Selection of Optimal Adjuvant Chemotherapy and Targeted Therapy for Early Breast Cancer

Publication Date: December 21, 2021

Recommendations

Patients with HER2-positive breast cancer with pathologic invasive residual disease at surgery following standard preoperative chemotherapy and HER2-targeted therapy should be offered 14 cycles of adjuvant trastuzumab emtansine (T-DM1) unless there is disease recurrence or unmanageable toxicity. (EB, B, H, S)
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Clinicians may offer any of the available and approved formulations of trastuzumab, including trastuzumab, trastuzumab and hyaluronidase-oysk, and available biosimilars. (EB, B, H, S)
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New Recommendations from 2021 Guideline Rapid Recommendation Update

Based on a secondary pre-defined analysis conducted by the FDA (https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/208716s006s007s008lbl.pdf), two years of abemaciclib (150 mg twice daily) plus ET may be offered to patients with HR-positive, HER2-negative, node-positive early breast cancer with a high risk of recurrence and a Ki-67 score of ≥20% as determined by an FDA-approved test. (EB, B, M, S)
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The Panel also recommends, based on analyses reported by Harbeck N, et al. that abemaciclib for two years plus ET for ≥5 years may be offered to the broader intent-to-treat population of patients with resected, HR-positive, HER2-negative, node-positive, early breast cancer at high risk of recurrence, defined as having ≥4 positive axillary lymph nodes, or as having 1–3 positive axillary lymph nodes and one or more of the following features: histologic grade 3 disease, tumor size >5 cm, or Ki-67 index ≥20%. (EB, B, M, S)
Qualifying Statements: Although exploratory analyses suggested similar HRs in favor of abemaciclib regardless of Ki-67 status, there were relatively few Ki-67 low tumors in monarchE. When discussing treatment options with patients, the potential benefits (improved IDFS) should be weighed against the potential harms (treatment toxicity, financial cost)
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Use of an Anthracycline-Taxane Regimen

In patients who can tolerate it, use of a regimen containing anthracycline-taxane is considered the optimal strategy for adjuvant chemotherapy, particularly for patients deemed to be at high risk.* (, , , )
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Optimal-Dose Anthracycline Regimen for Patients for Whom a Taxane Is Contraindicated

For patients with high-risk disease who will not receive a taxane, an optimal-dose anthracycline three-drug regimen (cumulative dose of doxorubicin ≥240 mg/m2 or epirubicin ≥600 mg/m2 but ≤720 mg/m2) that contains cyclophosphamide is recommended. The cumulative dose of doxorubicin in two-drug regimens should not exceed 240 mg/m2. (, , , )
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Adding Gemcitabine or Capecitabine to an Anthracycline-Taxane Regimen

The addition of gemcitabine or capecitabine to an anthracycline-taxane regimen is NOT recommended for adjuvant chemotherapy.* (, , , )
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Capecitabine in Patients Age ≥65 Years

In patients age ≥65 years, capecitabine is NOT recommended as an adjuvant chemotherapy option in lieu of standard regimens such as doxorubicin-cyclophosphamide or cyclophosphamide-methotrexate-fluorouracil (with oral cyclophosphamide). (, , , )
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Cyclophosphamide-Methotrexate-Fluorouracil As an Alternative To Doxorubicin-Cyclophosphamide

For patients in whom anthracycline-taxane is contraindicated, cyclophosphamide-methotrexate-fluorouracil (with oral cyclophosphamide) is an acceptable chemotherapy alternative to doxorubicin-cyclophosphamide.
  • Of note, the ASCO Panel recommends classic cyclophosphamide-methotrexate- fluorouracil (oral cyclophosphamide days 1–14 with intravenous [IV] methotrexate-fluorouracil days 1 and 8, repeated once every 28 days for six cycles) as the default adjuvant cyclophosphamide-methotrexate-fluorouracil regimen.
  • However, the Panel also recognizes that an all-IV cyclophosphamide-methotrexate-fluorouracil regimen once every 21 days is often used in clinical practice and was accepted by some clinical trials (eg, TAILORx; Trial Assigning Individualized Options for Treatment [Rx]) on the basis of convenience and tolerability despite the absence of efficacy data from randomized controlled trials.
(, , , )
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Adjuvant Regimen When an Anthracycline Is Not Preferred

Docetaxel-cyclophosphamide x 4 is recommended as an alternative to doxorubicin-cyclophosphamide x 4 and offers improved disease-free survival and overall survival. Classic cyclophosphamide-methotrexate-fluorouracil with oral cyclophosphamide for six cycles is another option.
  • As mentioned before, the ASCO Panel recommends classic cyclophosphamide-methotrexate-fluorouracil (oral cyclophosphamide days 1–14 with IV methotrexate-fluorouracil days 1 and 8, repeated once every 28 days for six cycles) as the default adjuvant cyclophosphamide-methotrexate-fluorouracil regimen.
(, , , )
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  • However, the Panel also recognizes that an all-IV cyclophosphamide-methotrexate-fluorouracil regimen once every 21 days is often used in clinical practice and was accepted by some clinical trials (eg, TAILORx) on the basis of its convenience and tolerability despite the absence of efficacy data from randomized controlled trials.
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Patient Selection and Adjuvant Trastuzumab Therapy

