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In Reply

Department of Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, TX

The comments from Durando et al correctly address the practicality of reporting pathologic information necessary to calculate residual cancer burden. When the coauthors planned this study, we gave serious consideration to finding an appropriate balance between theoretical best practice and usual practice. Practicality is an important priority for any tool, if it is to be used. Therefore, we restricted the methods of evaluation to those of macroscopic and microscopic pathology that could be adopted or modified to fit routine practice. We consider two-dimensional measurements of macroscopic tumor dimensions to be standard, at least in the macroscopic description. It is also reasonable to expect that a pathology report should indicate which slides represent the grossly identifiable tumor. With that information, pathologists can confirm the extent of invasive cancer within (and possibly beyond) the macroscopic tumor bed. This is standard practice to determine pathologic tumor stage. We suggest using these same methods to measure the residual tumor bed in two dimensions and to select the slides for assessment of cellularity. Of course, it is usual to report the number of involved lymph nodes. It is also routine at our institution to report the diameter of the largest metastasis, given that this information (combined with assessment of extranodal extension) may assist the radiation oncologists to plan treatments. This is not routine practice everywhere, but it takes minimal effort to use a dotting pen and a ruler (or micrometer) to measure this diameter.

Admittedly, it is not routine to report breast cancer cellularity by area. Therefore, we generated images of known percent cellularity within a circular field to emulate the microscopic appearance of breast cancer. This provides a Web-based reference for pathologists, to facilitate consistency and confidence (www.mdanderson.org/breastcancer_RCB). However, the findings from at least two groups demonstrate that this variable has prognostic relevance, so the information is useful.^1,2 We do know that assessment of percent involvement has been widely practiced in breast pathology, including percent intraductal component and percent immunostaining (Ki67, estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2), so it was not unreasonable to propose that it could be reported.

We note that there are widely variable practices for sampling the residual tumor bed for microscopic study, and that some encourage excessive numbers of tissue blocks to be processed into slides. Our preferred method is to define first the slides that represent the tumor bed (it would be easy to establish a routine of submitting the largest cross-section of the tumor bed and identify those slides in the report), and then to review the tumor bed in those slides to estimate the average cancer cellularity across the area of tumor bed. Perhaps our suggestion of submitting the greatest cross-sectional area of the tumor bed (or five blocks if the tumor diameter exceeds 50 mm) for microscopic study will lead to standardized sampling methods across different pathology practices, require fewer tissue blocks, and will allow more quantitative reporting of residual disease. In support of this approach, our results do suggest that exhaustively searching for rare residual cancer cells (minimal residual cancer burden, RCB-I) serves no purpose with respect to prognostic assessment.

We agree with the request from Durando et al for data regarding inter-pathologist reproducibility of residual cancer burden measurements. We have some supportive data (regarding inter-pathologist results) that is currently unpublished, but also encourage others to study this question. There is also the question of external validation of the prognostic utility of residual cancer burden when evaluated by other pathologists in a different clinical trial. Although preliminary data were presented by the I-SPY trial investigators at the San Antonio Breast Cancer Symposium in 2007, we must await external validation of our methods.³ Finally, Durando et al explain that histologic grade of the residual cancer is prognostic. We agree with this, but we consider that grade provides information different from that provided by residual cancer burden. A similar case can be made for hormone receptor status and proliferation index. When we designed our study, we chose to limit residual cancer burden index to represent the extent of residual disease, and so leave other factors (such as grade and receptor status) to be independent variables that represent biologic characteristics of the residual cancer cells.

It has been my observation that the methods for pathologic assessment of the breast and reporting of findings after neoadjuvant chemotherapy are quite variable and somewhat prone to descriptive, rather than quantitative interpretation. This might reflect a paucity of patient outcome data on which to base standard methods of pathology practice. We hope that current and future efforts to define and standardize pathologic methods of assessment after neoadjuvant chemotherapy will find the right balance between practicality and validated prognostic relevance.

AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment or Leadership Position: None Consultant or Advisory Role: W. Fraser Symmans, Nuvera Biosciences Inc (U) Stock Ownership: W. Fraser Symmans, Nuvera Biosciences Inc Honoraria: None Research Funding: None Expert Testimony: None Other Remuneration: None

REFERENCES

1. Ogston KN, Miller ID, Payne S, et al: A new histological grading system to assess response of breast cancers to primary chemotherapy: Prognostic significance and survival. Breast 12:320-327, 2003[CrossRef][Medline]

2. Symmans WF, Peintinger F, Hatzis C, et al: Measurement of residual breast cancer burden to predict survival after neoadjuvant chemotherapy. J Clin Oncol 25:4414-4422, 2007[Abstract/Free Full Text]

3. Hylton N, Carey L, DeMichele A, et al: Characterizing the biology and response of locally advanced breast cancer in women undergoing neoadjuvant therapy: Preliminary results from the I-SPY trial. Presented at 30th San Antonio Breast Cancer Symposium, San Antonio, TX, December 16, 2007 (abstr 80)

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Related Correspondence

• Measurement of Residual Disease After Neoadjuvant Chemotherapy
  Catherine Abrial, Emilie Thivat, Olivier Tacca, Xavier Durando, Marie-Ange Mouret-Reynier, Pierre Gimbergues, Frédérique Penault-Llorca, and Philippe Chollet
  JCO 2008 26: 3094 [Full Text]

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