SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. It is estimated that approximately 290,560 new cases of breast cancer were diagnosed in 2022 and about 43,780 individuals died of the disease, largely due to metastatic recurrence.
Adjuvant or postoperative systemic therapy is the mainstay of treatment for early-stage breast cancer, to eradicate micrometastatic disease and reduce the likelihood of metastatic disease. Neoadjuvant refers to the use of systemic therapy prior to surgery. Neoadjuvant therapy was initially used in breast cancer for the treatment of inoperable, locally advanced disease. Subsequently, multiple studies of both chemotherapy and endocrine therapy have shown that neoadjuvant treatment can increase the likelihood of breast-conserving surgery, reduce the extent and morbidity of curative surgery, establishing neoadjuvant treatment as a viable option in patients with operable disease. Further, interest in neoadjuvant therapy has focused on examining the role of response to neoadjuvant treatment as a predictive marker for benefit in long term outcomes.
ASCO convened an Expert Panel to conduct a systematic review of the literature on neoadjuvant therapy for breast cancer and the purpose of this guideline is to develop recommendations concerning the optimal use of systemic neoadjuvant therapy, including chemotherapy, endocrine therapy, and targeted therapy for patients with invasive breast cancer.
Guideline Question
What is the optimal use of neoadjuvant therapy for women with invasive, nonmetastatic breast cancer?
CLINICAL QUESTION 1
Which patients with breast cancer are appropriate candidates for neoadjuvant systemic therapy?
Recommendation 1.1.
Neoadjuvant chemotherapy is the treatment of choice for patients with inflammatory breast cancer or those with unresectable or locally advanced disease at presentation whose disease may be rendered resectable with neoadjuvant treatment
Recommendation 1.2.
Tumor histology, grade, stage and estrogen, progesterone, and HER2 expression should routinely be used to guide clinical decisions as to whether or not to pursue neoadjuvant chemotherapy. There is insufficient evidence to support the use of other immunochemical markers, morphological markers (eg, tumor-infiltrating lymphocytes) or genomic profiles to guide a clinical decision as to whether or not to pursue neoadjuvant chemotherapy
Recommendation 1.3.
Neoadjuvant systemic therapy should be offered to patients with high-risk HER2-positive or triple-negative breast cancer (TNBC) in whom the finding of residual disease would guide recommendations related to adjuvant therapy
Recommendation 1.4.
Neoadjuvant systemic therapy may be offered to reduce the extent of surgery (breast-conserving surgery and axillary lymph node dissection). Chemotherapy with or without targeted therapy, or endocrine therapy (if hormone receptor–positive [HR-positive]) may be offered
Recommendation 1.5.
In patients for whom a delay in surgery is preferable (eg, for genetic testing required for surgical treatment decision making, to allow time to consider reconstructive options) or unavoidable, neoadjuvant systemic therapy may be offered
CLINICAL QUESTION 2
How should response be measured in patients receiving neoadjuvant chemotherapy?
Recommendation 2.1.
Patients receiving neoadjuvant therapy should be monitored for response with clinical examination at regular intervals. Breast imaging may be used to confirm clinical suspicion of progression and for surgical planning. When imaging is used, the modality that was most informative at baseline-mammography, ultrasound, or magnetic resonance imaging—should be used at follow-up
Recommendation 2.2.
Blood- and tissue-based biomarkers should not be used for monitoring patients receiving neoadjuvant therapy
Recommendation 2.3.
Pathologic complete response (pCR), defined as absence of invasive disease in breast and lymph nodes, should be used to measure response to guide clinical decision making
CLINICAL QUESTION 3
What neoadjuvant treatment is recommended for patients with HR-positive/HER2-negative breast cancer?
Recommendation 3.1.
Neoadjuvant chemotherapy can be used instead of adjuvant chemotherapy in any patient with HR-positive, HER2-negative breast cancer in whom the chemotherapy decision can be made without surgical pathology data and/or tumor-specific genomic testing
Recommendation 3.2.
For postmenopausal patients with HR-positive/HER2-negative disease, neoadjuvant endocrine therapy with an aromatase inhibitor may be offered to increase locoregional treatment options. If there is no intent for surgery, endocrine therapy may be used for disease control
Recommendation 3.3.
For premenopausal patients with HR-positive/HER2-negative early-stage disease, neoadjuvant endocrine therapy should not be routinely offered outside of a clinical trial (Type: evidence-based; benefits outweigh harms; Evidence quality: intermediate; Strength of recommendation: moderate).
CLINICAL QUESTION 4
What neoadjuvant treatment is recommended for patients with HER2-positive disease?
Recommendation 4.1.
Patients with node-positive or high-risk node-negative, HER2-positive disease should be offered neoadjuvant therapy with an anthracycline and taxane or non–anthracycline-based regimen in combination with trastuzumab. Pertuzumab may be used with trastuzumab in the neoadjuvant setting
Recommendation 4.2.
Patients with T1a N0 and T1b N0, HER2-positive disease should not be routinely offered neoadjuvant chemotherapy or anti-HER2 agents outside of a clinical trial
CLINICAL QUESTION 5
What neoadjuvant systemic therapy regimens are recommended for patients with TNBC?
