Increasing focus on the use of tumor biomarkers as a guide for treatment decisions, as well as on patients’ response to cancer treatment, allows investigators to discover new biomarkers that can help improve outcomes for patients with different types of cancer.
Several developments in tumor biomarkers and their role in guiding the course of cancer treatment were reported at the 2018 annual meeting of the American Association for Cancer Research (AACR). This information may soon help doctors to incorporate this information into their daily practice and improve outcomes in patients with some types of cancer. Two of these developments are described in this article.
TMB: New Biomarker Identifies Patients for Immunotherapy Combination
Lung cancer remains the number 1 cause of cancer-related deaths in the United States. Chemotherapy is currently used as first treatment, alone or in combination with other therapies (with multiple chemotherapy drugs or with other types of therapy, including immunotherapy), for patients diagnosed with advanced non–small-cell lung cancer (NSCLC).
In a new clinical trial presented at the 2018 AACR, investigators identified a new tumor biomarker to guide the choice of first treatment for patients with advanced NSCLC. In this study, known as CheckMate-227, patients who had a specific tumor characteristic (tumor biomarker), called high tumor mutational burden (or TMB), had better outcomes when using a combination of 2 immunotherapies as first treatment instead of starting with conventional chemotherapy.
This new biomarker, TMB, is a measurement of the amount of mutations seen on tumor cells. In this study, patients with high TMB who received the immunotherapy combination of Opdivo (nivolumab) plus Yervoy (ipilimumab) as their first treatment had a longer period without cancer progression compared with patients who received conventional chemotherapy first.
“The identification of a new biomarker for patient selection for this immunotherapy combination is encouraging and allows us to use immunotherapy more efficiently, sparing the use of chemotherapy in the first-line setting,” said Matthew D. Hellmann, MD, Medical Oncologist, Memorial Sloan Kettering Cancer Center, New York City.
“This study validates the role of TMB to identify those patients with greatest benefit from the immunotherapy combination. TMB is a distinct and definable biomarker that can be determined by next-generation sequencing, which we are already using for treatment selection,” Dr. Hellmann added.
Another clinical trial (CheckMate-568) reported at the meeting also showed that high TMB can be used as a tumor biomarker to identify patients with advanced NSCLC whose cancer will respond positively to initial treatment with the combination of Opdivo plus Yervoy instead of chemotherapy. In this study, TMB identified patients who were most likely to respond to the combination immunotherapy, regardless of whether their tumor expressed another biomarker, PD-L1, which is a known biomarker for response to immunotherapy.
After 1 year of treatment, patients with advanced, stage IV or recurrent NSCLC, and high TMB who received initial treatment with Opdivo plus Yervoy lived significantly longer without cancer progression or death than those who received chemotherapy.
Although longer studies are needed to say for sure that patients with high TMB who receive initial treatment with combined immunotherapy will actually live longer than those who receive chemotherapy first, these results suggest that this is likely the case.
“There is a clear trend toward improved survival with the combination. The control arm performed quite well, but is still 7 months less than with the combination,” Dr. Hellmann said.
Commenting on this study, Naiyer A. Rizvi, MD, Director of Immunotherapeutics, Division of Hematology and Oncology, Columbia University Medical Center in New York City, said, “TMB should be a standard biomarker for initial evaluation of NSCLC. PD-L1 remains a standard of care and should be used in concert with TMB.”
HER2 mutation New Biomarker of Resistance to Therapy in Metastatic Breast Cancer
In patients with estrogen receptor (ER)-positive metastatic breast cancer, the cancer responds well to anti-ER therapies, but in most cases, resistance to the treatment occurs, and the drug stops working. It is also known that tumor characteristics change over time, which may affect the response to treatment.
A new study presented at the 2018 AACR involving women with ER-positive metastatic breast cancer showed that some of these patients who did not have the HER2 mutation before treatment had acquired the HER2 mutation after starting anti-ER therapy. Furthermore, in the women who acquired HER2 mutations after receiving treatment for breast cancer, the cancer stopped responding to treatment.
However, in this study, the use of an irreversible HER2 inhibitor, Nerlynx (neratinib), overcame the resistance (lack of response) to treatment in patients whose mutation was acquired after a breast cancer diagnosis, which suggests that this type of mutation may be a new biomarker to identify treatment resistance in patients with metastatic breast cancer.
This information holds promise for the treatment of patients with ER-positive metastatic breast cancer whose cancer is resistant to treatment. More studies are needed to determine what percentage of patients with ER-resistant metastatic breast cancer harbor the acquired HER2 mutation, and to establish whether Nerlynx is indeed effective in these patients or if other drugs are needed.
“Resistant ER-positive metastatic breast cancer remains the most common cause of breast cancer death. Although ER-directed therapies are highly effective, most patients invariably develop resistance and stop responding to these drugs,” said Utthara Nayar, PhD, Research Fellow in Medicine, Dana-Farber Cancer Institute, Boston.
The study was based on molecular profiling of metastatic tumor biopsies from patients with ER-positive metastatic breast cancer whose cancer stopped responding to hormone therapies. HER2 mutations were found in 12 patients, and 4 of them did not have HER2 before the start of therapy, suggesting that these mutations were acquired in response to the anti-ER therapy.
