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AJCC 8th edition—A step forward

The American Joint Commission on Cancer (AJCC) staging system provides a common system for both patients and physicians. It allows for a shared nomenclature and permits an “apples to apples” comparison of the literature. The AJCC staging system traditionally consists of definition of the anatomical stage, which is based on tumor size, lymph node involvement, and distant metastases. Although it is widely used, many have questioned its relevance in the modern era. A 1.5-cm low-grade, node-negative, early breast cancer is managed differently based on the presence of estrogen receptor (ER) and/or progesterone receptor (PR) positive as well as human epidermal growth factor receptor 2 (HER2). Yet, the AJCC staging system would not have differentiated them. The AJCC 8th edition, released in 2017,1 is a significant departure from the prior editions in that it will be continuously updated as data become available. The new edition addresses three important issues: (a) does lobular carcinoma in situ need to be staged—the panel decided against it, (b) How to deal with biologic variables of breast cancer, and 3) clarification of neo-adjuvant chemotherapy induced changes (and re-staging). The expert panel was confronted with the important question of whether the time for the inclusion of biological modifiers. In the new staging system, the anatomic (tumor size, node metastasis; TNM) staging is modulated by multiple parameters, which include tumor grade, prognostic markers such as ER, PR, and HER2, and even multigene assays. One of the hurdles in doing so was the recognition that in some areas that data were relatively sparse and subject to variability. For example, the role of grade has never been formally analyzed in a prospective randomized clinical trial. While some of the newer (and commercial) biomarkers were associated with stronger level I evidence. The inclusion of commercial markers also needed to be a careful balancing act to prevent perceptions of bias. Taken together, the 8th edition has retained the anatomic stage while seeking to establish a “prognostic stage” to give a better estimation of the projected outcomes. Prognostication is an art as well as a science. It is modified by patient parameters and therapeutic interventions, and therefore, it needs to be independently validated in multiple cohorts. A number of studies have evaluated the prognostic ability of the 8th edition in both neoadjuvant2,3 and adjuvant settings4 including the SEER data base.5,6 Additional studies have focused on Luminal A,7 HER2positive,8,9 and triple-negative breast cancer 5,10 subsets. These have documented that a significant percentage of patients (up to 50% 11) undergo stage-shift, largely due to the incorporation of tumor grade and expression of ER/PR and HER2 as well as molecular biomarkers such as Oncotype Dx.12,13 Lombardi et al14 retrospectively analyzed a large group of adjuvantly treated node-negative breast cancer patients for the impact of new staging system. Consistent with prior literature,2,15 prognostic staging down-staged patients had better with outcomes. The only patients that were not down-staged were triple-negative breast cancers; this is also consistent with prior literature.5,10 This single institutional data validates several prior studies in SEER data base and single institutional settings and document the prognostic impact of new staging system even in the absence of multigene panels.2,5,6,15-17 This is particularly relevant for lowand middle-income countries (LMIC) where gene expression testing cannot be not routinely undertaken. Looking forward, most of the advances in prognostication have benefited ER/PR and HER2-positive subgroups. Prognostication of triple-negative tumors has been difficult. Work undertaken by us, amongst others, has documented the value of assessment of tumor-infiltrating lymphocytes in TNBCs. These data support the addition of TILs as a prognostic modifier for TNBCs. The expression of PD-1 and PD-L1 in TNBCs is being used to determine therapy and has the promise to be an additional modifier in this subgroup. There are a number of exciting ongoing immunoncology clinical trials that will undoubtedly provide a wealth of information.18 As stated earlier, the genesis of the new prognostic staging was somewhat empirical due to lack of level I evidence for some of the parameters. The panel was able to be make guidelines based on evidence available from peer-reviewed literature and findings from large, unpublished (at the time of 8th edition publication) data bases. The current article adds to the body of literature that provide strong support for the updates to the eighth edition, particularly to the prognostic staging system. More specifically, the data validate the concept of using advances in clinical and laboratory science and translational research to modify the prior purely anatomic TNM staging. This paves the way for the addition of novel markers based on better understanding of tumor biology and their impact on prognosis, selection of therapy, and response to therapy.