The most recent update of the National Comprehensive Cancer Network (NCCN) guideline on breast cancer has undergone a number of “tweaks” with few major changes. The revisions include new recommendations for preoperative endocrine therapy, optimization of adjuvant endocrine therapy in premenopausal and postmenopausal women, an update on HER2-directed therapy for patients with operable breast cancer, and guidance on new agents for endocrine therapy in metastatic disease.
“There have been some tweaks, but I would not say major, major changes, within the guidelines,” said William J. Gradishar, MD, Director, Maggie Daley Center for Women’s Cancer Care, Northwestern University, Chicago, who presented the updated NCCN guideline at the 2016 NCCN annual conference.
Preoperative Systemic Therapy
“We made a modification that suggests that endocrine therapy can be used selectively in the preoperative setting for patients with estrogen receptor [ER]-positive disease, and there are different approaches that can be employed to accomplish the goal of treating the patient and downsizing the tumor,” said Dr Gradishar. Neoadjuvant endocrine therapy is typically considered in older postmenopausal women, but it can be considered in other groups, including premenopausal women with comorbidities that make them poor candidates for chemotherapy.
Dr Gradishar noted that neoadjuvant chemotherapy with or without anti-HER2 therapy is increasingly successful in producing a pathologic complete response (CR), but only in patients with ER-negative/HER2-positive cancers. A pathologic CR in such patients correlates with improved disease-free survival; this correlation is absent in patients with ER-positive disease.
A pathologic CR in patients with ER-positive disease is not critical, Dr Gradishar said, because pathologic CR is not as important in predicting the outcome in this group as it is in patients with ER-negative disease, in whom pathologic CR predicts an improvement in disease-free survival.
“We also have data with more recent agents, such as aromatase inhibitors, in this setting” (of ER-rich tumors), with clinical response rates of 60% to 72% and few patients with disease progression, he said.
Adjuvant Endocrine Therapy
New clinical trial data from the SOFT and TEXT clinical trials inform subtle changes in the updated guideline regarding the optimal approach for adjuvant endocrine therapy in premenopausal and postmenopausal women.
For premenopausal women at diagnosis, the guideline states that the optimal adjuvant endocrine therapy is tamoxifen for 5 years, with or without ovarian function suppression, or an aromatase inhibitor for 5 years with ovarian suppression or ablation. If a patient becomes postmenopausal after 5 years of endocrine therapy, tamoxifen should be considered for an additional 5 years, or the patient should switch to an aromatase inhibitor for 5 years. If the patient remains premenopausal, tamoxifen should be considered for an additional 5 years or no further endocrine therapy.
For postmenopausal women at diagnosis, “the data for an AI [aromatase inhibitor] beyond 5 years is really limited at this point…as it stands at this moment, we would say that 5 years of an AI is the optimal duration,” he said. In women with early-stage ER-positive disease, 5 years of tamoxifen has a carryover effect lasting for at least another 5 years in terms of a reduction in the odds of breast cancer recurrence and breast cancer mortality.
It is important to discuss with patients the expected side-effect profile of ovarian suppression, specifically musculoskeletal complaints, dyspareunia, vaginal dryness, and difficulty with arousal, Dr Gradishar said.
Neoadjuvant HER2-directed therapy, particularly with a trastuzumab (Herceptin)-containing regimen, is recommended for at least 9 weeks before surgery. A pertuzumab (Perjeta)-containing regimen can be considered for patients with HER2-positive disease and with T2 lesions and/or positive lymph nodes.
Preliminary data from the NeoSphere clinical trial indicate that a dual anti-HER2 regimen with pertuzumab and trastuzumab, added to docetaxel (Taxotere), translates into superior improvement in progression-free survival compared with the other treatment arms in the clinical trial. In addition, data from the CLEOPATRA clinical trial showed that overall survival was significantly improved with pertuzumab plus trastuzumab and docetaxel compared with placebo plus trastuzumab and docetaxel in patients with HER2-positive metastatic disease.
“This collation of all the data led to a provisional approval of pertuzumab in this setting, and that prompted us to put it in the guidelines,” said Dr Gradishar. “If the adjuvant APHINITY trial proves not to be positive, and representative of what we have seen in the preoperative setting, the guidelines may change.”
Recurrent or Stage IV Disease
The updated guideline states that premenopausal women with recurrent or stage IV hormone receptor–positive disease should have ovarian ablation or suppression, followed by a regimen recommended for the treatment of postmenopausal women.
Palbociclib (Ibrance) is a new option for this patient population, to be used in combination with letrozole or fulvestrant, based on data from the PALOMA-1 clinical trial. The results “were quite striking,” and in favor of palbociclib as first-line therapy for ER-positive metastatic disease, with a doubling of time to progression, and led to the approval of palbociclib in this setting, said Dr Gradishar.