ASCO GUIDELINES FOR ADJUVANT TREATMENT OF BREAST CANCER

For the first time, the American Society of Clinical Oncology (ASCO) has issued comprehensive clinical guidelines on adjuvant chemotherapy for early breast cancer and targeted adjuvant therapy for HER2-positive breast cancer.

The guidelines are largely adapted from the 2015 Cancer Care Ontario (CCO) clinical practice guidelines, with some additional guidance from ASCO. They were published online on April 18 in the Journal of Clinical Oncology.

"We adapted the Canadian guidelines because they were very comprehensive," said first author Neelima Denduluri, MD, chair-elect of the ASCO Clinical Practice Guideline Committee, and associate chair of the US Oncology Breast Research Committee.

"I don't know that there's much discordance between any of the guidelines we're talking about today, whether it's the Ontario guidelines, NCCN, or ASCO. They're all fairly similar on this particular topic," agreed William Gradishar, MD, from the Robert H. Lurie Comprehensive Cancer Center of Northwestern University in Chicago and chair of the National Comprehensive Cancer Network Guidelines panel for breast cancer.

Agreement across the various guidelines is "encouraging" and a "fundamental message" of the ASCO guidelines because it "reflects a standard that everyone has and accepts," he told Medscape Medical News.

Anthracycline- and taxane-based regimens are the standard of care for patients with high-risk HER2-negative disease and excellent performance status. Acceptable nonanthracycline regimens include four cycles of docetaxel and cyclophosphamide.

In high-risk HER2-positive disease, the guidelines recommend sequential anthracycline and taxanes given concurrently with trastuzumab or docetaxel, carboplatin, and trastuzumab for six cycles. An alternative for lower-risk node-negative HER2-positive disease is paclitaxel and trastuzumab in combination once weekly for 12 weeks, with trastuzumab then given for 1 year.

