HOLLYWOOD, FLA. (FRONTLINE MEDICAL NEWS) The latest updates to the National Comprehensive Cancer Network guidelines on breast cancer reflect a more nuanced approach to the use of systemic therapy in both the pre- and postoperative settings, with increasing emphasis on tailoring therapies to the unique clinical profiles of individual patients, according to Dr. William Gradishar.

The revised guidelines include new recommendations about preoperative endocrine and HER2-directed therapies, optimizing adjuvant endocrine therapy in both pre- and postmenopausal women, targeted agents as partner drugs for endocrine therapy in women with metastatic breast cancer, and recommendations about preservation of fertility in younger patients, said Dr. Gradishar, chair of the Robert H. Lurie Comprehensive Cancer Center at Northwestern University in Chicago.

“There have been some tweaks but I wouldn’t say major, major changes within the guidelines,” he said at the annual conference of the National Comprehensive Cancer Network.

Neoadjuvant therapy

One of the larger changes to this year’s guidelines is the addition of a page devoted to the principles of preoperative systemic therapy. The guidelines note that randomized clinical trials have shown similar long-term outcomes when patients receive the same treatment in either the pre- or post-op setting.

They add, however, that neoadjuvant systemic therapy “can render surgically inoperable tumors operable and offers potential benefits for patients with operable breast cancer. Importantly, preoperative systemic therapy can improve rates of breast conservation therapy eligibility and provides an opportunity to observe clinical and pathologic response to systemic therapy in an individual patient.”

The guidelines also note that a pathologic complete response to preoperative systemic therapy is predictive of “extremely favorable” disease-free and overall survival.

Patients who may be good candidates for neoadjuvant endocrine therapy include those with estrogen receptor–rich tumors (Allred score, 7 or 8), older postmenopausal women, and younger, premenopausal women with significant comorbidities that may make them poor candidates for chemotherapy, Dr. Gradishar said.

Adjuvant therapy

Regarding adjuvant therapy, the guidelines reflect data from recent clinical trials showing the benefits of both extended tamoxifen therapy, and for women who are premenopausal at diagnosis and are at high risk of recurrence, an aromatase inhibitor (AI) or steroidal aromatase inactivator plus ovarian suppression or ablation.

The recommendation to consider an AI and ovarian suppression in this population is based on data from the SOFT and TEXT trials ( N Engl J Med. 2014; 371:107-18 ), which showed a significant reduction in the recurrence of hormone receptor–positive early breast cancer in premenopausal women treated with exemestane (Aromasin) and ovarian suppression, compared with tamoxifen and ovarian suppression.

Although data supporting the use of endocrine therapy and ovarian suppression are compelling, “we have to individualize our choice of which patient is appropriate for this, because there is a price to pay in terms of side effects, and we have to figure out if that balance is right for an individual patient,” Dr. Gradishar commented.

Anti-HER2 therapy

The guidelines state that patients with HER2-positive tumors should receive neoadjuvant systemic therapy with trastuzumab (Herceptin) for at least 9 weeks prior to surgery. For patients with stage T2 or greater or nodal status N1 or greater HER2-positive disease, a pertuzumab (Perjeta)-containing regimen may be considered.

Recurrent/Stage IV disease

Premenopausal women with recurrent or stage IV hormone receptor–positive disease should have ovarian ablation or suppression, and then be treated with a regimen for postmenopausal women, the guidelines say. Agents used in therapy for advanced disease have included a nonsteroidal or steroidal AI, a combination of exmestane and everolimus, palbociclib (Ibrance) plus letrozole (Femara), palbociclib plus fulvestrant, tamoxifen, or toremafine, megesterol acetate fluoxymesterone, or ethinyl estradiol.

The updated guidelines note that “a single study (S0226) in women with hormone receptor–positive breast cancer and no prior chemotherapy, biological therapy, or endocrine therapy for metastatic disease demonstrated that the addition of fulvestrant to anastrozole resulted in prolongation of time to progression. Subset analysis suggested that patients without prior adjuvant tamoxifen and more than 10 years since diagnosis experienced the greatest benefit. Two studies with similar design (FACT and SOFEA) demonstrated no advantage in time to progression with the addition of fulvestrant to anastrozole.”

Chemotherapy regimens for recurrent/metastatic breast cancer include various combination regimens, as well as single-agent therapy with anthracyclines, taxanes, antimetabolites, or microtubule inhibitors (all of the above preferred single agents), or with cyclophosphamide, carboplatin, docetaxel, albumin-bound paclitaxel, cisplatin, epirubicin, or ixabepilone.

For HER2-positive disease, preferred agents include pertuzumab and trastuzumab with either docetaxel (category 1 recommendation) or paclitaxel. Trastuzumab can also be combined with other agents such as paclitaxel with or without cisplatin, docetaxel, vinorelbine, or capecitabine.

For patients with recurrent HER2-positve disease with prior trastuzumab exposure, combinations may include lapatinin with capecitabine, or trastuzumab with capecitabine, lapatinib (without cytoxic therapy), or other agents.

Fertility preservation

Lastly, the revised guidelines note that all premenopausal patients should be informed about the potential effects of chemotherapy on fertility, with women who express the wish to have future pregnancies referred to fertility specialists. The options presented should be “based on patient specifics, disease stage, and biology (which determine the urgency and type and sequence of treatment). Timing and duration allowed for fertility preservation, options inclusive of oocyte and embryo cryopreservation as well as evolving technologies, and the probability of successful pregnancies subsequent to completion of breast cancer therapy are also to be discussed,” the guidelines say.