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Role of Patient and Disease Factors in Adjuvant Systemic Therapy Decision Making for Early-Stage, Operable Breast Cancer: American Society of Clinical Oncology Endorsement of Cancer Care Ontario Guideline Recommendations
N. Lynn Henry, Mark R. Somerfield, Vandana G. Abramson, Kimberly H. Allison, Carey K. Anders, Diana T. Chingos, Arti Hurria, Thomas H. Openshaw, and Ian E. Krop
Which patient and disease factors should be considered in selecting adjuvant therapy for women with early-stage breast cancer?
Female patients who are being considered for, or who are receiving, systemic therapy for early-stage invasive breast cancer (stages I to IIA, T1N0-1, T2N0).
Medical oncologists, pathologists, surgeons, oncology nurses, patients, and caregivers.
Cancer Care Ontario Guideline Recommendations
For making adjuvant therapy decisions for women with early-stage breast cancer, the Cancer Care Ontario guideline recommends that lymph node status, T stage, estrogen receptor (ER) status, progesterone receptor (PgR) status, human epidermal growth factor receptor 2 (HER2) status, tumor grade, and presence of tumor lymphovascular invasion are relevant (either prognostic or predictive); that Oncotype DX score (for hormone receptor–positive, N0 or N1mic or isolated tumor cell, and HER2-negative cancers) and Adjuvant! Online may be used as risk stratification tools; and that age, menopausal status, and medical comorbidities should be considered.
For patients in whom chemotherapy would likely be tolerated and for whom chemotherapy is acceptable, adjuvant chemotherapy should be considered if the following characteristics are present: lymph node–positive tumor (one or more lymph nodes with a macrometastatic deposit > 2 mm), ER-negative tumor (> 5 mm), HER2-positive tumor, high-risk lymph node–negative tumors (> 5 mm) and another high-risk feature, and Adjuvant! Online 10-year risk of death from breast cancer greater than 10%.
The following features should be considered high risk, and patients who have them should be considered candidates for chemotherapy: lymph node–negative tumors with T greater than 5 mm, grade 3, triple-negative (ER-negative, PgR-negative, and HER2-negative) tumors, lymphovascular invasion positivity, Oncotype DX recurrence score (RS) associated with an estimated distant relapse risk of greater than 15% at 10 years, and HER2-positive tumors.
Patients with T less than 5 mm, lymph node–negative tumors, and no other high-risk features may not benefit from adjuvant chemotherapy. Finally, adjuvant chemotherapy may not be required in patients with HER2-negative, strongly ER-positive, and PgRpositive breast cancer and any of the following additional characteristics: positive lymph nodes with micrometastasis only (< 2 mm), or T less than 5mm, or an Oncotype DX RS with an estimated distant relapse risk of less than 15% at 10 years.
ASCO Panel Discussion Points
The ASCO panel highlighted three areas that warrant further consideration: tumor histology and adjuvant therapy recommendations, risk stratification tools and proposed Oncotype DX RS thresholds to guide decisions about chemotherapy, and patient factors in decision making.
ASCO believes that cancer clinical trials are vital to inform medical decisions and improve cancer care and that all patients should have the opportunity to participate.
|CCO Clinical Question||CCO Recommendation||ASCO Panel Discussion Points|
|Which disease characteristics (histopathological parameters) are considered relevant (either prognostic or predictive) when making a decision regarding adjuvant systemic therapies for breast cancer?||Lymph node status|
For making decisions about adjuvant systemic therapy, the CCO guideline recommendations highlight key tumor-related factors that should be considered in order to avoid over- or under-treatment of patients. In addition to the listed factors, the ASCO panel noted that some data suggest that certain uncommon breast cancer subtypes (e.g., tubular, mucinous) have favorable prognoses, and that this histologic information could also be relevant for making decisions about systemic therapy. However, large data sets are not currently available to confirm how best to treat these patients.
Chemotherapy should be considered for selected patients. However, there was no lower size limit provided in the CCO guideline for HER2-positive tumors, and the ASCO panel noted that there are no definitive data for use of chemotherapy and/or trastuzumab for HER2-positive tumors ≤ 5 mm. In addition, in the opinion of the ASCO panel, some of the factors, such as grade 3 and presence of LVI, should generally not be used to drive decision-making when considered in isolation, and need to be interpreted in the overall clinical context.
