Inflammatory Breast Cancer Registry Research Articles

Abstract PO1-09-10: County-level Social Vulnerability and Survival among Women with Inflammatory Breast Cancer

Abstract Purpose: Inflammatory breast cancer (IBC) is an aggressive form of breast cancer with a poor overall prognosis compared to other forms of breast cancer. Advances in treatment have contributed to improvement in IBC survival rates in recent years, yet disparities in outcomes persist. It is unclear whether social determinants of health impact IBC prognosis independent of access to quality cancer care. Thus, the aim of this study was to examine whether the US county-level social vulnerability index (SVI) was associated with IBC stage at diagnosis and overall survival (OS) among women with IBC treated at a single institution. Methods: Patients enrolled in the IBC registry at Dana-Farber Cancer Institute (DFCI) were included in this study. We linked participant’s residential zip codes to the 2020 CDC’s county-level SVI, which is calculated from 15 social determinants of health attributes from the American Community Survey including socioeconomic status, household composition, language and minority status, and housing and transportation factors. The SVI value reflects the percentile of counties in the nation that are less vulnerable than the county of interest. We assessed associations between SVI and stage at diagnosis using t-tests. Kaplan-Meier curves and log-rank tests were used to assess survival across SVI quartiles based on distribution (1st [least vulnerable] and 4th [most vulnerable]). Using hierarchical logistic regression models and Cox proportional hazards models with mixed effects incorporating cluster-specific random effects that modify the baseline hazard function, we assessed whether SVI is associated with the presence of de novo metastatic disease and OS in IBC. Results: A total of 586 women (86% White) enrolled in the IBC registry at DFCI between 1986 and 2021 were included in this study. Of these, 69.1% had stage III and 30.9% had de novo metastatic disease. 280 deaths occurred in the study population over a mean follow-up of 4.1 years. SVI for the counties where study participants resided ranged from 2.6% to 95.8% (median=34.2%). The mean SVI did not significantly differ according to stage at diagnosis (41.6% in non-metastatic and 40.8% in metastatic at presentation; p=0.70). OS did not significantly differ across SVI quartiles (p-value=0.63). In the age-adjusted models, the SVI was not associated with the presence of de novo metastatic disease (odds ratio (OR (95% CI)=0.99 (0.84, 1.16)) or OS (HR (95% CI)=0.79 (0.46, 1.33). Conclusions: Our findings that residing in socially vulnerable US counties is not associated with the presence of de novo metastatic disease or IBC survival among a subset of women accessing high-quality cancer care suggest that improving access to quality cancer care may overcome underlying socioeconomic factors that contribute to disparities in IBC outcomes. Future studies are needed to confirm these findings in other settings. Citation Format: Kelly Hirko, Elizabeth Troll, Sean Ryan, Faina Nakhlis, Jennifer Bellon, Olga Kantor, Christina Minami, Eren Yeh, Ilana Schlam, Laura Warren, Caroline Block, Susan Schumer, Filipa Lynce. County-level Social Vulnerability and Survival among Women with Inflammatory Breast Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-09-10.

Abstract 4852: High brain relapse rates in stage III triple negative inflammatory breast cancer are independent of systemic therapy

