Updates in Staging of Breast Cancer

Laila Khazai 3/3/18

Major Change

Addition of tumor grade, HER-2, ER, PR, and genomic assays as elements required to assign stage in conjunction with

anatomic information (i.e. TNM).

Evolution • The TNM system was developed in 1959 (by the International Union

Against Cancer; UICC), in the absence of effective systemic therapy and based on limited understanding of the biology of breast cancer as well as the then widely accepted paradigm of orderly progression for the tumor to regional nodes and then to distant sites.

• The system was generated to reflect the risk of distant recurrence and death subsequent to local therapy (surgery followed by radiation), and the primary objective was to provide standard nomenclature for prognostication to prevent futile care for those likely to die from disease.

• The AJCC used the principles of TNM system to serve as the basis for categorizing the extent of disease.

Evolution • The 1st edition of AJCC was published in 1977. • Over the past decade, there have been fundamental changes in our

understanding of the biology of breast cancer, raising questions about the ongoing relevance of TNM staging.

• Biologic factors have become as or more important than the anatomic extent of disease to define prognosis and select the optimal combination therapies.

• In this era treatment decisions are not based solely on the TNM stage and thus, modern staging system has moved toward incorporating biologic factors into the classification system.

AJCC, 8th Edition The Breast Cancer Expert Panel came to the conclusion that even though the anatomy/histology-based TNM system provide important insight into patient’s prognosis, biomarkers need to be included in staging.

• Anatomic Stage • Clinical Prognostic Stage • Pathological Prognostic Stage

Cancer registries and clinicians in the U.S. must use the Clinical and Pathological Prognostic Stage Group tables for reporting. If biomarkers are not available, the cancer should be reported as unstaged. The anatomic Stage Group System should only be used in regions of the world where biomarker testing for ER, PR, and HER-2 are not routinely available.

Basis for New Stage Groups • The national Cancer Data Base (NCDB), covering over 70% of breast

cancers diagnosed in the U.S), was used to study the impact of prognostic factors on staging.

• The analysis included 238,265 women diagnosed with invasive breast cancer in 2010-2011 with a median follow-up of 37.6 months.

• All patients had a complete set of variables. • The majority were offered and treated with appropriate adjuvant

endocrine and/or systemic chemotherapy.

Basis for New Stage Groups

• Survival calculations were performed for each prognostic subgroup based on 7th edition stage group, grade, HER-2, ER and PR status combinations.

• Survival ranges for stage groups were defined using 7th edition staging criteria to maintain consistency with previous stage survival expectations.

• Results were used to establish Prognostic Stage Groups for the 8th edition.

• Inclusion of grade, HER-2 and hormone receptor status for both Clinical and Pathological Prognostic Stage resulted in stage re-assignment of more than 35% of patients.

Why Keep the TNM System?

• The TNM staging classification based solely on anatomic/histological parameters is relevant to the part of the world where this is the only information available to practitioners.

• It remains useful as the fundamental basis of staging classifications for areas in the world where biological information is an integral part of the initial evaluation;

Provides continuity to investigators, in regards to studying categories of patients that accurately reflect prior grouping over the last six decades. Allows current investigators in the field to communicate with one another.

A few Points About Clinical Prognostic Staging…

• Clinical categorization of cancer is based on findings of history, physical exam, and any imaging studies that are done.

• Imaging studies are not required to categorized regional lymph nodes as negative.

• Biopsy is not necessary to categorize a lymph node as positive. • Information obtained from pathologic evaluation (FNA, core bx or

resection of SLN) are included as part of the Clinical Staging.

Confirmation of clinically detected metastatic disease by FNA/core or SLN excision is designated with an (f) or (sn) suffix. Nodal metastases confirmed by FNA or core bx are classified as macro-metastases (cN1), regardless of the size of tumor focus in the final pathological specimen.

A few Points About Pathologic prognostic Staging…

• Pathological staging includes all data used for clinical staging, plus data from surgical resection.

• In addition to ER,PR, and HER-2 status, genomic profile is factored in a subset of cases (T1N0M0 or T2N0M0 cancer that is ER+/HER-2-).

When T data are otherwise sufficient for pathological staging, a case may be assigned a pathological N category if any lymph nodes are microscopically examined, irrespective of the number of lymph nodes removed (this may be FNA, core bx, SLN biopsy or excision).