Recommendation 5.1.
Patients with TNBC who have clinically node-positive and/or at least T1c disease should be offered an anthracycline and taxane-containing regimen in the neoadjuvant setting
Recommendation 5.2.
Patients with cT1a or cT1bN0 TNBC should not routinely be offered neoadjuvant therapy outside of a clinical trial
Recommendation 5.3.
Carboplatin may be offered as part of a neoadjuvant regimen in patients with TNBC to increase likelihood of pCR. The decision to offer carboplatin should take into account the balance of potential benefits and harms
Recommendation 5.4. (UPDATED ASCO RECOMMENDATION FROM 2022: GUIDELINE RAPID RECOMMENDATION UPDATE)
For patients with T1cN1-2 or T2-4N0 (stage II or III), early-stage TNBC, the Panel recommends use of pembrolizumab (200 mg once every 3 weeks or 400 mg once every 6 weeks) in combination with neoadjuvant chemotherapy, followed by adjuvant pembrolizumab after surgery. Adjuvant pembrolizumab may be given either concurrent with or after completion of radiation therapy. Given that irAEs associated with pembrolizumab therapy can be severe and permanent, careful screening for and management of common toxicities are required.
The guideline panel addressed some of the questions that clinicians may encounter as they incorporate these recommendations into clinical practice.
QUESTION: SHOULD PEMBROLIZUMAB BE CONTINUED IN PATIENTS WHO ACHIEVE pCR AFTER NEOADJUVANT CHEMOTHERAPY PLUS PEMBROLIZUMAB?
The panel supports continuation of pembrolizumab in the adjuvant setting in all patients while awaiting data from other trials addressing this question.
QUESTION: CAN A CHEMOTHERAPY REGIMEN DIFFERENT FROM THE ONE USED IN KEYNOTE-522 BE USED WITH PEMBROLIZUMAB?
The panel supports the use of the full KEYNOTE-522 regimen. However, if a patient experiences toxicity, it is not unreasonable to dose reduce or discontinue the drug. In patients with TNBC who have contraindications to anthracycline therapy and are being considered for regimens such as docetaxel and cyclophosphamide, it would be reasonable to add pembrolizumab to their regimen.
QUESTION: SHOULD ADJUVANT CAPECITABINE BE ADMINISTERED WITH PEMBROLIZUMAB IN PATIENTS WHO FAIL TO ACHIEVE pCR WITH PEMBROLIZUMAB-BASED NEOADJUVANT THERAPY?
Patients with TNBC who have residual disease after neoadjuvant chemotherapy are currently offered adjuvant capecitabine chemotherapy on the basis of improved survival shown in CREATE-X trial. It is reasonable to administer capecitabine concurrently or sequentially in patients at high risk of recurrence although the long-term safety of this combination is not known.
QUESTION: SHOULD OLAPARIB BE ADDED TO PEMBROLIZUMAB FOR gBRCA1m AND/OR gBRCA2m CARRIERS WITH TNBC WHO HAVE RESIDUAL DISEASE AFTER NEOADJUVANT CHEMOTHERAPY?
Patients with TNBC are more likely to harbor a gBRCA1m and/or gBRCA2m, and such mutations have been reported in about 15% of patients with TNBC. The use of adjuvant pembrolizumab and olaparib concurrently or sequentially can be considered for eligible patients. The relative risks and benefits of a concurrent approach should be weighed, as the long-term safety of these combinations is not known.
QUESTION: SHOULD OTHER CHECKPOINT INHIBITORS BE USED IN THE NEOADJUVANT SETTING INSTEAD OF PEMBROLIZUMAB?
As only pembrolizumab has received regulatory approval, the panel does not recommend use of alternate immunotherapeutic agents.
QUESTION: SHOULD ADJUVANT PEMBROLIZUMAB BE USED IN PATIENTS WITH RESIDUAL DISEASE AFTER NEOADJUVANT CHEMOTHERAPY WITHOUT PEMBROLIZUMAB?
There are currently no data to support adjuvant pembrolizumab use in patients who did not receive neoadjuvant pembrolizumab.
In summary, addition of pembrolizumab to chemotherapy in the neoadjuvant setting followed by continuation in the adjuvant setting is the new standard of care for patients with high-risk TNBC as defined in KEYNOTE-522.
Neoadjuvant Chemotherapy, Endocrine Therapy, and Targeted Therapy for Breast Cancer Guideline Expert Panel. Use of Immune Checkpoint Inhibitor Pembrolizumab in the Treatment of High-risk, Early-stage Triple Negative Breast Cancer: ASCO Guideline Rapid Recommendation Update. Korde LA, Somerfield MR, Hershman DL, et al. J Clin Oncol. 2022;40:1696-1698.
Neoadjuvant Chemotherapy, Endocrine Therapy, and Targeted Therapy for Breast Cancer: ASCO Guideline. Korde LA, Somerfield MR, Carey LA, et al. DOI: 10.1200/JCO.20.03399 Journal of Clinical Oncology 39, no. 13 (May 01, 2021) 1485-1505.