“It was surprising to discover that HER2 mutations can be acquired in the metastatic setting, suggesting that these tumors evolve, and these mutations seem to be a mechanism of resistance to therapies that target the estrogen receptor,” said Nikhil Wagle, MD, Deputy Director, Center for Cancer Precision Medicine, Dana-Farber Cancer Institute.
“This study underlines the importance of profiling resistant metastatic tumors with repeat biopsies. Currently only the initial tumor is profiled in most cases,” Dr. Nayar said.
“Patients with ER-positive metastatic breast cancer and HER2 mutations should be directed to clinical trials testing strategies to overcome this mechanism of resistance,” she added.
A new, simple blood test called CancerSEEK has the potential to change the way patients are being screened for cancer. This new blood test screens for 8 types of cancer, including breast, colon, liver, lung, esophageal, ovarian, pancreatic, and stomach cancers, from circulating DNA in the blood (Figure).1 The test also identifies 16 different types of cancer-related genomic mutations (changes), which may increase risk for certain cancer and can affect what type of medications are appropriate for a specific patient.
This noninvasive test may help to detect cancer in early stages, when treatment has the most chance to be successful.
Early Detection of Cancer Biomarkers
“This study is a very important step toward the development of a test for the early detection of cancer,” said Nickolas Papadopoulos, PhD, Professor of Oncology and Pathology, in a Johns Hopkins press release,1 who led the research that developed the test at Johns Hopkins Kimmel Cancer Center. He cautioned, however, that more studies are needed to confirm the accuracy of the test before it can be used by doctors, including primary care doctors.
CancerSEEK was evaluated in 1,005 patients with ovarian, liver, stomach, pancreatic, esophageal, colon, lung, or breast cancer. All cancers were in early stages, and had not spread in the body.
“The use of a combination of selected biomarkers for early detection has the potential to change the way we screen for cancer,” said Dr. Papadopoulos.1The study’s findings were recently published in the journal Science.2 “Circulating tumor DNA mutations can be highly specific markers for cancer. To capitalize on this inherent specificity, we sought to develop a small yet robust panel that could detect at least one mutation in the vast majority of cancers,”1 said Joshua D. Cohen, an MD/PhD student at John Hopkins School of Medicine, and the first author of the article.
Overall, the blood test detected cancer 70% of the time. Ovarian cancer was detected most accurately in 98% of cases; breast cancer was the least accurate, with 33% of cases diagnosed.
Ovarian, liver, stomach, pancreatic, and esophageal cancers, which currently have no screening tests available, had detection rates ranging from 69% to 98%. In addition, in 83% of patients, the CancerSEEK test was able to determine where the cancer originated.
“Besides detecting cancer, we were actually able to localize the cancer to one or two sites in the body. This is very important, because if this test is validated in future studies, once you find a signal that an individual may have cancer, the next question is where, and in what organ,” Dr. Papadopoulos said.
Although the test cannot screen for all types of cancer, these 8 types account for more than 60% of cancer-related deaths in the United States, the researchers say.2 The test may also be expanded to other cancers later on, but the researchers decided to limit the number of mutations and cancers tested to increase accuracy.
“If we are going to make progress in early cancer detection, we have to begin looking at it in a more realistic way, recognizing that no test will detect all cancers,” said Bert Vogelstein, MD, Co-Director of the Ludwig Center, Clayton Professor of Oncology and Howard Hughes Medical Institute investigator, in the press release.1
Specificity is Key
This novel test differs from other molecular tests that analyze more cancer-driving genes that could be targeted by specific drugs, because its only purpose is to screen for cancer, with a more than 99% specificity for cancer.
“Very high specificity was essential, because false-positive results can subject patients to unnecessary invasive follow-up tests and procedures to confirm the presence of cancer,” said Kenneth Kinzler, PhD, Professor of Oncology and Co-Director of the Ludwig Center, in the press release.
The test also screened 812 healthy people, and only 7 of those had false-positive results, a very small percentage compared with other tests. Still, more work is needed to determine just how effective the test is at detecting early cancer. It is now being tested in people who have not been diagnosed with cancer.
Knocking on the Future’s Door
“Optimally, cancers would be detected early enough that they could be cured by surgery alone, but even cancers that are not curable by surgery alone will respond better to systemic therapies when there is less advanced disease,” said Anne Marie Lennon, MD, PhD, Director of the Multidisciplinary Pancreatic Cyst Program at Johns Hopkins, in the press release.1 The goal is to keep the cost of the test to less than $500 and to use it annually, along with other screening tests, such as mammograms and colonoscopies. Because a blood test is not invasive, it could be done by primary care doctors during routine annual blood tests.
“We would like to use it as a screening test for cancer. A simple test that everyone is willing to test,” Dr. Papadopoulos added. “We think that this type of test can change how we think about cancer, and put early detection as the main goal, and treating cancer as the second step.”1 “This test represents the next step in changing the focus of cancer research from late-stage disease to early disease, which I believe will be critical to reducing cancer deaths in the long term,” said Dr. Vogelstein.1
References1. Johns Hopkins Medicine. Single blood test screens for eight cancer types. Press release. January 18, 2018. www.hopkinsmedicine.org/news/media/releases/single_blood_test_screens_for_eight_cancer_types.
2. Cohen JD, Li L, Wang Y, et al. Detection and localization of surgically resectable cancers with a multi-analyte blood test. Science. (Feb 23)2018;359:926-930.