Abstract Background - Inflammatory breast cancer (IBC) is an aggressive subtype of invasive breast carcinoma that confers a comparatively poorer prognosis owing to consistently observed inferior responses to systemic therapies as compared to non-IBC cases. Triple negative (TN) breast cancer which is characterized by lack of estrogen receptor (ER) and progesterone receptor (PR) expression, as well as by lack of HER2 amplification portends particularly poor outcomes including high rates of brain failure. Here we reviewed our prospective IBC registry data for contemporary TNIBC patients to assess current outcomes and brain failure risk in the context of standard neoadjuvant immunotherapy. Methods - Given the change to the inclusion of pembrolizumab in addition to chemotherapy in the neoadjuvant setting in 2020, we reviewed records from 2016-2023 for Stage III TNIBC patients who presented to MD Anderson Cancer Center (MDACC) prior to receiving other therapy. TNIBC was defined as ER <1%, PR <1%, HER2 IHC 0/1+ or ISH-. N = 38. We examined PCR and brain mets as first failure by regimen (KN522, ACT, AC/TC) and compared using descriptive statistics. Log rank statistic was used to compare overall survival (OS) by PCR. Patients with stage III TNIBC who started the KN522 regimen achieved a pCR rate of 35% (N= 20) and pCR was less frequent in postmenopausal KN522 patients (1/7 PCRs. P = 0.016). Among this cohort, 20% of patients experienced relapse in the CNS as a site of first failure including two patients who achieved a PCR, and 25% had any brain failure at a median follow up post-surgery of 8M. Among 9 patients treated with AC/T 22% achieved pCR with 22% brain metastasis relapse rate as site of first failure and 33% overall was observed at a median follow up of 14M post-surgery. In 9 patients receiving AC/TC, the PCR was 44% and any brain relapse rate was 22%, 1/2 was a site of first failure, median follow up 38M. Despite similarities in brain relapse rates, achieving pCR nonetheless correlated with improved overall survival, P < 0.05. For comparison, among 11 stage IV TNIBC patients treated with neoadjuvant systemic therapy pre-KN522, median follow up 22M from initial diagnosis, 6/11 patients developed brain involvement, 5/6 as a site of first failure. Given small numbers it is difficult to compare PCR by regimen, however we note the PCR in KN522 is lower than expected, and the rate of brain metastases particularly as a site of first failure is consistently high across regimens regardless of PCR. It is critical to consider brain penetrance of neoadjuvant systemic therapies, brain staging and even prophylaxis of brain metastasis in patients with non-metastatic and metastatic TNIBC. Current efforts are ongoing to determine molecular signatures which may aid in prognostication and potentially study design to incorporate prophylactic therapies with the overarching goal of improving outcomes in patients with triple negative IBC. Citation Format: Azadeh Nasrazadani, Megumi Kai, Rachel Layman, Vicente Valero, Sadia Saleem, Bisrat G. Debeb, Anthony Lucci, Susie X. Sun, Swetha Bopparaju, Hope E. Murphy, Angela Alexander, Angela N. Marx, Michael C. Stauder, Bora Lim, Wendy A. Woodward. High brain relapse rates in stage III triple negative inflammatory breast cancer are independent of systemic therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4852.

Clinical outcomes of de novo metastatic HER2-positive inflammatory breast cancer

Inflammatory breast cancer (IBC) is a rare, aggressive form of breast cancer that presents as de novo metastatic disease in 20–30% of cases, with one-third of cases demonstrating HER2-positivity. There has been limited investigation into locoregional therapy utilization following HER2-directed systemic therapy for these patients, and their locoregional progression or recurrence (LRPR) and survival outcomes. Patients with de novo HER2-positive metastatic IBC (mIBC) were identified from an IRB-approved IBC registry at Dana-Farber Cancer Institute. Clinical, pathology, and treatment data were abstracted. Rates of LRPR, progression-free survival (PFS), overall survival (OS), and pathologic complete response (pCR) were determined. Seventy-eight patients diagnosed between 1998 and 2019 were identified. First-line systemic therapy comprised chemotherapy for most patients (97.4%) and HER2-directed therapy for all patients (trastuzumab [47.4%]; trastuzumab+pertuzumab [51.3%]; or trastuzumab emtansine [1.3%]). At a median follow-up of 2.7 years, the median PFS was 1.0 year, and the median OS was 4.6 years. The 1- and 2-year cumulative incidence of LRPR was 20.7% and 29.0%, respectively. Mastectomy was performed after systemic therapy in 41/78 patients (52.6%); 10 had a pCR (24.4%) and all were alive at last follow-up (1.3–8.9 years after surgery). Among 56 patients who were alive and LRPR-free at one year, 10 developed LRPR (surgery group = 1; no-surgery group = 9). In conclusion, patients with de novo HER2-positive mIBC who undergo surgery have favorable outcomes. More than half of patients received systemic and local therapy with good locoregional control and prolonged survival, suggesting a potential role for local therapy.

