Making Their Mark

IN OCTOBER 2022, 52-YEAR-OLD DANIEL WEST of Houston decided to be proactive about his health. Motivated by a family history of heart disease and his father’s death from a heart attack, West went in for a cardiac workup and got bad news of a different sort. Cardiac imaging revealed two concerning spots in his right lung. His doctor referred him to a specialist, where he received a bronchoscopy to biopsy the suspicious-looking lung tissue. West was at a convention in Chicago when he learned that he had non-small cell lung cancer (NSCLC).

As shocking as it was, West felt fortunate to catch his lung cancer at an early stage. More than half of people who have lung cancer find out after it has spread outside the lung—and typically only after they have symptoms. Still, West was skeptical when his doctors referred him to a surgeon to have a portion of his lung removed without suggesting he see an oncologist first. He decided to get a second opinion at the University of Texas MD Anderson Cancer Center, also in Houston. This is where West learned something his first doctors had not told him about his NSCLC. The surgeon who performed his initial biopsy had sent some of the cancerous tissue to a lab for testing. This test looked for DNA changes—also called biomarkers or molecular markers—in the tumor tissue that might help doctors to understand the cancer better and guide treatment decisions. The results showed his cancer had a mutation in a gene that encodes a protein called EGFR, short for epidermal growth factor receptor.

When located on the surface of normal cells, the EGFR protein receives signals that control tissue growth. EGFR mutations, which are found in 10% to 15% of lung cancer cases in the U.S., can cause abnormal growth. Knowing a lung cancer’s EGFR status is especially good information to have because targeted EGFR inhibitors, like Tagrisso (osimertinib) or Gilotrif (afatinib), can block that growth signal for some of the most common EGFR mutations found in NSCLC.

When his doctors at MD Anderson first mentioned the EGFR-positive result to West and his partner, neither had any idea the tumor tissue was tested or that the mutation could open the door to other treatments. “It was a good surprise, but a surprise nonetheless,” West says.

Biomarker Basics

There is a growing list of approved targeted therapies and many more in clinical testing linked to biomarkers found in different cancer types. In NSCLC, 10 biomarkers are now routinely tested to help physicians make treatment decisions. These cancer biomarkers, which include genes, proteins and other substances, can help physicians to personalize treatments based on a cancer’s unique features. Biomarkers can also signal that certain treatments are less likely to be effective, says thoracic oncologist Paul Paik at Memorial Sloan Kettering Cancer Center in New York City.

For example, a person like West who is diagnosed with NSCLC at a relatively young age despite having little to no smoking history has up to a 50% chance that the cancer will carry an EGFR mutation that could respond to an EGFR inhibitor. If test results show that a cancer has high expression of a protein biomarker known as PD-L1, the patient might be a good candidate for immunotherapy treatments that unleash the immune system against cancer. Still, studies show immunotherapy offers limited benefits for EGFR-positive lung cancer, Paik points out. What’s more, starting an EGFR inhibitor after taking immunotherapy comes with a higher risk of potentially life-threatening lung inflammation, a condition known as pneumonitis. Tumor testing provides information that allows physicians to choose treatments based on the tumor’s characteristics.

“For non-small cell lung cancer, biomarker testing has become the standard of care to the point where we really can’t make accurate treatment recommendations for patients at the time of diagnosis until we get at least some biomarker results back,” Paik says.

In some cases, this means physicians must decide whether to wait to get all results back before proceeding with treatment. Next-generation sequencing of tumor tissue is a comprehensive test that looks for changes in hundreds of genes at once, including EGFR, but it can take two to four weeks to get results, Paik says. PD-L1 testing to determine if a patient is a candidate for immunotherapy is done by looking at stained tumor tissue under a microscope, and results typically come back weeks sooner than a tumor’s genetic biomarker results.

If the goal is to start treatment as soon as possible, oncologists may choose to do a liquid biopsy test, which analyzes circulating tumor DNA in the blood. Liquid biopsy results typically take one to two weeks to come back, Paik says. Oncologists may opt to do blood tests first and confirm the results with tissue testing. Others may start chemotherapy “to buy some time” while waiting for results of tumor testing, Paik says. A study published March 2023 in Clinical Lung Cancer comparing tests results of circulating tumor DNA to DNA in biopsied tumor tissue in metastatic NSCLC shows both testing methods return comparable results—with liquid biopsy delivering results 26.8 days sooner on average than tissue testing. Still, the more rapid turnaround time for liquid biopsy did not lead to any significant differences in patient outcomes.

Testing in Early-stage Cancers

While tumor testing is often reserved for those with metastatic cancer or cancers that have few effective treatments, physicians are also exploring the utility of biomarker testing in earlier-stage cancers, a development Paik calls a “sea change.”

In fact, a June 4, 2023, study in the New England Journal of Medicine showed that people with early-stage, EGFR-positive NSCLC who took Tagrisso after surgery lived longer compared with those who took a placebo. The study divided 682 patients with stage IB to IIIA EGFR-positive NSCLC into two groups, one that took Tagrisso and one that took a placebo. (Those patients taking a placebo could switch to taking Tagrisso if they experienced disease recurrence.) The five-year overall survival was 88% for those taking Tagrisso compared with 78% for the placebo group.

