Selection of Optimal Adjuvant Chemotherapy and Targeted Therapy for Early Breast Cancer
Publication Date: May 20, 2024
Last Updated: May 20, 2024
Key Points
Key Points
- Adjuvant chemotherapy improves disease-free survival (DFS) and overall survival (OS) independent of age, nodal status, and estrogen receptor (ER) status.
- However, those with triple-negative and human epidermal growth factor receptor 2 (HER2)–positive breast cancer seem to derive the greatest proportional benefit from systemic chemotherapy and biologic therapy.
- The potential benefits and risks need to be carefully weighed before rendering a decision to administer chemotherapy.
- Comorbidities and burden of disease need to be considered for selection of optimal regimens.
Treatment
Treatment
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 2024 Guideline Rapid Recommendation Update
Abemaciclib for 2 years plus ET for ≥ 5 years may be offered to patients meeting the criteria of the ITT monarchE population with resected, hormone receptor-positive, HER2-negative, node-positive, early breast cancer at high risk of recurrence, defined as having ≥4 positive axillary lymph nodes (ALNs) or as having 1-3 positive ALNs plus at least one of the following features: grade 3 disease, tumor size ≥5 cm, or Ki-67 index ≥20%. Although the FDA’s language is broad, the Panel promotes the use of abemaciclib primarily in those who would have been eligible for monarchE based on that trial’s eligibility criteria. (, , H, S)
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The Panel recommends, based on the phase III NATALEE trial, that adjuvant ribociclib (400 mg once daily, 3 weeks on followed by 1 week off) for 3 years plus ET may be offered to patients with anatomic stage II or III breast cancer who would have met criteria for study entry and have a high risk of recurrence. (, , H, C)
Qualifying statements for Recommendations 1 and 2 on the use of adjuvant abemaciclib and ribociclib:
The Panel believes that adjuvant CDK4/6 inhibitor therapy may not provide meaningful clinical benefit to all patients who would have been eligible for the available trials, especially the lower-risk patients who were included in the NATALEE trial. For example, for most patients with node-negative disease, the risks of ribociclib may outweigh the benefits, with the exception of some patients with the highest risk, node-negative disease. However, the Panel acknowledges that there are insufficient data to specify which subgroups of patients do or do not warrant therapy. The Panel thus recommends considering the benefits, risks, costs, and preferences for each individual patient when deciding whether to recommend therapy.
Among patients meeting criteria for both monarchE and NATALEE, the Panel also notes that, of the two CDK4/6 inhibitors, abemaciclib has longer follow-up, a deepening benefit over time, a shorter duration of therapy, and FDA approval in the adjuvant setting. In this case, the Panel favors using abemaciclib, reserving use of ribociclib in patients who have a contraindication to (e.g., pre-existing high-grade diarrhea) or intolerance of abemaciclib. The Panel characterized the strength of the ribociclib recommendation as conditional, pending future efficacy data and regulatory updates. Although a formal cost-effectiveness analysis was out of scope for this update, it could be informative for some decision-makers considering the costs of both medications. Results from longer-term follow-up will further inform adjuvant therapy decision-making
The Panel believes that adjuvant CDK4/6 inhibitor therapy may not provide meaningful clinical benefit to all patients who would have been eligible for the available trials, especially the lower-risk patients who were included in the NATALEE trial. For example, for most patients with node-negative disease, the risks of ribociclib may outweigh the benefits, with the exception of some patients with the highest risk, node-negative disease. However, the Panel acknowledges that there are insufficient data to specify which subgroups of patients do or do not warrant therapy. The Panel thus recommends considering the benefits, risks, costs, and preferences for each individual patient when deciding whether to recommend therapy.
Among patients meeting criteria for both monarchE and NATALEE, the Panel also notes that, of the two CDK4/6 inhibitors, abemaciclib has longer follow-up, a deepening benefit over time, a shorter duration of therapy, and FDA approval in the adjuvant setting. In this case, the Panel favors using abemaciclib, reserving use of ribociclib in patients who have a contraindication to (e.g., pre-existing high-grade diarrhea) or intolerance of abemaciclib. The Panel characterized the strength of the ribociclib recommendation as conditional, pending future efficacy data and regulatory updates. Although a formal cost-effectiveness analysis was out of scope for this update, it could be informative for some decision-makers considering the costs of both medications. Results from longer-term follow-up will further inform adjuvant therapy decision-making
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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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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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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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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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Acceptable Adjuvant Chemotherapy Regimens for Patients with Higher-Risk Early Breast Cancer
These adjuvant chemotherapy regimens can be used for patients with early breast cancer:
- Fluorouracil-epirubicin-cyclophosphamide × 3 → docetaxel × 3 (superior to fluorouracil-epirubicin-cyclophosphamide x 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
- Dose-dense epirubicin 90 mg/m2, cyclophosphamide 600 mg/m2 every 2 weeks × 4 → paclitaxel 175 mg/m2 every 2 weeks × 4
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
Abbreviations
- ASCO: American Society Of Clinical Oncology
- CCO: Cancer Care Ontario
- DFS: Disease-free Survival
- ER: Estrogen Receptor
- HER2: Human Epidermal Growth Factor Receptor 2
- IV: Intravenous
- OS: Overall Survival
- TAILORx: Trial Assigning Individualized Options For Treatment
Source Citation
Freedman RA, Caswell-Jin J, Hassett M, et al. Optimal Adjuvant Chemotherapy and Targeted Therapy for Early Breast Cancer – CDK4/6 Inhibitors: ASCO Rapid Guideline Update. J Clin Oncol. 2024 May 20. doi: 10.1200/JCO.24.00886
Giordano SH, Freedman RA, and Somerfield MR. Abemaciclib with Endocrine Therapy in the Treatment of High-Risk Early Breast Cancer: ASCO Optimal Adjuvant Chemotherapy and Targeted Therapy Guideline Rapid Recommendation Update. J Clin Oncol. 2022 Jan 20;40(3):307-309
Denduluri N, Somerfield MR, Chavez-MacGregor M, et al. Selection of Optimal Adjuvant Chemotherapy and Targeted Therapy for Early Breast Cancer: ASCO Guideline Update. J Clin Oncol. 2021 Feb 20;39(6):685-693.