HER2-low inflammatory breast cancer: Clinicopathologic features and prognostic implications

BackgroundHER2)-low expression is a predictive biomarker for novel anti-HER2 antibody-drug conjugates. However, little is known about its clinical significance in inflammatory breast cancer (IBC). MethodsPatients diagnosed with HER2-negative IBC between December 1999 and December 2020 were identified from the Dana-Farber Cancer Institute IBC registry. Patients were divided into HER2-low (IHC 1+ or 2+/ISH–) and HER2-zero (IHC 0), comparing clinicopathologic features and disease outcomes between the two subgroups. ResultsThe study included 276 patients. Among patients with stage III (n = 209) and stage IV (n = 67) IBC, 54% and 39% had HER2-low tumours, respectively. Oestrogen receptor (ER)-expressing tumours were more common in patients with HER2-low versus HER2-zero stage III IBC (65% versus 38%, p < 0.01). Among stage III patients undergoing surgery (n = 182), pathologic complete response (pCR) rates were higher for HER2-zero versus HER2-low IBC (11% versus 6%, OR: 1.8, 95%CI:0.6–5.3), but minimal differences persisted when separately analysing pCR by ER status. Similar invasive disease-free survival (iDFS) outcomes were observed among ER-positive HER2-zero versus HER2-low IBC (48-month iDFS: 63% versus 63%, HR: 1.10, 95%CI:0.57–2.13) and ER-negative HER2-zero versus HER2-low IBC (48-month iDFS: 28% versus 25%, HR: 1.19, 95%CI:0.69–2.04). Differences in overall survival (OS) were small, both among ER-positive HER2-zero versus HER2-low IBC (48-month OS: 80% versus 81%, HR: 0.82, 95%CI:0.39–1.73) and ER-negative HER2-zero versus HER2-low IBC (48-month OS: 34% versus 47%, HR: 1.34, 95%CI: 0.74–2.41). ConclusionsMarginal differences in clinicopathologic features and outcomes were observed in HER2-low versus HER2-zero IBC when controlling for ER status, not supporting the definition of HER2-low as a distinct subtype of IBC.

Inflammatory breast cancer appearance at presentation is associated with overall survival.

BackgroundInflammatory breast cancer (IBC) is a clinical diagnosis. Here, we examined the association of a “classic” triad of clinical signs, swollen involved breast, nipple change, and diffuse skin change, with overall survival (OS).MethodBreast medical photographs from patients enrolled on a prospective IBC registry were scored by two independent reviewers as classic (triad above), not classic, and difficult to assign. Chi‐squared test, Fisher's exact test, and Wilcoxon rank‐sum test were used to assess differences between patient groups. Kaplan–Meier estimates and the log‐rank test and Cox proportional hazard regression were used to assess the OS.ResultsWe analyzed 245 IBC patients with median age 54 (range 26–81), M0 versus M1 status (157 and 88 patients, respectively). The classic triad was significantly associated with smoking, post‐menopausal status, and metastatic disease at presentation (p = 0.002, 0.013, and 0.035, respectively). Ten‐year actuarial OS for not classic and difficult to assign were not significantly different and were grouped for further analyses. Ten‐year OS was 29.7% among patients with the classic sign triad versus 57.2% for non‐classic (p < 0.0001). The multivariate Cox regression model adjusting for clinical staging (p < 0.0001) and TNBC status (<0.0001) demonstrated classic presentation score significantly associated with poorer OS time (HR 2.6, 95% CI 1.7–3.9, p < 0.0001).ConclusionsA triad of classic IBC signs independently predicted OS in patients diagnosed with IBC. Further work is warranted to understand the biology related to clinical signs and further extend the understanding of physical examination findings in IBC.

Dermal Lymphatic Invasion, Survival, and Time to Recurrence or Progression in Inflammatory Breast Cancer.