Biomarker testing can also make a significant difference in the “lived experience” of people who are eligible for targeted therapy, says Paik. Before newer treatments were available, standard treatment for lung cancer involved intravenous chemotherapy once every three weeks for the duration of the disease, which led to serious side effects like hair loss, peripheral neuropathy and low blood counts, he says. Today, targeted medicines like Tagrisso for EGFR-positive lung cancer and Alecensa (alectinib) for ALK-positive lung cancer offer a less-toxic alternative for patients with cancers that have these biomarkers. ALK mutations occur in about 5% of NSCLCs and more often in younger never-smokers.

For those whose cancers have certain mutations, targeted therapy “offers flexibility and tolerability,” Paik says. “I can see patients once every three or even four months. It affords a great deal of freedom [for patients] to focus on all the other things that are important in their lives aside from cancer. The biggest boon for patients and families is that ability for us to put cancer in the background.”

More Cancer Types

Tumor testing that leads to targeted treatments is not a new phenomenon nor is its application limited to lung cancer. The 1958 discovery of estrogen receptors on cells would lead to tamoxifen as a treatment for breast cancer in the 1970s and today’s estrogen-blocking treatments. In the late 1980s, researchers learned that about 30% of breast cancers express high amounts of a protein called HER2, which would fuel research into HER2-targeted treatments, like Herceptin (trastuzumab) and current-day antibody-drug conjugates that deliver toxic payloads directly to the cell. And for various cancers, biomarker testing for PD-L1 expression or high microsatellite instability (MSI-H) can help physicians determine whether a person’s cancer is likely to respond to immunotherapies.

Michael Sapienza, CEO of the Colorectal Cancer Alliance, a patient support and advocacy group, points to the importance of biomarker testing for people with colorectal cancer. Treatments are available for patients with colorectal cancer that carries a specific mutation in the gene involved in controlling cell growth known as BRAF-V600E. About 10% of colorectal cancers have a BRAF mutation with V600E being the most common, and a BRAF/EGFR inhibitor combination treatment is now the standard of care for these patients. Colorectal cancers also should be tested for MSI-H, which means that the cancer has a deficiency in its ability to repair damaged DNA and could respond to immunotherapy. Studies of patients with MSI-H colorectal cancers who were treated with immunotherapy combinations have shown overall response rates as high as 65%. While most people with colorectal cancer won’t test positive for these biomarkers, Sapienza recommends testing for all patients so they can receive treatment based on their tumors’ characteristics.

Biomarker testing is especially important in cancers that do not typically respond to currently available treatments, says Lynn Matrisian, chief science officer for the Pancreatic Cancer Action Network (PanCAN). She notes that National Comprehensive Cancer Network guidelines recommend tumor testing for all people with advanced pancreatic cancer who are healthy enough for further treatment. Using data gathered through PanCAN’s Know Your Tumor program, a 2020 study published in Lancet Oncology found that 26% of pancreatic cancers carry molecular alterations for which there was evidence that a targeted therapy could offer a benefit. The research also showed that patients who received therapies matching their molecular alterations lived longer, with a median overall survival of 2.58 years, compared with those treated with unmatched therapies, 1.51 years, or those without actionable alterations, 1.32 years.

A study at the University of Texas MD Anderson Cancer Center called the IMPACT trial also showed that patients with advanced cancer who had their tumor tested for biomarkers and received a matched targeted therapy had higher response rates, as well as longer progression-free and overall survival, compared with those who didn’t get a matched therapy. Oncologist Apostolia Tsimberidou, who led the IMPACT trial at MD Anderson in Houston, urges patients with any type of advanced cancer to ask for tumor testing.

“It is my personal opinion that all patients with cancer should be screened for a number of reasons and because you can never predict,” Tsimberidou says. “You can be surprised, and there are so many FDA-approved targeted therapies for molecular alterations for specific tumor types or across tumor types.”

Matrisian’s recommendation to all newly diagnosed cancer patients is to get on what she calls the “right track.” This means making sure they have the experts they need to help with their disease. It also includes ordering the right biomarker tests to direct them to the right treatment, including through clinical trial participation. “Right team, right test, right treatment is the way we frame it,” she says.

After West’s surgery, several lymph nodes tested positive for cancer, which changed his diagnosis from an early stage I cancer to a more advanced stage IIB. To make a disease recurrence less likely, he received four rounds of chemotherapy. In June 2023, he started taking Tagrisso based on his cancer’s known EGFR-positive status. Now more than a year later, West still has no evidence of disease. He expects to continue taking Tagrisso for at least three years, with scans every three months to check for signs of a recurrence.

“I don’t see why anyone wouldn’t want to have biomarker testing done,” West says. At the time of his diagnosis, “I didn’t have any idea around treatment. I didn’t know what to ask. I thought my only options were chemo and surgery. I’m very thankful, obviously, for the [targeted] medicine.”

Cancer Today magazine is free to cancer patients, survivors and caregivers who live in the U.S. Subscribe here to receive four issues per year.