NCCN: 8th Edition AJCC Breast Cancer Staging Incorporates Gene Tests, Excludes LCIS

The 8th edition of the American Joint Committee on Cancer (AJCC) Staging Manual incorporates biologic factors to refine and improve the prognostic stratification of patients with breast cancer, according to an update presented at the 2019 National Comprehensive Cancer Network (NCCN) Annual Meeting, held March 21–23 in Orlando, Florida.

“Biologic factors and multigene panels have been incorporated into the 8^th edition of the AJCC,” said Aysegul A. Sahin, MD, a professor in the Department of Pathology, and Section Chief of the Breast Pathology Section at The University of Texas MD Anderson Cancer Center in Houston, Texas.

Clarifications were also added to more clearly define pathological T (tumor) and N (nodal involvement) status. Lobular carcinoma in situ (LCIS) is no longer considered a breast malignancy and is now excluded from the staging system as a noninvasive tumor in situ (Tis) neoplasm, she added.

Revisions to the new 8^th edition staging system are likely in the years ahead, she cautioned.

Traditional prognostic and predictive factors in breast cancer include age, tumor grade, histological subtype, estrogen receptor (ER)/progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) status, vascular invasion, and tumor margins, Sahin said.

“Breast carcinoma is, like other solid tumors, a very heterogeneous disease, based on the clinical presentations and based on histological subtypes, and there can be over-expressions of ER/PR and HER2,” Sahin explained.

“So, when we diagnose a patient with breast carcinoma, we use these factors to make therapy decisions,” she said. “Basically, we grade histological subtype, we evaluate the prognostic parameters, such as vascular invasion [and] treatment margins, and then we look at ER/PR, HER2, and proliferation markers.”

Prior to the 7^th edition of AJCC, conventional TNM staging was the main set of criteria to stratify patients by prognosis. TNM staging remains an important component of prognostic stratification today, but tumor behaviors vary within the resulting stage categories, with the same adjuvant treatments for identically-staged tumors yielding different responses.

“Unfortunately, the same stage disease exhibits significantly variable clinical behavior,” she said. “We see quite wide variation from patient to patient.”

That is now understood to be due in large part to clinically relevant variation in molecular factors and gene expression profiles. For example, a retrospective study of 3,728 patients treated at the MD Anderson Cancer Center showed that adding biologic markers like ER status to the AJCC staging system improved the prognostic power of stage stratifications.

A subsequently-developed prognostic stratification model was validated that yielded better separation of outcomes among prognostic categories. Using that system, 50% of the 3,728 patients were restaged, with half of those restaged being down-staged and the other half being up-staged, she said.

Recent evidence also suggests tumor microenvironmental factors, such as tumor-infiltrating immune lymphocytes, are also prognostic and predictive markers, she noted.

Until the 8^th edition, however, the AJCC staging system did not take molecular factors into account, Sahin said.

Today, treatment recommendations are based importantly on biological factors and the updated prognostic model, she said.

“While TNM classification makes the basis for the staging groups, we also incorporated these biomarkers,” she said.

The AJCC 8^th edition recommendations include consideration of whether patients were treated with adjuvant therapy and includes multigene panels, when available, as “stage modifiers,” Sahin explained. “The prognostic staging system provided more accurate stratification with respect to disease-specific survival than did the anatomic [TNM] staging [alone].”

Patients with HR-negative, HER2-negative, lymph node–negative breast cancer can be assessed using the 21-gene Oncotype Dx Recurrence Score, MammaPrint, the 12-gene EndoPredict, or the PAM50 test.

The 8^th edition also clarified pathological T and N (pT and pN) status definitions, Sahin said. Maximum invasive tumor size is “a reasonable estimate” of tumor volume, she said, noting that past definitions of T size were “quite vague.”

Things are now much clearer, she said. “Tumor size is evaluated on gross measurement and should be confirmed by microscopic assessment,” she explained. “Small, microscopic satellite foci of tumor around the primary tumor are not added to the maximum tumor size.”

T staging for adenocarcinomas can be challenging, however. Microscopic size measurements should include only the invasive adenocarcinoma and not cystic spaces, which can cause “major discrepancies” between pT and cT size estimations, she noted.

Tumors sized between 1.0 and 1.5 mm should not be rounded to the nearest millimeter, but tumors between > 1.0 mm and < 2.0 mm “should be reported rounding to 2 mm,” she said.

Microinvasive cancer is defined as a tumor foci 1.0 mm or smaller. When there are multiple microinvasive tumor foci, the size of only the largest focus should be used-not the sum of individual foci, Sahin emphasized.

Tumors with any direct extension into the chest wall or the skin are defined as T4 tumors, with chest wall extensions categorized as T4a and satellite nodules defined as T4b, she said.

Postneoadjuvant therapy pT (ypT) staging is based on the largest residual tumor focus. An “m” (multiple) modifier notation is used to identify cases in which multiple foci of residual tumor are identified, Sahin noted.