Dermal lymphatic invasion (DLI) with tumor emboli is a common pathologic characteristic of inflammatory breast cancer (IBC), although its presence is not required for diagnosis. We examined whether documented DLI on skin biopsy was associated with survival and time to recurrence or progression in IBC. A total of 340 women enrolled in the IBC Registry at Dana-Farber Cancer Institute between 1997 and 2019 were included in this study. Kaplan-Meier curves and multivariable Cox proportional hazards models were used to estimate hazard ratios and 95% confidence intervals for associations of DLI and overall survival, time to locoregional recurrence/progression, and distant metastasis by stage at presentation. DLI was detected in 215 (63.2%) of IBC cases overall. At disease presentation, IBC with DLI had a higher prevalence of de novo metastases (37.7% vs. 26.4%), breast skin ulceration (6.1% vs. 2.4%), and lymphovascular invasion within the breast parenchyma (52.9% vs. 25.5%) and a lower prevalence of palpable breast mass (48.2% vs. 70.6%) than IBC without DLI. Over a median follow-up of 2.0 years, 147 deaths occurred. DLI was not associated with survival or recurrence in multivariable models (all P ≥0.10). For example, among women with stage III disease, hazard ratios (95% confidence intervals) for DLI presence was 1.29 (0.77-2.15) for overall survival, 1.29 (0.56-3.00) for locoregional recurrence, and 1.71 (0.97-3.02) for distant metastasis. Although the extent of tumor emboli in dermal lymphatics may be associated with biological features of IBC, DLI was not an independent prognostic marker of clinical outcomes in this study.

Abstract PS14-04: A picture worth a thousand words - “classic” inflammatory breast cancer (IBC) appearance associated with overall survival

Abstract Background: IBC is considered a clinical diagnosis characterized by rapid onset of diffuse skin changes in the setting of a breast cancer diagnosis. A wide variety of visual changes are accurately diagnosed as IBC. Here, we sought to determine whether the most subjectively “classic” appearing presentation (swollen, involved breast with nipple inversion and diffuse skin change) was associated with worse outcomes. Method: We reviewed the images and charts of patients from the prospective IBC registry from the MD Anderson IBC Clinic. Breast medical photographs were reviewed by a non-expert and the visual presentation was scored as classic (as above), not classic, and in between. Comparative analyses were used to assess differences between patient groups using Chi-squared test, or Fisher’s exact test for categorical variables. Wilcoxon rank sum test was used for continuous measures. We used the Kaplan Meier estimator and the log-rank test to investigate association between scoring and survival distributions. Cox proportional hazard regression was employed to assess the impact of important covariates on the overall survival. Results: We analyzed 245 IBC patients with median age 55 (range, 26-81), M0 vs. M1 status (157 and 88 patients, respectively), 68 TNBC vs. 177 non-TNBC patients. The classic presentation was significantly associated with smoking, post-menopausal status, and metastatic disease at presentation (P = 0.002, 0.018, and 0.004, respectively). Presentation was significantly associated with OS in univariate analysis (P &amp;lt; 0.001). 10 year overall survival was 57% vs. 33% for classic (score 3) versus non-classic or in between presentation. The multivariable Cox regression model adjusting for clinical staging (P&amp;lt;0.001) and TNBC status (P&amp;lt;0.001) demonstrated classic presentation score was significantly associated with poorer OS time (HR 2.4, CI 1.6-3.6, p&amp;lt;0.001). Conclusions: A visual inspection of presentation photograph for “classic” appearance, obvious swelling, skin change, and nipple inversion, independently predicted poorer OS in IBC. Further work is warranted to understand the differences in classic and non-classic presentations, and the relationship between smoking and breast cancer presentation. Citation Format: Wintana Balema, Diane Liu, Yu Shen, Randa El-Zein, Megumi Kai, Beth Overmoyer, Kathy D Miller, Carisa Le-Petross, Naoto T Ueno, Wendy A Woodward. A picture worth a thousand words - “classic” inflammatory breast cancer (IBC) appearance associated with overall survival [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS14-04.

Characteristics associated with inflammatory breast cancer (IBC): An epidemiologic study from a dedicated IBC program.

