William J. Gradishar, MD
There were no major changes to the 2016 update to the NCCN Breast Cancer Guideline, but there were some “tweaks,” according to William J. Gradishar, MD.
At the 2016 NCCN Annual Conference, Gradishar, a professor of Breast Oncology at the Feinberg School of Medicine at Northwestern University, discussed updates to the NCCN Breast Cancer Guideline and the latest research developments in the field.
Neoadjuvant Endocrine Therapy
“We made [guideline] modifications suggesting that endocrine therapy can be used selectively in the preoperative setting for patients with ER+ disease,” said Gradishar.
The most suitable patients for neoadjuvant endocrine therapy are patients with ER rich cancers who are older (postmenopausal), or if they are younger, those who have significant morbidities that make them poor candidates for chemotherapy.
The multicenter, open-label phase III ACOSOG Z1031 study randomized women with stage II/III ER-rich (Allred score 6-8) breast cancer to 16 weeks of neoadjuvant treatment with exemestane, letrozole, or anastrozole.1
The clinical response rate ranged between 60% and 72% among the 3 treatment arms.
“These data were primarily in postmenopausal women, but if you were to treat a premenopausal woman with an aromatase inhibitor [AI], you would obviously have to render her postmenopausal with ovarian suppression ablation before doing so,” said Gradishar.
Gradishar also noted that neoadjuvant chemotherapy with or without anti-HER2 therapy is increasingly successful in producing pathologic complete responses (pCRs), but only in ER-negative/HER2-positive cancers.
He cited the pivotal phase II NeoSphere trial,2
which showed that pertuzumab (Perjeta), combined with trastuzumab (Herceptin) and docetaxel, significantly improved pCR when compared with 3 other neoadjuvant regimens (trastuzumab plus docetaxel, pertuzumab plus trastuzumab, or pertuzumab plus docetaxel) in newly diagnosed patients with HER2-positive, early-stage breast cancer, leading to the FDA approval of the pertuzumab regimen.
In each of the 4 cohorts in the NeoSphere trial, pCR was higher among patients who were HR-negative. Gradishar stressed, however, that pCR in ER-positive patients may not be as critical in predicting outcomes.
In a study by Ring et al3
of 435 patients who received neoadjuvant chemotherapy for operable breast cancer, overall survival (OS) outcomes were improved in patients who achieved a pCR compared with those who did not (5-year OS, 91% vs 73%; P
= .02). This correlation held up in ER-negative patients (5-year OS, 90% vs 52%; P
= .005), but pCR did not have prognostic significance in ER-positive patients (5-year OS, 93% vs 79%; P
Adjuvant Endocrine Therapy in Pre- and Postmenopausal Women
The NCCN guidelines stipulate that for premenopausal women at diagnosis, the optimal adjuvant endocrine therapy is tamoxifen for 5 years with or without ovarian function suppression (OFS) or an AI for 5 years with OFS.
If a patient becomes postmenopausal after 5 years, physicians should consider tamoxifen for an additional 5 years or switch to an AI for 5 years. If a patient remains premenopausal, physicians should consider tamoxifen for an additional 5 years or no further endocrine therapy.
“In postmenopausal women [at diagnosis] we have several different options, that include tamoxifen to start, switching over [to an AI] at some point, or, really what we view as the standard for most women, is to start with an AI," saidGradishar . "And, again, the data for an AI beyond 5 years is really limited at this point…as it stands at this point we would say that 5 years of an AI is the optimal duration.”
Gradishar cited a combined analysis4
of the ATLAS and aTTom trials, which examined the long term-impact of tamoxifen in women with early-stage, ER+ great cancer.
The combined data showed that in years 5 through 9, the impact of tamoxifen was not evident, with an HR for breast cancer mortality of 0.97 and an HR for OS of 0.99. However, in years 10 and beyond, tamoxifen was associated with a 25% reduction in the risk of breast cancer mortality (HR, 0.75) and a 16% improvement in OS (HR, 0.84).
“So we have justification for using longer durations of therapy based on this data set,” said Gradishar.
There have also been efforts made by the NCCN guideline panelists to consider the appropriate use of OFS in premenopausal women with ER+ and/or PR+ breast cancer.
Gradishar said physicians should consider use of OFS plus tamoxifen or OFS plus an AI in patients aged <35 years who need chemotherapy (ie, greater risk of recurrence), who remain premenopausal, and who have larger, higher-grade tumors with multiple positive nodes. He added that the optimal duration of OFS-based therapy is uncertain, but suggested a trial period of 3 to 5 years.