Revolutionizing cancer care: Next-gen diagnostic tests empower precision therapy

Shock and then fear. That is how Marika Battarola first reacted to her ovarian cancer diagnosis in 2021. “I was afraid of dying and leaving my 4-year-old daughter,” she recalls. Fortunately, she was diagnosed at one of the largest teaching hospitals in Milan, Italy and thus had access to the latest technology. Using a biopsy of the cancer, the hospital analyzed the tissue for specific mutations that might point to a therapy that would target her specific type of cancer.

The test revealed that the cancer harbored homologous recombination deficient mutations, or HRD, which make it difficult for cancer cells to repair themselves. At the same time, however, the mutations make the cells more sensitive to certain types of cancer therapy. 

After surgery to remove cancerous tissues and first line treatment with chemotherapy, Battarola’s doctors put her on a combination of two targeted therapies, bevacizumab and olaparib – a second line treatment for a subset of women with specific types of ovarian cancers that include Battarola’s (bevacizumab works by blocking blood vessel growth in tumors, while olaparib disrupts DNA repair in cancer cells, causing their death).

In recent years, targeted therapies such as olaparib and bevacizumab have given patients with advanced ovarian cancer new hope. A 2023 study, for example, found that at 5 years after diagnosis, 46% of advanced stage ovarian cancer patients with HRD-positive tumors taking the drug combination were still in remission. In comparison, only 19% of those taking placebo plus bevacizumab remained in remission (1).

“Targeted therapy is certainly helping to prolong patient survival,” says Marzia Del Re, Pharm.D., Ph.D., assistant professor in the Department of Clinical and Experimental Medicine at the University of Pisa. “But we are just at the beginning.” 

Making precision medicine even more precise

Technologies such as digital PCR (dPCR), which can pick up very small quantifiable signals in biological samples, are becoming more widely available. This gives researchers the capability to develop a new generation of companion diagnostic tests that go beyond merely identifying the presence or absence of a mutation or biomarker. Del Re, for example, is using blood samples from lung and colon cancer patients to monitor genetic changes in cancers. A change might signal that a patient should be shifted to other treatments, she says.

Technologies such as dPCR are now proving sensitive enough to even predict which patients will relapse before metastases happen.

“That’s powerful information we can use to change treatment and perhaps drastically improve outcomes in patients with advanced cancer,” says Del Re.

Over the past 20 years, the number of FDA approved companion diagnostic assays have steadily gone up. By the end of 2022, the U.S. Food and Drug Administration had approved 48 companion diagnostic tests – all in cancer indications. The analytical platforms are diverse and cover technologies like immunohistochemistry, in situ hybridization, polymerase chain reaction, next generation sequencing, and imaging.

The companion diagnostic portfolio from QIAGEN includes multiple tests for use in cancer settings. The therascreen FGFR RGQ RT-PCR Kit helps identify urothelial cancer patients who might benefit from treatment with erdafitinib; therascreen PIK3CA RGQ PCR Kit can identify advanced breast cancer patients who might best respond to alpelisib; therascreen KRAS RGQ PCR Kit identifies patients with non-small-cell lung cancer who might best respond to sotorasib and adagrasib, and patients with colorectal cancer who might best respond to cetuximab and panitumumab. Finally, the therascreen EGFR RGQ PCR Kit identifies patients with non-small-cell lung cancer who might best respond to afatinib, gefitinib, and dacomitinib.

Case examples using new technologies

One lab that has evolved with the new molecular diagnostic tests and technologies available is the MVZ Labor Dr. Limbach in Heidelberg, Germany. Initially founded in 2000, the Department of Molecular Endocrinology lab can now perform all manner of assays that include companion diagnostics in cancer treatment and pharmacogenomic tests to parse patients who will respond to specific drugs from those who won’t.

For example, not all patients with depression will respond to medication, says Dr. med. Egbert Schulze, head of the molecular endocrinology division. “We can personalize treatment by looking for mutations in genes that affect drug metabolism.” Understanding whether a patient is low or high metabolizer can also help clinicians minimize side effects and better manage their patients’ treatment plans, says Schulze, who has been working in the field of molecular diagnostics for over 30 years, and was an early adopter of several QIAGEN products for molecular diagnostics and molecular analysis.

At the University of Pisa, Del Re is looking at biomarkers in whole blood, a liquid biopsy, to learn about cancer's behavior.

Using the QIAcuity Digital PCR System, Del Re has been able to quantify levels of DNA coming from cancer cells present in a blood sample by measuring levels of specific mutations. She analyzes samples before treatment and at each follow-up.

Molecular results are also compared to radiological images to give a more comprehensive view of a patient’s disease status, says Del Re. Right now, her lab is using this monitoring method mainly in lung cancer patients because there are several biomarkers that have been identified and that can be measured in blood.

Based on whether the level of mutations is increasing or decreasing, “we can predict if the cancer is progressing or whether treatment is having an effect…often before metastases might become apparent,” she explains.

Del Re is also using liquid biopsy analysis in colorectal cancer patients to monitor the appearance of RAS mutations. Patients who test positive might receive a rechallenge treatment, says Del Re, which means reintroducing a treatment to which a tumor has grown resistant, after an intervening treatment.

Helping push continued advancements

Del Re hopes that her work with liquid biopsies as companion diagnostics to monitor the effectiveness of treatments will help advance personalized cancer treatment and improve outcomes even more.

By identifying whether a patient’s cancer has become resistant to a specific therapy, or whether they are not responding to first line therapy, clinicians can make better informed decisions about additional therapy, she says.

Del Re works with the QIAcuity Digital PCR System because it is automated and enables her to obtain results quickly enough. Sample preparation for digital droplet PCR, for example, requires many steps and consequently, “the risk of incurring errors from operators is quite high,” she adds.

This use case of a liquid biopsy as a companion diagnostic has yet to be standard clinical practice - it is still in the research phases. At her institution in Pisa, however, “clinicians believe in it and ask for it,” she says. But she must work with them in an interdisciplinary fashion to help them understand and interpret results. 

On the patient side, this means hope for a future with faster diagnosis, but it is still a shocking journey no matter what. How did Battarola cope, for example? After her diagnosis, Battarola consulted a professional “support coach.” The coach helped her remain calm before her surgery and taught her to focus on the positive things in her life, she says.

“He helped me learn to enjoy what I have every single day, my house, food and my daughter. Sometimes we forget this,” she says. During her treatment, she also consulted an oncology nutritionist, a homeopathic doctor and an osteopath, who all contributed to a holistic treatment plan. She also meditated every day, she says.

She is still taking olaparib as maintenance therapy to keep the cancer from returning.

“I’m working on my faith,” she says, but she is not referring to religion. “It’s the engine of life and helps people live in the present. My plan for the future is to enjoy every day of my life.”