NCCN Guidelines Version 1.2016 NCCN指南2016年第1版
A central component of the treatment of breast cancer is full knowledge of extent of disease and biologic features. These factors contribute to the determination of the stage of disease, assist in the estimation of the risk that the cancer will recur, and provide information that predicts response to therapy (eg, estrogen receptor [ER], progesterone receptor [PR], human epidermal growth factor receptor 2 [HER2]). These factors are determined by examination of excised tissue and are provided in a written pathology report. Accurate pathology reporting requires communication between the clinician and the pathologist relating to relevant patient history, prior breast biopsies, prior irradiation to the chest, pregnancy status, characteristics of the abnormality biopsied (eg, palpable, mammographically detected microcalcifications), clinical state of lymph nodes, presence of inflammatory change or other skin abnormality, and any prior treatment administered (eg, chemotherapy, radiation therapy). The specimens should be oriented for the pathologist, and specific requests for determination of biomarkers should be stated (eg, ER, PR, and HER2 status). The use of consistent, unambiguous standards for reporting is strongly encouraged. Data from both national and local surveys show that as many as 50% of pathology reports for breast cancer are missing some elements critical to patient management. Significant omissions include failure to orient and report surgical margins and failure to report tumor grade consistently.
The College of American Pathologists (CAP) has developed pathology reporting protocols to promote complete and standardized reporting of malignant specimens. CAP provides a protocol for each disease site that includes cancer case summaries (checklists) along with background documentation. These checklists form the basis for a synoptic, standardized reporting of pathologic findings. The checklists are available without charge through the CAP website at www.cap.org. Consistent, unambiguous, and complete pathology reporting is a cornerstone of quality breast cancer care, and the NCCN Breast Cancer Panel endorses the use of the CAP protocols for reporting the pathologic analysis of all breast cancer specimens.
ER status should be determined for all samples of ductal carcinoma in situ (DCIS), and ER and PR tumor status should be determined for all samples of invasive breast cancer. ER and PR tumor status is normally determined by immunohistochemistry (IHC) testing. Although this method is considered reliable when performed by experienced pathology personnel, there have been several reports indicating that the reliability of ER and PR determinations can vary widely from one laboratory to another. These inter-laboratory differences may be attributable to the diverse methodologies and diverse interpretation schema used to evaluate tumor hormonal status. An NCCN Task Force and a panel of ASCO and CAP members have reviewed this topic and issued recommendations on ER and PR testing in breast cancer. Breast cancers that have at least 1% of cells staining positive for ER should be considered ER-positive.
Principles of HER2 Testing
Along with ER and PR, the determination of HER2 tumor status is recommended for all newly diagnosed invasive breast cancers and for first recurrences of breast cancer whenever possible. The NCCN Breast Cancer Panel endorses CAP accreditation for anatomic pathology laboratories performing HER2 testing.
HER2 status can be assessed by measuring the number of HER2 gene copies using in situ hybridization (ISH) techniques, or by a complementary method in which the quantity of HER2 cell surface receptors is assessed by IHC. Assignment of HER2 status based on mRNA assays or multigene arrays is not recommended. The accuracy of HER2 assays used in clinical practice is a major concern, and results from several studies have shown that false-positive as well as false-negative HER2 test results are common. A joint panel from ASCO and CAP has issued updated HER2 testing guidelines to avoid such false-positive or false-negative results. These updated guidelines have been published in the Archives of Pathology & Laboratory Medicine and ASCO's Journal of Clinical Oncology. The NCCN Panel endorses these updated ASCO/CAP recommendations for quality HER2 testing and has outlined these recommendations in Principles of HER2 Testing.
HER2 testing should be performed in laboratories accredited by CAP or another equivalent authority to carry out such testing. Further, these laboratories should have standardized HER2 testing procedures in place, as well as programs to periodically evaluate the proficiency of personnel performing HER2 testing. HER2 test reports should also include information on site of tumor, specimen type, histologic type, fixation method and time, block examined, and details on the HER2 testing method(s) used. Clinicians should be familiar with the significance of these criteria when making clinical recommendations for an individual patient.
Consistent with the ASCO/CAP guidelines, the NCCN Panel considers either IHC or ISH with either a single or dual probe as an acceptable method for making an initial determination of HER2 tumor status. Breast cancer tumors are classified as HER2-positive if they are scored as 3+ by an IHC method defined as uniform membrane staining for HER2 in 10% or more of tumor cells or demonstrate HER2 gene amplification by an ISH method (single probe, average HER2 copy number ≥6.0 signals/cell; dual probe HER2/CEP17 ratio ≥2.0 with an average HER2 copy number ≥4.0 signals/cell; dual probe HER2/ chromosome enumeration probe (CEP)17 ratio ≥2.0 with an average HER2 copy number<4.0 signals/cell; HER2/CEP17 ratio <2.0 with an average HER2 copy number ≥6.0 signals/cell).
High average copy number of HER2 (≥6.0 signals/cell) is considered positive regardless of the HER2/CEP17 ratio. The rationale cited by the joint committee for including rare scenarios such as HER2 positivity when dual probe HER2/CEP17 ratio is greater than or equal to 2.0 and average HER2 copy number is less than 4.0 signals/cell is that the first- generation trials of adjuvant trastuzumab included a small number of patients with a HER2/CEP17 ratio greater than or equal to 2.0 and an average HER2 copy number less than 4.0 signals/cell. There is no trend in these data, suggesting that these patients were not responsive to trastuzumab and the trastuzumab has a favorable safety profile.
The NCCN Panel agrees with the ASCO/CAP HER2 committee that results of IHC are equivocal if scored as IHC 2+ “based on circumferential membrane staining that is incomplete and/or weak/moderate and within greater than 10% of the invasive tumor cells or complete and circumferential membrane staining that is intense and within less than or equal to 10% of the invasive tumor cells.” In such cases, the panel recommends reflex testing using the ISH method on the same specimen or repeating tests if a new specimen is available.
Similarly, samples with equivocal results by an ISH assay (for example, single probe ISH average HER2 copy number ≥4.0 and<6.0 signals/cell; and dual probe HER/CEP17 ratio <2.0 with an average HER2 copy number ≥4.0 signals/cell) must be confirmed by reflex testing using the IHC method on the same specimen or repeating tests if a new specimen is available.