There are scant data identifying epidemiologic characteristics among individuals diagnosed with inflammatory breast cancer (IBC), which is considered the most aggressive subtype of breast cancer. The purpose of this study was to evaluate the epidemiologic features among patients seen at a dedicated IBC program, to elucidate the potential causes of this disease and guide prevention strategies. We reviewed retrospective data from 447 patients enrolled in an IRB-approved IBC registry through Dana-Farber Cancer Institute from 1997 to 2016. The data examined included the following: demographics, medical, reproductive and family history, duration of symptoms prior to the diagnosis of IBC, pathologic characteristics, and clinical outcome. JMP statistical software was used to compile the data. Descriptive statistics were used to evaluate the data. The majority of patients (66.0%) were overweight or obese (body mass index [BMI] ≥25) at the time of diagnosis. Fifty patients (11.1%) had "secondary" IBC, defined as developing IBC after a previous history of non-IBC breast cancer in an ipsilateral breast. Of those patients with secondary IBC, 60% were also overweight or obese at the time of IBC diagnosis. Approximately 58% of IBC patients had a family history of breast or ovarian cancer, including first- and second-degree relatives. This analysis suggested a high frequency of familial breast/ovarian cancer among IBC patients which supports further evaluating genetic risks. This may have implications for screening and prevention strategies as well as insight into additional contributing risk factors. The prevalence of a high BMI among both pre- and postmenopausal women with IBC, including those diagnosed with secondary IBC, warrants focusing on strategies targeting the obesity crisis as a potential means of reducing the risk of developing this disease.

Prevalence of germline variants in inflammatory breast cancer.

Inflammatory breast cancer (IBC) is an uncommon and aggressive subtype of breast cancer associated with early disease recurrence and short survival. The prevalence of germline variants in cancer predisposition genes has not been systematically evaluated in women with IBC. Among 301 women enrolled in the clinical IBC registry at a single institution between 2010 and 2017, 168 had documented genetic testing. A second cohort of 200 IBC cases who had panel-based germline testing performed through a commercial testing laboratory from 2012 to 2017 was added to the analyses. Personal and family cancer histories and genetic testing results were evaluated when they were available for both cohorts. Among 501 IBC cases, 368 had documented genetic testing. Germline mutations (56 total) were identified in 53 cases (14.4%). BRCA1 or BRCA2 mutations were found in 7.3% of the subjects, 6.3% had a mutation in other breast cancer genes (PALB2, CHEK2, ATM, and BARD1), and 1.6% had mutations in genes not associated with breast cancer. The prevalence of mutations was 24% (22 of 92) among women with triple-negative IBC, 13% (13 of 99) among women with estrogen receptor- and/or progesterone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative disease, and 9.3% (10 of 108) among women with HER2-positive IBC. The prevalence and diversity of germline genetic mutations among patients with IBC suggest that further studies should be performed to assess the role of inherited mutations in IBC carcinogenesis in comparison with non-IBC breast cancer. Since IBC has a high metastatic potential associated with poor prognostic outcomes, proposed future studies may also inform targeted treatment options.

Abstract P6-09-10: Association of dermal lymphatic involvement and survival in inflammatory breast cancer

