Will Oncologists Change Their Treatment Patterns Based on New Clinical Evidence?

In medical parlance, there is a wide gap between the terms “prognostic” and “predictive.” At a plenary session at the 2018 American Society of Clinical Oncology (ASCO) meeting, results presented from the TAILORx clinical trial cast a spotlight on that gap, and narrowed it. The question now is, will physicians and patients take action and cease the use of chemotherapy when its effectiveness can be predictively deemed ineffective, despite the challenges of hope and habit?

Joseph A. Sparano, MD, lead investigator of the study and Professor, Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, presented the study results at ASCO 2018. The study was simultaneously published in the New England Journal of Medicine.¹

TAILORx: New Evidence

The TAILORx study began in 2006 and had a median follow-up of more than 7 years. The results provided new findings that will affect women with estrogen-sensitive, HER2-negative, early-stage breast cancer whose tumor is between 1 cm and 5 cm and has not spread to the lymph nodes, and whose Oncotype DX Breast Cancer Assay score is between 11 and 25.

The Oncotype DX breast cancer assay is the most widely used genetic test in the United States for early-stage breast cancer after surgery to determine whether chemotherapy will benefit the patient. Earlier research has clarified that scores of ≤10 on the Oncotype DX Breast Cancer Recurrence Score indicate that chemotherapy will not benefit the patient, and scores of >26 indicate that chemotherapy will be of benefit. The challenge for patients and physicians was what to do when the score was between 11 and 25.

In 2000, the National Cancer Institute recommended the use of chemotherapy for most women with breast cancer, including when the cancer had not spread to the lymph nodes. However, with the availability of new data, questions arose about whether chemotherapy was being prescribed for some patients who did not gain any benefit from it. The TAILORx study was developed to answer those questions.

Chemotherapy Is Not Always Helpful

In the study, patients who had surgery received radiation therapy and were then randomized to endocrine therapy alone or to endocrine therapy plus chemotherapy. Approximately 9800 patients had complete follow-up information, and 70% of them had Oncotype DX scores between 11 and 25. Results showed that the use of chemotherapy did not provide any advantage in the patients with an Oncotype DX score between 0 and 25.

After 9 years, 93.9% of the patients were still alive in the endocrine-only arm compared with 93.8% of the patients who received endocrine therapy plus chemotherapy. In addition, some evidence showed that the chemotherapy benefit varied with age and disease recurrence score—40% of women aged ≤50 years and a recurrence score of 16 to 25 had some benefit from the chemotherapy. However, women older than 50 years did not benefit from chemotherapy if their disease recurrence score was between 11 and 25.

So where does that leave patients and physicians? According to the TAILORx study, by using the Oncotype DX Breast Recurrence Score, 70% of women with node-negative, hormone receptor (HR)-positive, HER2-negative, early-stage breast cancer can be safely treated with endocrine therapy alone.

“Any woman with early-stage breast cancer 75 years or younger should have the test and discuss the results of TAILORx with her doctor to guide her decision regarding chemotherapy after surgery to prevent recurrence,” Dr Sparano said.

Breast cancer is the most common cancer diagnosed in women in the United States; with HR-positive, ­axillary node–negative disease accounts for approximately 50% of all cases of breast cancer. If as many as 70% of these women are receiving chemotherapy that is not beneficial, how much improvement in patient outcomes, quality of life, and reduced financial burden can be achieved by not subjecting those women to the physical, emotional, and financial burden of toxic chemotherapy? How many of the limited staff and financial resources of cancer centers, medical practices, and hospitals can be freed up by choosing not to treat these patients?

“Prognostic” or “Predictive”?

What is the significance of the difference between prognostic and predictive? In oncology, prognostic tests help physicians to determine patients at high- and low-risk for breast cancer recurrence, whereas predictive tests help physicians estimate whether chemotherapy as a treatment choice will work for specific patients.

The Oncotype DX and other cancer assays are regulated by federal agencies according to the Clinical Laboratory Improvement Amendments. The Oncotype DX assay, which was launched in 2004, has been incorporated into national guidelines and clinical pathways—and is covered by payers—as a predictive test to be used for predicting or detecting a patient’s response to therapy, or to select the optimal therapy for patients. According to the results of an earlier clinical trial, “The recurrence score assay not only quantifies the likelihood of breast cancer recurrence in women with node-negative, estrogen receptor–positive breast cancer, but also predicts the magnitude of chemotherapy benefit.”²

The US Food and Drug Administration (FDA) issues 510(k) premarketing notifications for medical devices and identifies the intended use for the product or the device. Other breast cancer recurrence assays that came after Oncotype DX, including the Prosigna Breast Cancer Prognostic Gene Signature Assay and the MammaPrint assay, requested additional review by the FDA, and are now approved as prognostic markers or indicators. The FDA issued an added special condition for the Prosigna assay, saying that the assay is “not intended for diagnosis, or to predict or detect response to therapy, or to help select the optimal therapy for patients.”³ The MammaPrint assay was approved by the FDA “for use by physicians as a prognostic marker only, along with other clinicopathological factors.”⁴

Will You Change Your Treatment Decisions?

With the growing use of value-based care and performance contracts, use of the Oncotype DX assay to identify patients with a disease recurrence score of ≤25 for whom chemotherapy does not appear to have any benefit would seem to be an absolute given, especially because it has the distinction of being recognized nationally as a predictive test and can lead to appropriate clinical treatment decisions rather than being just a prognostic tool.

Patients do not have to suffer the side effects of toxic chemotherapy. Neither patients nor payers will have to incur the costs of chemotherapy that will make no difference in patients’ outcomes, and physicians can free up their staff and facilities to care for other patients for whom chemotherapy is the standard of care.

The 1-million-dollar question is—how much difference will these new findings make? One would hope that there is enough confidence in the predictive value of the Oncotype DX assay, which is recognized as a standard of care in clinical guidelines and pathways across the country.

However, there is hope and there is habit. If your practice follows these new findings, it will mean a new culture of breast cancer treatment for your staff and your patients to embrace. There has been so much lay press coverage about these findings, that it will be hard to imagine women not arriving at their physician’s office and asking about their own test results before deciding on their treatment options. For example, the New York Times published an article on June 3 titled “Good News for Women With Breast Cancer: Many Don’t Need Chemo,” and a press release from ASCO on that day was titled “Most Women With Early Stage Breast Cancer Can Forgo Chemotherapy When Guided by a Diagnostic Test.”

Physicians and patients have a chance to benefit from changing habits and hopes that have incorrectly driven thousands of patients to receive unnecessary chemotherapy. This is the promise of personalized medicine, which we hope is coming to life at an oncology practice near you.

References

1. Sparano JA, Gray RJ, Makower DF, et al. Adjuvant chemotherapy guided by a 21-gene expression assay in breast cancer. N Engl J Med. 2018 Jun 3. Epub ahead of print.
2. Paik S, Tang G, Shak S, et al. Gene expression and benefit of chemotherapy in women with node-negative, estrogen receptor–positive breast cancer. J Clin Oncol. 2006;24:3726-3734.
3. US Food and Drug Administration. 510(k) substantial equivalence determination: decision summary: assay and instrument combination template. 510(k) no K130010. www.accessdata.fda.gov/cdrh_docs/reviews/K130010.pdf. Accessed June 22, 2018.
4. US Food and Drug Administration. Section 5: 510(k) summary. 510(k) no K070675. June 22, 2007. www.accessdata.fda.gov/cdrh_docs/pdf7/k070675.pdf. Accessed June 22, 2018.