Inflammatory Breast Cancer: A Complex Disease

This article reviews the following: Molecular Determinants of the Inflammatory Breast Cancer Phenotype

The recognition of the existence of an aggressive, lethal subtype of breast cancer known as inflammatory breast cancer (IBC) dates back to 1924, when the first comprehensive assessment of IBC, based on a series of 28 patients, was presented by Lee and Tannenbaum.[1] However, the disease is rare, accounting for approximately 2.5% of all newly diagnosed breast cancers in the United States,[2] and its diagnosis is based mainly on a set of nonspecific clinical criteria. Both of these factors have contributed to the inability to accurately define prognostic and predictive markers as well as distinct molecular signatures of IBC that would distinguish it from non-IBC subtypes.

In this issue of ONCOLOGY, Houchens and Merajver[3] have commendably attempted to summarize the results of existing research into the molecular determinants of this aggressive disease. The authors have focused specifically on classical prognostic and predictive markers, although these are not specific to the IBC breast tumor subtype. They have also critically examined data pertaining to the RhoC GTPase and WISP3 genes that have been found to be altered in most IBC tumors. A number of other issues surrounding IBC also deserve special attention to complement the story of this complex disease, including the prognostic impact of a multidisciplinary approach to management, the prognostic role of the HER2/neu gene, and the paradox surrounding the effect of race on survival.

A Multidisciplinary Approach
Perhaps one of the most striking elements of progress witnessed in the management of IBC has been the sequential incorporation of preoperative systemic chemotherapy, followed by surgery and radiation therapy. This multidisciplinary approach has essentially transformed IBC from being a once uniformly fatal disease to one where 15-year survival rates of 20% to 30% have been reported.[4,5] The use of preoperative chemotherapy afforded us the opportunity to observe patients who were able to attain a pathologic complete response (pCR)-a marker that has been shown to be a good surrogate for improved long-term survival outcomes.[6]

The M.D. Anderson group has published one of the largest experiences of preoperative chemotherapy among women with IBC.[5] In this study, women with IBC exhibited 15-year disease-free survival rates of 44%, 31%, and 7% among those who had attained a complete, partial, and less than partial response, respectively,[5] indicating that even among women with IBC, response to treatment is an important surrogate for survival outcome.

The HER2/neu Story
nt out in their review, although a higher proportion of IBC tumors tend to overexpress HER2/neu compared to non–IBC tumors, this marker cannot distinguish between the two subtypes. However, HER2/neu may not confer the same prognostic significance among women with IBC tumors compared to those with non-IBC tumors.

Our group recently reported on a cohort of 179 women with stage III IBC treated at the M.D. Anderson Cancer Center.[7] Among women with HER2/neu-positive disease, trastuzumab (Herceptin) was administered only upon recurrence and not in the adjuvant setting. Our results indicated that unlike findings in women with non-IBC tumors-where HER2/neu overexpression confers a poor prognosis-in the absence of the monoclonal antibody trastuzumab, HER2/neu overexpression did not affect recurrence-free survival. Furthermore, the administration of trastuzumab upon recurrence of disease among women with HER2/neu-positive tumors resulted in improved overall survival above and beyond those with HER2/ neu-negative tumors.

Our group also recently reported that a 60% pCR was achieved in women with HER2/neu-positive IBC tumors who received a combination of preoperative chemotherapy and trastuzumab.[8] This pCR rate is similar to those seen among women with non-IBC HER2/neu-positive tumors receiving a similar combination. Whether the use of adjuvant trastuzumab among women with HER2/neu-positive IBC tumors will achieve the same therapeutic efficacy resulting in survival outcomes similar to those reported in the adjuvant efficacy trastuzumab trials is a question that should be the subject of future prospective observational studies.

The Race Paradox
Several studies have reported a lower incidence of breast cancer associated with a higher mortality among African-American women compared to white women.[9,10] As appropriately pointed out in the review by Houchens and Merajver,[3] this racial disparity appears to be particularly striking among women with IBC, with evidence indicating a higher age-adjusted incidence of IBC and worse prognosis among black women compared to white women. However the authors allude to the fact that the racial disparity observed with this subtype of breast tumor may suggest underlying biologic differences in IBC tumors between black and white women.