Abstract Purpose: The pathologic hallmark of inflammatory breast cancer (IBC) is the presence of tumor emboli within the papillary and reticular dermis of the skin, termed dermal lymphatic invasion (DLI). DLI can be confirmed with a skin-punch biopsy in approximately 75% of cases, but its presence is not required for the diagnosis of IBC because of variability of tumor emboli in affected areas. The impact of confirming DLI by skin biopsy on the clinical outcome of IBC is unknown. We hypothesize that the ability to confirm DLI by biopsy is associated with a higher tumor emboli load and consequently a poorer disease prognosis. Therefore, we examined whether documented DLI was associated with poorer overall survival (OS) in IBC. Methods: Clinical characteristics were evaluated among 286 women presenting with IBC between 1999 and 2016 and enrolled in the IRB-approved IBC registry at Dana-Farber Cancer Institute. Kaplan-Meier curves were used to estimate overall survival and the log-rank test to examine survival differences based upon the presence of DLI. Multivariable Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals for associations of DLI and risk of death among women with IBC. Results: A total of 102 deaths occurred in our study population over a median follow-up of 2.5 years (yr) (range 10 days to 16 yr). Compared to IBC without DLI, IBC with confirmed DLI was more likely to be associated with the presence of lymphovascular invasion in breast biopsies (73.1% vs. 37.7%; p-value &amp;lt;0.01) but less likely to be seen with edema of the skin (59.1% vs. 81.1%; p-value=0.02). Documented DLI was not related to the presence of de novo metastasis at presentation (11.5% vs. 28.7%; p-value=0.07). OS did not significantly differ among women with IBC based upon the presence of DLI (log-rank test p-value=0.68). In multivariable models, DLI was not independently associated with OS in inflammatory breast cancer, HR(95%CI) = 0.92(0.48-1.78). Conclusions: Our findings suggest that IBC presenting with documented DLI on skin biopsy may vary with regard to clinical characteristics at diagnosis, including lymphovascular invasion within the breast, edema of the skin of the breast, and the presence of de novo metastases. These clinical distinctions suggest potential differences in biology of IBC according to the presence or absence of DLI, and the extent of tumor emboli. However, in this study, DLI was not found to be an independent prognostic factor in IBC with respect to OS. Due to the variability in the clinical features of IBC at presentation and inherent complexities in selecting skin biopsy sites, studies to investigate the accuracy of determining DLI based on punch biopsy are necessary to more comprehensively assess the impact of DLI on clinical outcomes in IBC. Citation Format: Hirko KA, Schlossman J, Harrison BT, Yeh ED, Jacene HA, Nakhlis F, Schlosnagle E, Overmoyer BA. Association of dermal lymphatic involvement and survival in inflammatory breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-09-10.

Distinct epidemiological profiles associated with inflammatory breast cancer (IBC): A comprehensive analysis of the IBC registry at The University of Texas MD Anderson Cancer Center.

BackgroundTo date, studies on inflammatory breast cancer (IBC) lack comprehensive epidemiological data. We analyzed detailed prospectively collected clinical and epidemiological data from the IBC Registry at The University of Texas MD Anderson Cancer Center.MethodsPatients with IBC (n = 248) were consecutively diagnosed and prospectively enrolled between November 2006 and April 2013. All patients were newly diagnosed and at least 18 years old. Secondary IBC was excluded. Overall 160 variables were collected and evaluated including sociodemographics, anthropometrics, tobacco and alcohol consumption, reproductive variables, and family history data.ResultsMean age at diagnosis was 51.6 (±11.5 SD) years, and the majority of patients were White (77.8%). A mean BMI ≥ 25 kg/m2, irrespective of menopausal status, was observed in 80.2% of all patients, with 82.6% of African Americans being obese. Approximately 42.2% of patients were ever smokers, and 91% reported ever being pregnant. A history of breastfeeding was reported in 54% of patients, with significant differences between ethnic groups in favor of White women (P<0.0001). Other reproductive factors such as use of birth control pills & hormone replacement therapy were also more frequently associated with White women compare to other ethnic groups (P < 0.05). In the multivariate Cox proportional hazard analysis, African American or Hispanic ethnicity, not having breastfed, higher clinical stage, and TNBC subtype were associated with shorter survival.ConclusionOur data suggest that IBC is associated with distinct epidemiological profiles. This information could assist in targeting patients with specific preventive strategies based on their modifiable behavioral patterns.

Abstract P6-18-02: Patterns of breast reconstruction in patients diagnosed with inflammatory breast cancer

