Beyond Chemotherapy in Georgia

Chemotherapy has greatly improved survival rates for breast cancer and is an important part of treatment for many. But because it works by attacking rapidly dividing cells, it can also damage healthy cells in the body, leading to a wide range of adverse side effects – hair loss, fatigue, nausea, vomiting and nerve damage – and making it one of the treatments women dread most.

Today, more and more women with early-stage breast cancer are learning they do not have to undergo chemotherapy to be cancer-free, thanks in large part to advances in genomic testing.

What Is Genomic Testing?

Genomic testing allows doctors to learn more about the biological characteristics of a person’s breast cancer. Using this knowledge, doctors can better assess how likely the early-stage cancer is to recur and if the person will benefit from chemotherapy.

“Breast cancer is not just one type of cancer arising from the breast, but it is actually driven by different factors, which help us in tailoring the treatment for each individual,” says Dr. Nakita Sharma, a medical oncologist and hematologist at City of Hope in Atlanta.

People often confuse genomic testing with genetic testing, but the two provide different types of information. Genetic testing identifies inherited DNA changes that increase a woman’s lifetime risk of developing certain cancers and other diseases. These inherited changes are found in every cell of the body and can be passed from one generation to the next. Genomic testing, by contrast, examines the tumor itself to help guide treatment decisions.

“Many people think of genetic testing as looking for gene mutations they inherited from their mother or father. This is different,” says Dr. Amelia Zelnak, a hematologist and medical oncologist at Northside Hospital. “It’s looking at genes in the breast cancer that are known to be important for the biology of the cancer.”

To do genomic testing, doctors examine tissue samples taken during a biopsy or, more commonly, after the tumor has been removed during surgery. Instead of simply determining whether certain genes are present, genomic testing evaluates how actively selected genes are expressing themselves within the cancer cells. “It’s not just saying whether a gene is positive or negative,” Zelnak explains. “It’s actually looking at how much of that gene is being expressed – how active that gene is.”

Several validated genomic tests are available, including Oncotype DX, MammaPrint, Breast Cancer Index and Prosigna. Doctors select the most appropriate test based on a patient’s clinical characteristics. Those factors include whether she is pre- or postmenopausal, her hormone receptor status and the number of lymph nodes involved, says Dr. Sujatha Hariharan, a hematologist/oncologist with the Wellstar Health System.

Who Benefits Most from Genomic Testing

Traditionally, genomic testing has been used primarily to guide treatment decisions for women with the most common type of breast cancer – hormone receptor-positive, HER2-negative disease. These cancers have receptors that allow them to grow in response to hormones such as estrogen or progesterone, so they are called hormone receptor-positive. But they do not produce excess amounts of the HER2 protein, which can promote faster cell growth, so they are classified as HER2-negative. Because these cancers can vary widely in how likely they are to recur, genomic tests can help identify which women are most likely to benefit from chemotherapy.

Offering Guidance: Dr. Amelia Zelnak is a hematologist and medical oncologist at Northside Hospital. Photo credit: Daemon Baizan

“Some of those cancers are more aggressive than others,” Zelnak says. “These genomic tests are primarily used for that type of breast cancer to determine whether it’s a lower-risk or a higher-risk cancer.”

“We used to always just say, ‘Okay, well, if you had a big tumor or lymph nodes involved, you need chemo,’” says Dr. Katie Bennett, a surgical oncologist who specializes in breast surgical oncology at Memorial Health University Medical Center in Savannah. “Now we’re really understanding, based on the tumor biology [and] not just size or nodes, that it’s not always the most effective treatment.”

In recent clinical trials, about 60% to 85% of postmenopausal women in the study populations who might traditionally have been considered for chemotherapy were classified as low risk by genomic testing, meaning they could potentially avoid chemotherapy.

Genomic testing, however, is only one part of the decision-making process, Bennett says. Doctors also evaluate each patient’s imaging results, pathology findings, overall health and personal circumstances when recommending treatment. Most breast centers present each new patient diagnosed with breast cancer at a multidisciplinary conference where specialists from multiple disciplines review the case before recommending a course of action.

At Memorial Health, Bennett notes “myself, the surgeon, as well as the radiologist, the pathologist, medical oncology, radiation oncology, as well as social workers, are all there participating in the care and making recommendations.”

“It’s not typically just a sole provider saying, ‘Hey, this is exactly how it has to go,’” Bennett says. “You have the whole team’s input up front, which is really nice.”

How Clinical Trials Changed Treatment

Much of what physicians know today about using genomic testing to guide treatment decisions comes from a series of large clinical trials.

“Over the last 25 years, we have had about four large randomized clinical trials to study if these genomic [tests] can predict which patient may benefit from chemotherapy,” says Sharma. Oncotype DX was one of the first genomic tests to gain widespread usage. It was initially studied in women with hormone receptor-positive, HER2-negative breast cancer whose cancer had not spread to the lymph nodes.

Two large clinical trials – TAILORx and later RxPONDER – found that many women whose genomic test results showed a low risk of recurrence got little or no benefit from chemotherapy. These two landmark trials changed clinical practice, allowing many women to safely avoid chemotherapy without negatively affecting their outcomes.