Our group recently reported on a cohort of women with early-stage triple-receptor–negative breast cancer who received similar treatment and follow-up, including those with IBC, and observed similar survival outcomes between black and white women.[11] Furthermore, Dean-Colomb and colleagues[12] evaluated the transcriptional profiles of triple-receptor–negative breast tumors and noted that no genes were differentially expressed among black women compared to other women.

Taken together, these pieces of data suggest that the biologic differences seen between racial groups may in fact be due to the higher incidence of adverse prognostic subtypes of breast tumors (eg, triple-receptor–negative subtypes) among black women compared to white women, rather than differences at the genetic level. However further study with larger cohorts specifically looking at this phenomenon among women with IBC tumors is warranted to clarify these observed racial differences.

Moving Beyond the Existing Data
The data on the molecular determinants of IBC as presented by Houchens and Merajver are comprehensive.[3] However, it is clear that these data are limited, with no clear progress made in the past decade regarding our understanding of the molecular features of IBC that drive its aggressive nature. In addition, due to the poor prognosis associated with IBC, prospective clinical trials exclude women with this subtype of breast tumor, resulting in a dearth of data pertaining to ideal treatment regimens suited to this patient population.

Retrospective studies have indicated the importance of a multidisciplinary approach in improving prognostic outcomes, and have given us limited information on the molecular aspects of this disease. We now need larger prospective trials evaluating targeted regimens and looking at the association between response to these regimens and molecular features distinct to this cohort. As the disease is rare, however, such studies need to be multicenter investigations involving diverse geographic locations. The M.D. Anderson Cancer Center has established a group dedicated solely to accurately defining the epidemiology as well as the clinical and molecular features of this disease, with the goal of improving prognostic outcomes in this cohort.

References:

1. Lee BJ, Tannenbaum EN: Inflammatory carcinoma of the breast. Surg Gynecol Obstet 39:580-595, 1924.
2. Hance KW, Anderson WF, Devesa SS, et al: Trends in inflammatory breast carcinoma incidence and survival: The Surveillance, Epidemiology, and End Results program at the National Cancer Institute. J Natl Cancer Inst 97:966-975, 2005.
3. Houchens NW, Merajver SD: Molecular determinants of the inflammatory breast cancer phenotype. Oncology (Williston Park) 22:1556-1561, 2008.
4. Low J, Berman A, Steinberg S, et al: Long-term follow-up for locally advanced and inflammatory breast cancer patients treated with multimodality therapy. J Clin Oncol 22:4065-4074, 2004.
5. Ueno NT, Buzdar AU, Singletary SE, et al:Combined modality treatment of inflammatory breast carcinoma: Twenty years of experience at M.D. Anderson Center. Cancer Chemother Pharmacol 40:321-329, 1997.
6. Kuerer HM, Newman LA, Smith TL, et al: Clinical course of breast cancer patients with complete pathological primary tumor and axillary lymph node response to doxorubicin-based neoadjuvant chemotherapy. J Clin Oncol 17:460-469, 1999.
7. Dawood S, Broglio K, Gong Y, et al, for the Inflammatory Breast Cancer Research Group: Prognostic significance of HER-2 status in women with inflammatory breast cancer. Cancer 112:1905-1911, 2008.
8. Dawood S, Gonzalez-Angulo AM, Broglio K, et al: HER-2 positive inflammatory breast cancer: High pathological response rate with trastuzumab-based neoadjuvant therapy (abstract 4060). Breast Cancer Res Treat 106(suppl 1):2007.
9. Chu KC, Lamar CA, Freeman HP: Racial disparities in breast carcinoma survival rates: Separating factors that affect diagnosis from factors that affect treatment. Cancer 97:2853-2860, 2003.
10. Chlebowski RT, Chen Z, Anderson GL, et al: Ethnicity and breast cancer: Factors influencing differences in incidence and outcome. J Natl Cancer Inst 97:439-448, 2005.
11. Dawood SS, Broglio K, Shu-Wan Kau S,et al: Triple receptor-negative breast cancer: The effect of race on response to primary systemic treatment and survival outcomes (abstract 87). Presented at the 2008 Breast Cancer Symposium; Washington, DC; September 5-7, 2008.
12. Dean-Colomb W, Yan K, Liedtke C, et al: Transcriptional profiles of triple receptor-negative breast cancer: Are Caucasian, Hispanic, and African-American women different (abstract 22014)? J Clin Oncol 26(15S):750s, 2008.