Final Word

The Prognostic Stage is preferred for patient care and is to be used for reporting of all cancer patients in

the U.S.

AJCC 7th Vs. 8th

• Staging results in 501,451 women in the NCDB diagnosed in 2004 to 2014, excluding patients undergoing neoadjuvant chemotherapy.

• 19.3% of women stages I-III will be upstaged and 23.8% will be down-staged.

• The largest proportion of down-staged patients were noted in stage IB (becoming IA).

Validation • Prognostic Stage was assigned to patients from a combined data base

(3327 from MDACC treated between 2007 and 2013, plus 54727 patients from the CCR treated between 2005 and 2009).

• The Prognostic Stage provided more accurate prognostic information than the anatomic stage alone in both groups.

Problems: A Prognostic Stage could not be assigned in a subset of patients (13% of MDACC and 7% of CCR cases), due to:

N1mic disease in patients with larger than T1. Uncategorized combinations of T and N categories with grade and HR/HER-2 status.

Future • One factor that could influence integration of the Prognostic Staging is its

complexity. • It is unlikely that clinical decisions regarding treatment recommendations

will be made based on the Prognostic Stage, because they are routinely guided by the tumor size, nodal status, receptor status, and the results of genomic profiling.

• Therefore, Prognostic Stage is less likely to be used to facilitate communication between health acre professionals, and is more likely to be used in counselling patients regarding prognosis if they receive the recommended treatment plan.

Bioscore • Study undertaken to develop a staging system incorporating biologic

factors in addition so standard anatomic factors in the AJCC pathologic stage to assess disease specific survival.

• Multivariate analysis of factors, including pathologic stage, T, N, grade, ER status, and HER-2 status were performed on 3327 patients treated with surgery as an initial intervention at MDACC from 2007 to 2013.

• An external cohort from the California Cancer Registry (CCR) including 67944 patients diagnosed between 2005 and 2010, was used for validation.

• Multiple staging models were then constructed, and a new staging model (Bioscore) was proposed.

Bioscore • Even though the system was developed at a single center, validation

with the large cohort from the CCR, suggests broad applicability. • Although the 8th edition of AJCC staging did not formally incorporate

the Bioscore, the prognostic pathologic stage incorporates “almost” the same biologic factors.

Future • It is recognized that in the coming years additional data from the NCDB

and other large populations of patients with full prognostic factor information and increasingly longer follow-up will become available, with resultant revision of the Prognostic Stage Group Table.

• It is also likely that high-level evidence related to multi-gene assays will also become available.

• The AJCC Expert Panel will regularly review new data as they become available and make necessary revisions as needed.

References

• AJCC Cancer Staging Manual, eight edition. • Evolution of the Staging System in Breast Cancer. Donovan et al, Ann Surg Oncol (2017) 24:3469-3470. • Breast Cancer-Major Changes in the American Joint Committee on Cancer Eight Edition Cancer Staging Manual.

Giuliano et al, CA Cancer J Clin (2017) 67:290-303. • Bioscore: A staging System for Breast Cancer patients that Reflects Prognostic Significance od Underlying Tumor

Biology. Hunt et al, Ann Surg Oncol (2017) 24:3502-3509. • Incorporation of Treatment Response, Tumor Grade and Receptor Status Improves Staging Quality in Breast Cancer

Patients Treated with neoadjuvant Chemotherapy. Mittendorf et al, Ann Surg Oncol (2017) 24: 3510-3517. • Validation Study of the American Joint Committee on Cancer Eighth Edition Prognostic Stage Compared With the

Anatomic Stage in Breast Cancer. Weiss et al, JAMA Oncol (2018) 4: 203-209. • How Much Information Do We Really Need After Neoadjuvant therapy for Breast Cancer. Loibl et al, JCO (2017) 10:

1029-1030. • Staging of Breast Cancer in the Neoadjuvant Setting. Jeruss et al, Cancer Res (2008) 68: 6477-6481. • The Neo-Bioscore Update for Staging Breast Cancer Treated with Neoadjuvant Chemotherapy; Incorporation of

Prognostic Biologic Factors Into Staging After Treatment. Mittendirf et al, JAMA Oncol (2016) 2:929-936.

Thank You