A significant adaptation concerns trastuzumab in small HER2-positive tumors. The CCO guidelines say that patients with these tumors should only receive trastuzumab as part of a trial, but data published since the CCO guidelines were developed provide support for the fact that trastuzumab improves mortality. "I think we have enough data that say we should definitely give trastuzumab in the smaller HER2-positive tumors, especially the 1 to 2 cm tumors, and it should be an individualized decision in the very small tumors," Dr Denduluri told Medscape Medical News. "Adjuvant trastuzumab needs to be an individualized decision in consideration of the whole picture of the patient, such as comorbidities and number of tumor foci," she added. The guidelines also include special considerations for two gray areas in medical research: platinum salts and pertuzumab. The question of whether platinum-based regimens should be used as a standard component of adjuvant regimens in triple-negative disease stems from inconsistent data. "Routine use of carboplatin in the adjuvant setting is not established. We know that it does improve pathologic complete response in various studies, but we don't yet have consistent data suggesting an improvement in survival. We are awaiting results from large randomized trials," Dr Denduluri reported. Although the ASCO guidelines do not recommend the routine use of carboplatin in triple-negative disease, they remain ambiguous about the routine use of pertuzumab. In 2013, the US Food and Drug Administration gave accelerated approval for up to six cycles of pertuzumab in the adjuvant treatment of early-stage breast cancer in the preoperative setting. Confirmation of this approach will come from the APHINITY trial, which is looking at the safety and efficacy of pertuzumab for 1 year after surgery. "Everyone's waiting for the data to mature from the very large randomized APHINITY trial. Once that trial is reported, we'll be able to say definitively whether adjuvant pertuzumab has a role for all patients with HER2-positive disease," Dr Gradishar said. The guidelines also specifically mention that life expectancy and geriatric assessment tools should be used when making decisions about adjuvant therapy in older patients. To develop the guidelines, ASCO convened an expert panel that followed ASCO guidelines for adapting certain recommendations according to the local context and clinical practice experience of panel members. ASCO also updated the CCO literature search, originally conducted for articles published from January 2008 to March 2012, to include randomized controlled trials, meta-analyses, and systematic reviews published in English since the completion of the CCO guidelines. Recommendations Taken Verbatim From the CCO Guidelines Anthracycline–taxane regimens are the optimal strategy for adjuvant chemotherapy in patients who can tolerate them, especially high-risk patients. Adding gemcitabine or capecitabine to an anthracycline–taxane regimen is not recommended. Trastuzumab plus chemotherapy is recommended for all patients with HER2-positive node-positive breast cancer and for patients with HER2-positive node-negative breast tumors over 1 cm. Trastuzumab can be administered with any acceptable adjuvant chemotherapy regimen. Docetaxel–trastuzumab, and docetaxel–carboplatin–trastuzumab are recommended for patients at higher risk for cardiotoxicity; docetaxel–carboplatin–trastuzumab has less cardiotoxicity than doxorubicin–cyclophosphamide. No phase 3 evidence exists for adding trastuzumab to some chemotherapy regimens, like docetaxel–cyclophosphamide. Such regimens might already be in clinical use and represent reasonable options, especially for decreasing cardiotoxicity. Patients should be offered 1 year total of adjuvant trastuzumab; cardiac function should be regularly assessed during that time period. Recommendations Adapted From the CCO Guidelines In patients with high-risk disease and when a taxane is contraindicated, the optimal dose of an anthracycline three-drug regimen that contains cyclophosphamide is recommended, with a cumulative dose of doxorubicin ≥240 mg/m² or epirubicin ≥600 mg/m², but no higher than 720 mg/m². The cumulative dose of doxorubicin in two-drug regimens should not exceed 240 mg/m². Capecitabine is not recommended as adjuvant chemotherapy in patients 65 years and older in lieu of standard regimens, like doxorubicin–cyclophosphamide or oral cyclophosphamide–methotrexate–fluorouracil. If anthracycline–taxane is contraindicated, oral cyclophosphamide–methotrexate–fluorouracil is acceptable as an alternative to doxorubicin–cyclophosphamide.   The default adjuvant cyclophosphamide–methotrexate–fluorouracil regimen should be classic cyclophosphamide–methotrexate–fluorouracil (oral cyclophosphamide on days 1 to 14 with intravenous [IV] methotrexate–fluorouracil on days 1 and 8, repeated once every 28 days for six cycles).   An all-IV cyclophosphamide–methotrexate–fluorouracil regimen once every 21 days is often used in clinical practice and has been accepted by some clinical trials, such as TAILORx (Trial Assigning Individualized Options for Treatment), because of convenience and tolerability, even though efficacy data from randomized controlled trials remain to be seen. Acceptable adjuvant chemotherapy regimens for patients with higher-risk early breast cancer:   Fluorouracil–epirubicin–cyclophosphamide × 3 → docetaxel × 3 (superior to fluorouracil–epirubicin–cyclophosphamide × 6)   Doxorubicin–cyclophosphamide × 4 → docetaxel × 4 (superior to doxorubicin cyclophosphamide × 4)   Docetaxel–doxorubicin–cyclophosphamide × 6 (superior to fluorouracil–doxorubicin–cyclophosphamide × 6)   Doxorubicin–cyclophosphamide × 4 → paclitaxel administered once per week   Dose-dense doxorubicin–cyclophosphamide → paclitaxel administered once every 2 weeks Adjuvant regimens when an anthracycline is not preferred:       Docetaxel–cyclophosphamide × 4 is an alternative to doxorubicin–cyclophosphamide × 4 and offers improved disease-free survival and overall survival   Classic cyclophosphamide–methotrexate–fluorouracil with oral cyclophosphamide for six cycles is another option   The default adjuvant cyclophosphamide–methotrexate–fluorouracil regimen should be classic cyclophosphamide–methotrexate–fluorouracil (oral cyclophosphamide on days 1 to 14 with IV methotrexate–fluorouracil on days 1 and 8, repeated once every 28 days for six cycles)       An all-IV cyclophosphamide–methotrexate–fluorouracil regimen once every 21 days is often used in clinical practice and has been accepted by some clinical trials, such as TAILORx, because of convenience and tolerability, even though efficacy data from randomized controlled trials remain to be seen Adjuvant trastuzumab should be offered only to patients with HER2-positive breast cancer (overexpressed based on immunohistochemistry [3+] or amplified based on in situ hybridization [ratio ≥2.0 or average HER2 copy number ≥6.0]). Trastuzumab plus chemotherapy can be considered in small node-negative HER2-positive tumors ≤1 cm. Giving trastuzumab at the same time as the anthracycline component of a chemotherapy regimen is not recommended because of possible increased cardiotoxicity. Trastuzumab should be given at the same time as a nonanthracycline chemotherapy regimen, not sequentially.