Denduluri N, Chavez-MacGregor M, Telli ML, et al. Selection of Optimal Adjuvant Chemotherapy and Targeted Therapy for Early Breast Cancer: ASCO Clinical Practice Guideline Focused Update. J Clin Oncol. 2018;36(23):2433-2443.
Denduluri N, Somerfield MR, Eisen A, et al. Selection of Optimal Adjuvant Chemotherapy Regimens for Human Epidermal Growth Factor Receptor 2 (HER2)-Negative and Adjuvant Targeted Therapy for HER2-Positive Breast Cancers: An American Society of Clinical Oncology Guideline Adaptation of the Cancer Care Ontario Clinical Practice Guideline. J Clin Oncol. 2016 Jul 10;34(20):2416-2427.
Eisen A, Fletcher GG, Gandhi S, et al. Optimal systemic therapy for early breast cancer in women: A clinical practice guideline. Curr Oncol. 22:S67-S81, 2015 (suppl 1).
Disclaimer
This pocket guide is derived from recommendations in the American Society of Clinical Oncology Guideline. This resource is a practice tool based on ASCO® practice guidelines and is not intended to substitute for the independent professional judgment of the treating physician. Practice guidelines do not account for individual variation among patients. This pocket guide does not purport to suggest any particular course of medical treatment. Use of the practice guidelines and this resource are voluntary. The practice guidelines and additional information are available at www.asco.org/breast-cancer-guidelines. Copyright © 2024 by American Society of Clinical Oncology. All rights reserved.
Codes
CPT Codes
| Code | Descriptor |
|---|---|
| 21601 | Excision of chest wall tumor including rib(s) |
| 81162 | BRCA1 (BRCA1 |
| 0009U | Oncology (breast cancer) |
| 0132U | Hereditary ovarian cancer-related disorders (eg |
| 0546T | Radiofrequency spectroscopy |
| 96413 | Chemotherapy administration, intravenous infusion technique; up to 1 hour, single or initial substance/drug |
| 0134U | Hereditary pan cancer (eg |
| 81163 | BRCA1 (BRCA1 |
| 86300 | Immunoassay for tumor antigen |
| 81216 | BRCA2 (BRCA2 |
| 86316 | Immunoassay for tumor antigen |
| 81308 | PALB2 (partner and localizer of BRCA2) (eg, breast and pancreatic cancer) gene analysis; known familial variant |
| 81164 | BRCA1 (BRCA1 |
| 81522 | Oncology (breast) |
| 81277 | Cytogenomic neoplasia (genome-wide) microarray analysis |
| 0131U | Hereditary breast cancer-related disorders (eg |
| 81519 | Oncology (breast) |
| 0135U | Hereditary gynecological cancer (eg |
| 81165 | BRCA1 (BRCA1 |
| 81309 | PIK3CA (phosphatidylinositol-4 |
| 0581T | Ablation |
| 82378 | Carcinoembryonic antigen (CEA) |
| 96415 | Chemotherapy administration, intravenous infusion technique each additional hour (List separately in addition to code for primary procedure) |
| 0137U | PALB2 (partner and localizer of BRCA2)(eg, breast and pancreatic cancer) mRNA sequence analysis (List separately in addition to code for primary procedure) |
| 81217 | BRCA2 (BRCA2 |
| 83950 | Oncoprotein; HER-2/neu |
| 81520 | Oncology (breast) |
| 81166 | BRCA1 (BRCA1 |
| 81167 | BRCA2 (BRCA2 |
| 81521 | Oncology (breast) |
| 81215 | BRCA1 (BRCA1 |
| 81307 | PALB2 (partner and localizer of BRCA2) (eg, breast and pancreatic cancer) gene analysis; full gene sequence |
| 21603 | Excision of chest wall tumor involving rib(s) |
| 0138U | BRCA1 (BRCA1 |
| 88361 | Morphometric analysis |
| 81212 | BRCA1 (BRCA1 |
| 88360 | Morphometric analysis |
| 21602 | Excision of chest wall tumor involving rib(s) |
ICD-10 Codes
| Code | Descriptor | Documentation Concepts | Quality/Performance |
|---|---|---|---|
| C50.511 | Malignant neoplasm of lower-outer quadrant of right female breast | Morphology Anatomy Gender Localization/Laterality Estrogen receptor status | HCC12, RXHCC19 |
| C50.911 | Malignant neoplasm of unspecified site of right female breast | Morphology Anatomy Gender Localization/Laterality Estrogen receptor status | HCC12, RXHCC19 |
| C50.111 | Malignant neoplasm of central portion of right female breast | Morphology Anatomy Gender Localization/Laterality Estrogen receptor status | HCC12, RXHCC19 |
| Z17.0 | Estrogen receptor positive status [ER+] | ||
| C50.311 | Malignant neoplasm of lower-inner quadrant of right female breast | Morphology Anatomy Gender Localization/Laterality Estrogen receptor status | HCC12, RXHCC19 |
| Z17.1 | Estrogen receptor negative status [ER-] |