The ASCO panel also felt, consistent with the 2015 St Gallen International Expert Consensus, those tumors that are welldifferentiated, especially those that are “luminal A-like” should also be considered for omission from chemotherapy.
|Estrogen receptor (ER) status|
|Progesterone receptor (PR) status|
|Human epidermal growth factor receptor 2 (HER2) status|
|Presence of tumor lymphovascular invasion (LVI)|
|What risk stratification tools may be used in determining the utility of certain systemic therapies in patients with early-stage breast cancer?||Oncotype DX score (for HR+, N0 or N1mic or ITC, and HER2 negative cancers)|
The ASCO panel notes that in addition to the Oncotype DX assay, there are now multiple risk stratification tools available for routine clinical use and that this is a rapidly evolving field. The panel recommends that providers refer to the current ASCO guideline on use of biomarkers for decision-making for treatment of patients with early stage breast cancer for recommendations about use of several other risk stratification tools and in the setting of other disease characteristics, such as lymph node positive breast cancer.
The ASCO Panel suggests a slight revision to the CCO language concerning the Oncotype DX intermediate recurrence score, as follows: “The utility of chemotherapy in the intermediate recurrence score zone is currently less clear, although a phase III clinical trial (TAILORx), once reported might help to address that question for patients with a recurrence score 11-25.”
|Adjuvant! Online (www.adjuvantonline.com)|
|Which patient factors should be considered in making adjuvant systemic therapy decisions?||Age||The ASCO panel agreed with the patient factors listed by CCO that should be considered when making decisions about adjuvant systemic therapy. Panel members also felt that the preferences of the patient are an important factor in the selection of adjuvant systemic therapy. In addition, for patients with advanced age, the ASCO panel also recommends measurement of estimated life expectancy and other factors included in validated geriatric assessment tools such as functional status, comorbidity, cognitive function and social support, rather than relying solely on chronologic age when making decisions about adjuvant systemic therapy.|
|Medical comorbidities (including validated tools used to measure health status)|
|In those patients in whom chemotherapy would likely be tolerated and is acceptable to the patient, adjuvant chemotherapy should be considered for patients with which tumor characteristics?||In no particular order:||The ASCO panel suggests a slight revision to the CCO language concerning the Adjuvant! Online: a 10-year risk of death judged to be greater than 10% or 15% using the Adjuvant! Online model is a reasonable threshold for considering chemotherapy.|
|Lymph node positive: one or more lymph nodes with a macro-metastatic deposit (>2 mm)|
|ER− with T size >5mm|
|High-risk lymph node negative tumors with T size >5 mm and another high-risk feature (see next recommendation, R5)|
|Adjuvant! Online 10−year risk of death from breast cancer >10%|
|When considering lymph node negative tumors with T>5mm, what should be considered high-risk features (thus considered candidates for chemotherapy)?||Grade 3||The ASCO panel suggests a slight revision to the CCO language concerning the Oncotype DX threshold for this recommendation. Specifically, for lymph node-negative tumors with T > 5mm, Grade 3, triple negative (ER-, PR-, and HER2-), LVI positive, Oncotype DX recurrence score (RS) associated with an estimated distant relapse risk of > 20 % at 10 years, and HER2+ should be considered high-risk features and thus considered candidates for chemotherapy|
|Triple negative (ER-, PR-, and HER2-)|
|An Oncotype DX recurrence score (RS) that is associated with an estimated distant relapse risk of 15% or more at 10 years|
|Patients with which disease characteristics may not benefit from adjuvant chemotherapy?||T <5 mm, lymph node negative and no other high-risk features (see previous recommendation)|
|Adjuvant chemotherapy may not be required in patients with HER2−, strongly ER+ and PR+ breast cancer with any of the following additional characteristics?||Lymph node positive with micrometastasis (<2 mm) only, or||The ASCO panel suggests a minor revision from CCO’s “…Oncotype DX RS with an estimated distant relapse risk of less than 15% at 10 years” to “an Oncotype DX RS with an estimated distant relapse risk of less than 10% at 10 years.”|
|T <5mm, or|
|An Oncotype DX RS with an estimated distant relapse risk of less than 15% at 10 years|
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