Even so, important questions remained. Most of the evidence came from women whose cancer had either not spread to the lymph nodes or had spread to only one to three lymph nodes. For women with four or more positive lymph nodes, chemotherapy was still recommended because there was no evidence showing that it could safely be omitted.

Extending Genomic Testing to Higher-Risk Patients

Making Recommendations: Dr. Katie Bennett works at Memorial Health University Medical Center in Savannah as a surgical oncologist with a focus in breast surgical oncology. Photo credit: Frank Fortune

The OPTIMA trial was designed to find out more.

“The main difference between this study and the other studies that have already been reported is that the majority of patients had positive lymph nodes,” says Dr. Kevin Kalinsky, a breast medical oncologist at Emory University. “The other thing that was unique about the OPTIMA study is that it included patients with four to nine lymph nodes involved as well. None of the other prior genomic assay studies included that population.”

“For a patient who comes in after surgery and has five positive lymph nodes, chemotherapy has generally been automatic,” Zelnak says. “Not necessarily because we knew it would help every patient, but because we didn’t have evidence showing it wasn’t beneficial.”

The OPTIMA trial suggests that approach may not be necessary for every patient, Sharma says. “The OPTIMA study has reinforced and broadened our knowledge as to how to utilize genomic expression signatures for some of the higher clinical-risk patients.”

According to Kalinsky, the findings suggest some women whose cancer has spread to more lymph nodes may not get a meaningful benefit from adding chemotherapy to endocrine therapy, depending on the tumor’s biological makeup.

Endocrine therapy is the standard treatment for hormone receptor-positive breast cancer. Rather than attacking rapidly dividing cells like chemo, it works by blocking or lowering estrogen, which fuels the growth of many of these cancers.

OPTIMA’s findings do not mean that every woman with four or more positive lymph nodes can safely skip chemotherapy. Rather, they suggest that genomic testing may help identify higher-risk women whose tumors are biologically less aggressive and who are less likely to benefit from chemotherapy. As more data become available, the findings have the potential to expand the use of genomic testing in carefully selected higher-risk patients.

Access and Coverage

As genomic testing becomes part of routine breast cancer care, another crucial question is whether insurance will cover it. In many cases, insurance coverage has expanded along with the growing body of clinical evidence supporting its use.

“The evidence base for genomic testing in breast cancer has matured considerably over the past two decades, and our medical policies have evolved alongside it,” says Dr. Judy Mouchawar, senior policy medical director for the Blue Cross Blue Shield Association. Early coverage was limited, she says, but as large clinical trials demonstrated that genomic testing could safely identify women who would likely not benefit from chemotherapy, insurance coverage expanded for eligible patients.

Although genomic tests can be expensive, physicians say they often reduce overall healthcare costs by helping people avoid chemotherapy that is unlikely to provide benefit.

“While genomic tests may cost several thousand dollars, they are typically far less expensive than the total cost of chemotherapy when accounting for drug costs, infusion services, supportive medications, monitoring and side-effect management,” says Dr. Tina Dasgupta, a radiation oncologist at Kaiser Permanente. “More importantly, genomic testing helps determine whether chemotherapy will actually provide meaningful benefit to the patient and their risk of cancer recurrence, allowing us to avoid treatments with a high side effect profile when they are unlikely to improve results.”

Mouchawar emphasizes that coverage decisions are based upon clinical evidence rather than economics. “When a test shows chemotherapy is unlikely to help a particular patient, avoiding it spares the patient harm and avoids care that would not have improved the outcome,” she says. “The evidence, not the arithmetic, drives the policy.”

Getting the Right Treatment

The goal of genomic testing is not simply to determine whether a patient should receive chemotherapy. Instead, it helps physicians identify the treatment most likely to benefit each patient based on her cancer’s biology. For some women, genomic testing indicates that endocrine therapy alone may be sufficient. For others, it confirms that chemotherapy or additional treatments are likely to improve outcomes.

For many women with hormone receptor-positive, HER2-negative breast cancer, endocrine therapy is still the foundation of treatment. Depending on her risk of recurrence, physicians may also recommend adding targeted drugs known as CDK4/6 inhibitors, which help slow cancer cell growth, to endocrine therapy.

Assessing Benefits and Risks: Dr. Kevin Kalinsky, director of the Glenn Family Breast Center at Emory’s Winship Cancer Institute. Photo credit: Ben Rollins

Hariharan says that patients with early-stage breast cancer should discuss treatment options with their medical oncologist, including whether a genomic assay may help guide decisions.

Research continues to refine these treatment decisions. The ongoing OFSET trial, for example, is evaluating whether some premenopausal women with hormone receptor-positive, HER2-negative breast cancer can safely avoid chemotherapy and instead receive endocrine therapy along with treatment that stops the ovaries from producing estrogen.

Ultimately, genomic testing is helping physicians move beyond a one-size-fits-all approach to breast cancer treatment. Rather than relying primarily on traditional factors such as tumor size and lymph node involvement, physicians can increasingly combine those factors with genomic testing to better match treatment to each person’s individual risk.

“We’re trying to accurately treat them and give them exactly what they need,” Bennett says. “Not undertreat or overtreat them.”