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Is Chemotherapy Necessary? Findings From the TAILORx Study

Bullen Love, Danielle

doi: 10.1097/01.COT.0000553968.36135.20
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Hormone-receptor-positive and HER2-negative, axillary node-negative breast cancer accounts for about half of breast cancer diagnoses in the U.S. (N Engl J Med 2018;379(2):111-121). Many women are prescribed adjuvant chemotherapy, along with endocrine therapy and surgery. Is this overtreatment? Is chemotherapy necessary for all these patients? The TAILORx study sought to find out.

Traditionally, oncologists rely on the 21-gene recurrence-score assay (Oncotype DX) to predict the benefits of chemotherapy on recurrence rates for HR+, HER2- breast cancer. The test analyzes 21 genes to determine a given patient's chance breast cancer will return and if she would benefit from chemotherapy for early-stage cancer.

“Treatment has evolved with time. Since the Oncotype became available, the use of chemotherapy in the U.S. has declined. We have a higher level of evidence supporting the treatment decisions for a particular patient,” explained Joseph A. Sparano, MD, Professor of Medicine at the Albert Einstein College of Medicine in New York, and the lead author on the study.

Former data showed women with scores of 10 or lower did not benefit from adjuvant chemotherapy. Women with scores of 26 or higher did benefit, as they had a 13 percent risk of recurrence after 9 years, according to Sparano.

What about those patients in the mid-range? Would chemotherapy improve the odds of their cancer not recurring?

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Weighing Treatment Options

Tests like the 21-gene recurrence score assay are a valuable tool for oncologists. They are used to confirm clinical suspicions and make educated treatment decisions. Larissa Korde, MD, Head of Breast Cancer and Melanoma Therapeutics at the NCI, which co-funded the study, remarked, “In the past, we understood breast cancer to be one disease. With genomic testing, we understand the biology of cancers differently. We can tailor treatments to the patients.”

Maureen Trudeau, MA, MD, FRCPC, medical oncologist at Sunnybrook Health Sciences Centre's Odette Cancer Centre, Toronto, one of the TAILORx sites, noted the scores help oncologists and patients feel more comfortable about using endocrine therapy alone or supplementing it with chemotherapy.

“It also reduces overtreatment in patients for whom chemotherapy would provide little to no benefit. Oncologists can say more definitively to certain patients, ‘You will do well and don't have to go through toxicity of chemotherapy,’” she explained.

With the side effects well-documented, reducing overtreatment and reliance on chemotherapeutic agents is a goal both providers and patients can easily get behind.

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Results With or Without Chemo

TAILORx recruited 9,179 patients ages 18-75 at multiple sites. Sixty-nine percent (6,711) had Oncotype scores between 11 and 25. They were randomly assigned to two groups. One group received chemotherapy and endocrine therapy and one group received endocrine therapy alone.

Thirty-six percent of women were premenopausal and 64 percent were post-menopausal. For endocrine therapies, 91 percent of post-menopausal women received an aromatase inhibitor; among pre-menopausal women 78 percent received tamoxifen or tamoxifen followed by an aromatase inhibitor. For chemotherapies, the most common agent was docetaxel-cyclophosphamide. All patients in the 11-25 range had undergone surgery. Seventy-two percent had a lumpectomy and 28 percent had a mastectomy.

The 5-year rate of invasive, disease-free survival was 92.8 percent among all women who underwent only endocrine therapy. The rate was 93.1 percent among all women who underwent endocrine therapy plus chemotherapy. When pushed out to 9 years, the invasive disease-free survival rates were 83.3 percent and 84.3 percent, without and with adjuvant chemotherapy, respectively.

Overall survival rates were even more closely aligned. At 5 years, they stood at 98 percent without chemotherapy and 98.1 percent with chemotherapy; at 9 years, they stood at 93.8 percent with chemotherapy and 93.9 percent without, a miniscule, but intriguing flip of the script (N Engl J Med 2018;379(2):111-121).

With those low differentials, many women with scores of 11-25 can feel confident declining chemotherapy, if that is their wish. Before any genetic tests, practitioners and patients must have a conversation about various risk factors and whether such a test would provide information to move forward with a treatment plan. Beyond the Oncotype, considerations include the size and grade of the tumor, lymphatic or vascular invasion, the age of the patient, and the levels of estrogen and progesterone receptors.

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Caution Ahead

Although the results were overwhelming positive, researchers found some caveats for a couple sub-groups.

A slightly greater benefit to chemotherapy was found among women under age 50 with Oncotype scores of 21-25. After 5 years, their invasive disease-free survival rate was 92.1 percent with adjuvant chemotherapy and 86.3 percent with endocrine therapy alone (N Engl J Med 2018;379(2):111-121).

Chemotherapy has been known to induce early menopause. “It's long been thought that for estrogen-positive tumors, inducing menopause and suppressing hormones in and of itself is an effective treatment,” Korde explained. Perhaps it is the hormone-suppressing effect of chemotherapy and not the treatment itself that offers the most benefit.

She also noted past data had shown a tendency towards more aggressive tumors in patients under age 30. Such women, she speculated, could have biologically more advanced tumors that benefit from chemotherapy. TAILORx only grouped participants into over and under age 50, so this theory can't be quantified for this particular study.

The study also showed that, given the same treatments, black women had a higher risk of recurrence and a higher risk of mortality. Within the mid-range group, black women had an 80 percent higher risk of recurrence and a 67 percent higher risk of mortality. This was despite comparable 21-gene score distributions among races and similar rates of endocrine therapy and adjuvant chemotherapy (2018 San Antonio Breast Cancer Symposium, Abstract GS4-07).

Sparano, who presented on this finding at the 2018 San Antonio Breast Cancer Symposium, admitted, “We don't have an explanation for it.” Black women have long been known to have higher rates of breast cancer mortality. In one recent study, the mortality rate for all types of breast cancers was 29.5 percent among non-Hispanic black women, the highest of any race or ethnicity (CA Cancer J Clin 2017;67(6):439-448).

As Sparano remarked, many considerations, from body mass index to socioeconomic factors like lack of access to care, have been thought to contribute to racial disparities among breast cancer diagnosis and survival.

“Previous work has shown obesity is associated with worse outcomes in HR+, HER- breast cancer. This effect of race was independent of body mass index. When we eliminated the noise and adjusted for other factors, we still saw these disparities,” he explained.

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Creating Confidence

The oncologists interviewed for this story were not surprised by the overall results, saying it confirmed what they expected. With the TAILORx findings, “Clinicians can make treatment decisions for individual patients with greater confidence,” said Sparano.

Trudeau added, “I know my colleagues and I have adopted many of the approaches from TAILORx, and the study gives us greater confidence in those decisions.”

The 21-gene assay is just one of many tests available to guide treatment decisions. Another option is the MammaPrint test, which analyzes 70 genes to gauge the benefits of adjuvant chemotherapy for both hormone-receptor-positive and hormone-receptor-negative breast cancers. The parameters for that test are more restrictive. Cancer must be invasive, present in three or fewer lymph nodes, and the tumor measure 5 centimeters or less (https://www.breastcancer.org/symptoms/testing/types/mammaprint).

Korde called TAILORx a good basis for future work. “There is ongoing study being done in women with node-positive disease. It's a natural next step that will help us provide individual information to women about their risk of recurrence.”

The results of the study showed adjuvant chemotherapy may not be the best choice for certain women. TAILORx is yet another example of how genetic testing creates targeted therapies for breast cancer. Science may not have yet eradicated this disease, but significant strides have been made towards improving survival.

Danielle Bullen Love is a contributing writer.

Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.
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