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Gene assay identifies women who can be spared chemotherapy for breast cancer
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A 21-gene expression assay accurately identified women with ER-positive, HER-2–negative, axillary node-negative breast cancer who had a low risk for 5-year recurrence, according to the results of a prospective trial presented at European Society of Medical Oncology’s European Cancer Congress.
Based on results of the 21-gene recurrence score (Oncotype Dx Recurrence Score, Genomic Health), these women may safely receive endocrine therapy alone without chemotherapy, according to the researchers.
“The compelling results seen in this global study provide unequivocal evidence supporting the clinical utility of Oncotype DX to risk stratify patients with early-stage breast cancer, and indicate that the findings are generalizable to every day clinical practice,” Joseph A. Sparano, MD, professor of medicine and obstetrics, gynecology and women’s health at Albert Einstein College of Medicine and vice-chairman of medical oncology at Montefiore Einstein Center for Cancer Care in New York, said in a press release. “The findings provide the highest level of evidence supporting expert-derived clinical practice guidelines which have recommended Oncotype DX in patients with early-stage ER-positive breast cancer.”
Many women with ER-positive breast cancer may be overtreated with chemotherapy because they may be adequately treated with endocrine therapy alone. Earlier studies have shown that gene expression assays provide clinically useful prognostic information to predict benefit from adjuvant chemotherapy, according to study background.
Thus, Sparano and colleagues conducted a prospective trial of women with ER-positive, HER-2–negative, axillary node-negative breast cancer who had tumors between 1.1 cm and 5 cm in the greatest dimension who met established guidelines for adjuvant chemotherapy receipt based on clinicopathologic features.
Researchers calculated a risk score for recurrence based on a reverse-transcriptase–polymerase-chain-reaction assay of 21 genes on paraffin-embedded tumor tissue. The researchers assigned women with a recurrence score between 0 and 10 — indicating a very low risk for recurrence — to endocrine therapy alone.
A time-to-event analysis of the rate of survival free from invasive cancer served as the primary endpoint. Freedom from recurrence of breast cancer at a distant site, freedom from any recurrence and OS served as secondary endpoints.
The trial included 10,253 eligible women, of whom 15.9% (n = 1,626; median age, 58 years) were assigned to endocrine therapy alone based on recurrence score.
Endocrine therapy modalities included aromatase inhibition (n = 963; 59%), tamoxifen (n = 560; 34%), sequential tamoxifen followed by aromatase inhibition (n = 13; 1%), ovarian-function suppression (n = 44; 3%) and other therapies (n = 46; 3%).
The median follow-up in this cohort was 69 months.
Results — simultaneously published in The New England Journal of Medicine — showed 93.8% (95% CI, 92.4-94.9) of women with a low recurrence score achieved 5-year invasive DFS. The rate of freedom from recurrence at a distant site was 99.3% (95% CI, 98.7-99.6) and the rate of freedom from recurrence at a distant or locoregional site was 98.7% (95% CI, 97.9-99.2).
Ninety-eight percent (95% CI, 97.1-98.6) of the cohort achieved 5-year OS. Death or progression to invasive cancer occurred in 88 women, with 30 deaths reported within 5 years of study entry.
In a multivariate analysis that included age (≤ 50 years vs. 51 to 60 years vs. 61 to 75 years), tumor size (2.1 cm to 5 cm vs. ≤ 2 cm in the greatest dimension), histologic grade (high vs. intermediate vs. low) and surgery type (mastectomy vs. lumpectomy), only histologic grade appeared significantly associated with freedom from recurrence. However, histologic grade did not appear associated with rate of invasive DFS or freedom from distant recurrence.
“The risk of developing a second primary cancer was about three-fold greater than having a recurrence of the original breast cancer, but we wouldn’t expect chemotherapy to prevent these cancers from developing,” Sparano said. “Further follow-up of the trial is ongoing to determine whether chemotherapy may also be effectively spared in patients who have a mid-range Recurrence Score between 11 and 25.”
Despite positive study findings, questions remain concerning cost and availability of the assay, Clifford A. Hudis, MD, chief of breast medicine service, vice president for government relations and chief advocacy officer at Memorial Sloan Kettering Cancer Center, wrote in an accompanying editorial.
“This multigene assay is unlikely to be the only test that can provide a prediction of chemotherapy benefit,” Hudis wrote. “A less expensive and broadly distributed test would be valuable globally. For now, however, this assay is the most rigorously tested option and provides proof of the principle that we can develop reproducible predictive tests to select patients who should not receive chemotherapy.” – by Cameron Kelsall
Disclosure: The NCI provided funding for this study. Sparano reports grant support from the NCI during the conduct of this study, as well as a patent related to tests to predict responsiveness of patients with cancer to chemotherapy treatment options. Please see the full study for a list of all other researchers’ relevant financial disclosures. Hudis reports grant support from Genomic Health.
Perspective
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Andrew D. Seidman, MD
The transition from relying solely on anatomic and histologic features of breast cancer for estimation of prognosis and guiding systemic adjuvant therapy began with ER assays, further evolved with assessment of HER-2 status and now incorporates multi-gene testing. Oncotype DX (Genomic Health) testing has been in clinical use for well over a decade and has enabled oncologists to parse more refined decisions on the use of chemotherapy for those many patients diagnosed each year with node-negative, ER-positive, HER-2–negative invasive breast cancers, most of whom are destined to be cured without it.
Prior prospective and retrospective study has given medical oncologists some confidence in omitting chemotherapy for select patients whose cancers have Oncotype DX Recurrence Scores (RS) of less than 19; the key subset data reported by Sparano and colleagues provides the first prospective evidence that it is indeed appropriate — in fact, desirable — not to employ chemotherapy for patients with RS less than 11. Over 99% of patients receiving antiestrogen therapy alone in this group were free of distant recurrence at 5 years. Even recognizing the risk for late recurrence in this population, it is hard to imagine a possible benefit for cytotoxic chemotherapy of any meaningful magnitude, if any at all. Only 4% of patients were aged younger than 41 years, and only 8% had tumors greater than 3 centimeters in diameter, providing less confidence in decision-making for such scenarios. Notably, clinical and pathologic variables such as age, grade and tumor size indeed can contribute to assessment of prognosis when considered with RS, but have not contributed to the predictive value of the 21-gene Recurrence Score in determining chemotherapy benefit.
Although these results help us and our patients today, prospective randomized trial data on the utility of other genomic assays that may influence clinical care, and the primary results of the RS 11-25 “intermediate” RS cohort of the TAILORx trial are eagerly awaited. Until then, the ability to define a group of patents for whom “less is more” data is welcome and should motivate the use of endocrine therapy as sole systemic treatment for patients represented by the 1,626 patients in the RS less than 11 cohort.
Paik S, et al. J Clin Oncol. 2006;doi:10.1200/JCO.2005.04.7985.
Tang G, et al. J Clin Oncol. 2011;doi:10.1200/JCO.2011.35.3714.
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