102 (methoxyamine) in a phase 1 clinical trial. TRC102 inhibits the DNA base excision repair pathway, a pathway that produces resistance to alkylating and antimetabolite chemotherapeutic agents.
• A patient with metastatic, estrogen receptor-positive breast cancer received anastrozole (Arimidex) and, because of high ERBB2 amplification, trastuzumab. This resulted in a partial response lasting 2.4 years that was still ongoing. Although the patient was clinically HER2-positive, her tumor had extremely low ERBB2 mRNA expression. Molecular profiling classified the tumor as basal-like rather than HER2-enriched. According to the authors, this meant trastuzumab was unlikely to have contributed to the exceptional response. Because the patient was estrogen receptor-positive, anastrozole, an aromatase inhibitor, was thought to be responsible.
• Gastrointestinal stromal tumor in a patient with a KIT exon 11 deletion mutation had recurred after first-line imatinib treatment. This patient then received sunitinib (Sutent) and achieved a complete response. When the patient underwent comprehensive genetic analysis, not only high KIT expression but also high expression of genes encoding several tyrosine kinases targeted by sunitinib (KDR, Flt-1, and FLT3) was detected. This may have explained the patient’s response.

What are favorable genomic features?

The authors identified certain genetic features that might predict a favorable course. Although patients had relapsed after first-line treatment, their exceptional responses after salvage therapy may have been linked to favorable genomic features.

For example, several patients with high-grade GBMs and astrocytomas had genetic features generally more common in low-grade glioma and associated with a slow clinical course after standard treatment.

The authors also evaluated the immune response. They compared immune-cell infiltration in responding tumors with control cases and found higher signatures of B cells and activated (CD56dim) natural killer cells in tumors with exceptional responses. In a patient with metastatic bladder cancer who experienced disease progression after chemotherapy, radiotherapy, and surgery, nivolumab (Opdivo) treatment produced a complete response lasting 7 months. Such an outcome occurs in only approximately 3% of bladder cancer patients. The tumor was positive for high mRNA levels of the gene encoding the nivolumab target PD-1, PDCD1, and for expression of CD274, which encodes the PD-1 ligand PD-L1. There was also high amplification of IFNG (IFNG encodes interferon-gamma, a cytokine linked to a favorable response to immune checkpoint blockade).

Lessons for precision oncology

Co-lead author S. Percy Ivy from the NCI Division said, "Genetic testing at diagnosis and again when disease progresses is very valuable because there may be genetic changes, and these can change treatment."

"The aim of this study was to understand the genetic makeup that led these patients to be classified as exceptional responders, and we hope we can uncover it." she added.

Conclusion

There is much to learn from patients with exceptional responses!

Genetic tests, drugs directed at genetic targets, and immunotherapy in the right patients will help us move toward precision oncology. We are not yet at a point where we can provide this to all cancer patients, but by studying more deeply and learning more, we can offer better care.

To encourage researchers around the world to join this effort, the NCI team and colleagues made the molecular profiling results and clinical information publicly available in the NCI Genomic Data Commons.