Only 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]) should be offered adjuvant trastuzumab. (, , , )
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Trastuzumab Plus Chemotherapy in Patients with Higher-Risk HER2-Positive Disease

Trastuzumab plus chemotherapy is recommended for all patients with HER2-positive, node-positive breast cancer and for patients with HER2-positive, node-negative breast cancer (>1 cm).* (, , , )
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Trastuzumab Plus Chemotherapy in Patients with HER2-Positive T1a-B N0 Disease

Trastuzumab therapy can be considered in small, node-negative tumors (≤1 cm). (, , , )
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Selection of Chemotherapy Regimens in Patients Receiving Trastuzumab

Trastuzumab can be administered with any acceptable adjuvant chemotherapy regimen.* (, , , )
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Use of Trastuzumab and an Anthracycline-Containing Regimen

The administration of trastuzumab concurrently with the anthracycline component of a chemotherapy regimen is NOT recommended because of the potential for increased cardiotoxicity. (, , , )
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Concurrent Administration of Adjuvant Trastuzumab and Non-Anthracycline Chemotherapy Regimens

Trastuzumab should be preferentially administered concurrently (not sequentially) with a non-anthracycline chemotherapy regimen. (, , , )
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Trastuzumab-Based Chemotherapy or Trastuzumab Regimens For Patients at Higher Risk of Cardiotoxicity

Less cardiotoxicity is seen with docetaxel-carboplatin-trastuzumab than with doxorubicin-cyclophosphamide → docetaxel-trastuzumab, and docetaxel-carboplatin-trastuzumab is recommended for patients at higher risk for cardiotoxicity.* (, , , )
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Addition of Trastuzumab to Chemotherapy Regimens Not Evaluated in a Phase III Trial

No phase III evidence exists for the addition of trastuzumab to some chemotherapy regimens, such as docetaxel-cyclophosphamide. However, those regimens might be in use and are reasonable options, particularly for mitigating cardiotoxicity in certain patients.* (, , , )
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Duration of Trastuzumab Therapy and Cardiac Function

Patients should be offered 1 year total of adjuvant trastuzumab with regular assessments of cardiac function during that period.* (, , , )
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Adjuvant Capecitabine

Patients with early stage HER2-negative breast cancer with pathologic invasive residual disease at surgery following standard anthracycline and taxane-based preoperative therapy may be offered up to 6–8 cycles of adjuvant capecitabine. (EB, B, I, M)
Qualifying Statements: If clinicians decide to use capecitabine, then the Expert Panel preferentially supports the use of adjuvant capecitabine in the hormone receptor-negative, HER2-negative patient subgroup. The capecitabine dose used in the CREATE-X study (1250mg/m2 twice daily) is associated with higher toxicity in patients ≥ 65 years old.
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Adjuvant Pertuzumab

Clinicians may add one year of adjuvant pertuzumab to trastuzumab-based combination chemotherapy in patients with early-stage, HER2-positive breast cancer. (EB, B, H, M)
Qualifying Statements: The Expert Panel preferentially supports pertuzumab in the node-positive, HER2-positive population, in view of the clinically insignificant absolute benefit observed among node-negative patients. After a median follow-up of 3.8 years, pertuzumab was found to offer a modest disease-free survival benefit; the first planned interim analysis did not show an overall survival benefit. There are no data to guide the duration of pertuzumab in patients who received neoadjuvant pertuzumab and achieved a pathologic complete response.
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Adjuvant Neratinib

Clinicians may use extended adjuvant therapy with neratinib in patients with early-stage, HER2-positive breast cancer. (EB, B, H, M)
Note: Neratinib causes substantial diarrhea, and diarrhea prophylaxis must be used. Qualifying Statements. The Expert Panel preferentially favors use of neratinib in hormone receptor-positive and node-positive patients. At 5.2-year follow-up, no OS benefit has been observed. Patients who began neratinib within one year of trastuzumab completion appeared to derive the greatest benefit. There are no data on the added benefit of neratinib in patients who also received pertuzumab in the neoadjuvant or adjuvant setting.
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NOTE: Recommendations identified by an asterisk (*) are taken verbatim from the Cancer Care Ontario [CCO] guideline. Otherwise, recommendations have been substantively adapted or reworded for clarity by the American Society of Clinical Oncology [ASCO] Panel.

Recommendation Grading

Disclaimer

Overview

Title

Selection of Optimal Adjuvant Chemotherapy and Targeted Therapy for Early Breast Cancer

Authoring Organization

Publication Month/Year

December 21, 2021

Document Type

Guideline

External Publication Status

Published

Country of Publication

US

Inclusion Criteria

Female, Adult, Older adult

Health Care Settings

Ambulatory, Emergency care, Hospital, Long term care

Intended Users

Social worker, nurse, nurse practitioner, physician, physician assistant

Scope

Treatment, Management

Diseases/Conditions (MeSH)

D000072656 - Breast Cancer Lymphedema

Keywords

breast cancer, neoadjuvant chemotherapy, Adjuvant chemotherapy, Targeted Therapy

Supplemental Methodology Resources

Data Supplement, Evidence Tables

Methodology

Number of Source Documents
73
Literature Search Start Date
January 1, 2018
Literature Search End Date
February 19, 2020