Recommendations for standardized pathological characterization of residual disease for neoadjuvant clinical trials of breast cancer by the BIG-NABCG collaboration

Abstract

Neoadjuvant systemic therapy (NAST) provides the unique opportunity to assess response to treatment after months rather than years of follow-up. However, significant variability exists in methods of pathologic assessment of response to NAST, and thus its interpretation for subsequent clinical decisions. Our international multidisciplinary working group was convened by the Breast International Group-North American Breast Cancer Group (BIG-NABCG) collaboration and tasked to recommend practical methods for standardized evaluation of the post-NAST surgical breast cancer specimen for clinical trials that promote accurate and reliable designation of pathologic complete response (pCR) and meaningful characterization of residual disease. Recommendations include multidisciplinary communication; clinical marking of the tumor site (clips); and radiologic, photographic, or pictorial imaging of the sliced specimen, to map the tissue sections and reconcile macroscopic and microscopic findings. The information required to define pCR (ypT0/is ypN0 or ypT0 yp N0), residual ypT and ypN stage using the current AJCC/UICC system, and the Residual Cancer Burden system were recommended for quantification of residual disease in clinical trials.

Keywords: breast cancer; neoadjuvant systemic therapy; pathologic assessment; pathologic complete response; residual disease; response evaluation.

Figure 1.

Patterns of response in the breast and problems related to sampling for histologic evaluation: schematic overview with gross and microscopic illustrations. Photos courtesy of Veerle Bossuyt. (A) In some cases with complete response, a residual tumor bed is visible. In others, the tumor bed is indistinct and sampling of the correct area can only be confirmed by thorough clinical and imaging correlation and identification of a clip. Often, residual microscopic disease is identified when there is no residual tumor grossly. (a) Gross photograph of tumor bed (arrow). (b) Low-power hematoxylin and eosin (H&E) slide of this tumor bed. No residual tumor is identified. (c) High-power of H&E slide of the tumor bed from a different patient with rare residual invasive carcinoma cells (small arrows). (B) A partial response ranges from a decrease in cellularity with unchanged tumor size to concentric tumor shrinking with unchanged tumor cellularity. Often the decrease in cellularity is heterogeneous and residual disease extends beyond the grossly visible tumor bed. (a) Gross photograph of tumor bed with residual tumor (arrow). (b) H&E slides (low and high power) of different patient with residual invasive carcinoma concentrated in a nodule with high cellularity within the tumor bed (concentric shrinking). (c) Gross photograph of most common pattern of residual disease with scattered residual tumor across a fibrous tumor bed. (d,e) Medium power of H&E slides from two different blocks of the tumor bed (black and blue boxes) illustrating that cellularity often varies greatly from block to block. (C) When decrease in cellularity is heterogeneous, random sampling can lead to very different estimates of cellularity. When the decrease in cellularity is so heterogeneous that there are apparent areas with complete response (no residual disease) and apparent multiple foci of residual tumor (scatter pattern), there are interobserver variability and inconsistencies among guidelines in size measurements and when to consider multiple foci. For example, for AJCC staging, the largest contiguous focus of invasive carcinoma should be measured [23]. Intervening areas of fibrosis are specifically excluded, whereas other systems include these areas [–26, 32, 33]. Moreover, there can be interobserver variability in how much fibrosis to allow within this largest contiguous focus.

Figure 2.

Example of mapping of a post-NAST lumpectomy specimen. The specimen is serially sliced and radiographed (A). A diagram allows the pathologist to correlate the microscopic findings with the gross findings and the specimen radiograph and to reconstruct the location of the microscopic residual disease in the specimen for size measurements (B) [30]. The cellularity is assessed across the largest cross section of residual microscopic disease and compared with a computer-generated standard to improve reproducibility (C) [25, 30]. (The average cellularity in this example is ∼30%.). Adapted by permission from the American Association for Cancer Research: Symmans WF. “Pathologic Evaluation After Neoadjuvant Chemotherapy: Standardizing Management of the Surgical Specimen and Assessing Response to Neoadjuvant Therapies: The Promises and Challenges of Pathologic Complete Response.” Regulatory Science and Policy Session, 8 April 2013. Washington, DC: American Association for Cancer Research (AACR) Annual Meeting 2013. http://webcast.aacr.org/console/player/20130?mediaType=audio&