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Journal of Clinical Oncology, Vol 23, No 16 (June 1), 2005: pp. 3860-3862 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.05.294
In Reply:Division of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center, Duarte, CA We appreciate the interest and constructive comments of Gonzalez-Angulo et al, and will address their concerns regarding both patient selection and strategies to improve treatment outcome for patients with inflammatory breast cancer. As described in the Patients and Methods section of our article,1 all patients included in our analysis had met the strict clinical criteria of inflammatory breast cancer as defined by the presence of inflammatory changes involving one third or more of the breast surface area, with or without dermal lymphatic invasion. The diagnosis of inflammatory breast carcinoma was established either in the community setting by the referring oncologist or surgeon, or by members of the breast cancer team if a patient came to the City of Hope Comprehensive Cancer Center, Duarte, CA, for primary therapy. Under the former scenario, when patients were referred to us after they had received their conventional-dose therapy and underwent surgery, the referring physician's clinical impression of inflammatory breast cancer was always verified via direct contact with that particular physician (or physicians). As we have stated in the Histopathologic Analysis section of our article, all primary tumors were reviewed and analyzed by a staff pathologist of the City of Hope Comprehensive Cancer Center. The diagnosis of inflammatory breast carcinoma is made based on the presence of specific clinical features at presentation. Dermal lymphatic invasion, although supportive of such diagnosis, is not always detected in a limited-size biopsy specimen at diagnosis, nor is it always present in mastectomy specimens, possibly due to the beneficial effects of neoadjuvant chemotherapy. While the incidence of dermal lymphatic invasion is not shown in Table 1 of our article, it was seen in approximately 60% of all primary tumors. In the interest of saving space, Table 1 listed only the percentage of estrogen-receptor (ER)/progesterone-receptor (PR) positive, or ER/PR unknown tumors, and the incidence of high-grade features. However, ER/PR and grade status were assessed, not, as stated by Gonzalez-Angulo et al, in only 62% of cases, but in almost all primary tumors. Accordingly, 68 (57%) of tumors were ER and/or PR positive, 47 (39%) were negative, and ER/PR status was unknown in 4%. Of the 120 tumors 78 (65%) were high grade, while the rest of the tumors were either low or intermediate grade, and only in one case were we unable to assess grade. Gonzalez-Angulo et al are correct in pointing out that our database of molecular markers is incomplete: we were able to procure unstained slides or blocks to assess HER-2/neu status in only 62% of cases due to regulatory and logistical problems, and we had encountered great difficulty in procuring specimens from tumors/patients whose diagnosis and treatment took place during the first few years of the study period (more than a decade ago). Hence, our reported incidence of HER-2 positivity (39%) needs further validation because of both incomplete sample size, and the need to apply more rigorous technology. Despite these technical problems, the incidence of HER-2 positivity in our series is similar to what has been reported previously in the literature. As a side note, the hurdles we have encountered in obtaining access and procuring archived tissue are not unique. Preservation of patient confidentiality is extremely important, and less restrictive regulation allowing access to research on archived tissue from patients with long follow-ups is needed. Information obtained from investigating such tissue samples could lead to designing more effective methods of prevention, detection, and treatment. Next, I would like to address comments regarding treatment and outcome. Inflammatory breast carcinoma is not always inoperable, although we agree that a surgeon's willingness and ability to perform an operation does not mean that such approach should be encouraged. While up-front surgery is not the current recommendation in the management of inflammatory breast cancer, lack of familiarity with neoadjuvant strategies and inflammatory carcinomatous presentation, especially in our earlier cases, did lead to the occasional primary surgical intervention followed by adjuvant chemotherapy. Our patient population was somewhat heterogeneic both from the biologic and treatment point of view, but we did not include any patient with metastatic sites beyond regional lymph nodes. The conventional-dose neoadjuvant therapy prescribed to our patients, especially before 1998, might be considered suboptimal, and we did observe a relatively low pathologic complete response rate. Modern regimens consisting of either sequential or combined administration of anthracyclines, alkylating agents, taxanes, and more recently platinum, or navelbine, as well as—for patients with HER-2 overexpressing tumors—trastuzumab, are likely to result in increased pathologic complete response rates. In our series, none of the seven patients with a pathologic complete response after neoadjuvant therapy has relapsed, although these patients represent a very small sample. However, the effect on long-term relapse-free and overall survival after accomplishing such a theoretically desirable primary goal, is still unclear. Despite many decades spent on evaluating an ever-increasing number of treatment regimens, the optimal components—including targeted therapeutic agents—sequence, total duration of neoadjuvant and adjuvant therapy, and the potential role of dose-intense (tandem or single) chemotherapy consolidation are still unknown. Inflammatory breast cancer patients would be well served by coordinated efforts of centers of excellence with expertise in treating this entity. Sequential or randomized phase II trials aiming at understanding the unique biology, incorporating targeted therapeutic agents, optimizing chemotherapy regimens, treatment duration, and dose-intensity in the neoadjuvant setting (with the primary pathologic end point of complete response rate) as well in the adjuvant setting are necessary, to advance our knowledge and success in helping our patients back to the future. Author's Disclosure of Potential Conflicts of Interest The following author or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Research Funding: George Somlo, Bristol-Myers Squibb. For a detailed description of these 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 of Information for Contributors found in the front of every issue. REFERENCES
1. Somlo G, Frankel P, Chow W, et al: Prognostic indicators and survival in patients with stage IIIb inflammatory breast carcinoma after dose-intense chemotherapy. J Clin Oncol 22:1839-1848, 2004
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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