Abstract Background Inflammatory Breast Cancer (IBC) is a rare and aggressive type of breast cancer treated by multimodality therapy. Due to the presence of dermal lymphatic involvement by disease it is unknown whether a skin sparing mastectomy (SSM) would be safe, even after completion of preoperative chemotherapy, therefore immediate breast reconstruction (BR) following modified radical (MRM) is discouraged. We sought to explore the patterns of BR outcomes in IBC patients (pts) and to evaluate their surgical outcomes. Methods A retrospective analysis was performed using an IRB-approved database of IBC pts evaluated at Dana Farber Cancer Institute (DFCI) from 1997 until 2014. Pts with stage III IBC who received preoperative systemic therapy followed by MRM and post-mastectomy radiation (PMRT) were analyzed. Receipt and timing of BR, post-operative morbidity and subsequent esthetic issues were collected. We also analyzed oncologic events which may have hindered receipt of BR. Results 318 pts were enrolled in the IBC registry at DFCI between 1997 and 2014. 181 pts with stage III IBC were identified, with a median follow-up of 57 months (mo) from MRM. 33/181 pts (18%) underwent BR; 2 pts were not evaluable due to lack of details concerning BR. 12 pts had immediate BR, 10 of which were performed elsewhere, prior to initial evaluation at DFCI. These included 3 tissue expander (TE) reconstructions, 3 single stage implants, 1 deep inferior epigastric perforator (DIEP) flap, 4 transverse rectus abdominis myocutaneous (TRAM) flaps, 1 latissimus dorsi (LD) flap. 19 had delayed BR. These included 1 TE, 5 DIEP flaps, 2 LD flap, 1 TE+LD flap, 10 TRAM flaps. Delayed BR occurred at a median of 13 mo (range 3-64 mo) following completion of PMRT. Complications post-BR were rare. Among the immediate BR pts, 1 pt with a TRAM flap BR required a reoperation 15 days (d) following BR for a partial TRAM flap necrosis. Among the delayed BR pts, one had a reoperation for abdominal TRAM flap donor site wound dehiscence 29 d after BR. Another delayed BR pt, who had a TE+LD flap BR, had her reconstruction implant removed due to chronic hematoma 79 mo after her initial BR; this occurred following 3 operative attempts to salvage her reconstruction by evacuating the hematoma. Overall, 12 reoperations were performed including 6 immediate BR (6/19 (31.6%) and 6 delayed BR pts (6/12 (50.0%); 6 of these reoperations (50%) were done for minor esthetic issues, such as reconstruction revisions for fat necrosis and capsular contracture, in addition to the more significant surgeries described above. Among 148 pts who did not undergo BR, 69 (47%) had disease recurrence following MRM (66 distant +/- local-regional recurrence (LRR); 3 LRR only); within 12 mo of MRM disease recurrence developed in 22% of pts (33/148). Conclusion Only 11% of pts presenting with stage III IBC recieved delayed BR in this retrospective analysis of 181 pts. The majority of these pts achieved successful BR, except for 1 pt. It is possible that BR was not sought more frequently due to a fairly high rate of distant disease relapse (47% in this cohort). Further studies addressing the outcomes of BR in IBC pts are needed in order to assist in counseling pts regarding their reconstructive expectations. Citation Format: Nakhlis F, Regan M, Chun YS, Dominici LS, Jacene HA, Yeh ED, Bellon JR, Warren LE, Hirko K, Hirshfield-Bartek J, Hazra A, Overmoyer BA. Patterns of breast reconstruction in patients diagnosed with inflammatory breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P6-18-02.

Initial Response to Chemotherapy, Not Delay in Diagnosis, Predicts Overall Survival in Inflammatory Breast Cancer Cases

To determine whether chemotherapy response and diagnostic delay affect overall survival (OS) of classic inflammatory breast cancer (IBC) cases receiving chemotherapy as initial treatment and to determine whether OS differs between classic and "atypical" IBC cases. This is a prospective cohort study of 155 patients enrolled in the IBC Registry. "Classic" IBC cases met AJCC or SEER case definitions. "Atypical" IBC cases exhibited classic features but involved <1/2 breast without documented dermal lymphatic invasion. Variables included OS (years from initial chemotherapy treatment until death or last contact), chemotherapy response (complete, partial, or none), diagnostic delay (days from first medical contact for signs/symptoms of abnormal breast to definitive pathologic IBC diagnosis), age at diagnosis (y), and triple-negative status (yes or no). OS curves stratified by individual predictors were estimated and compared using Kaplan-Meier methods and log-rank tests. Associations between OS and predictors were examined collectively using Cox proportional hazards regression. Classic IBC cases with complete, partial, or no response had respective median (95% confidence interval [CI]) OS times of 10.30 (6.78, +), 6.27 (4.42, +), and 2.86 (1.11, 11.42) years (P=0.0072). Chemotherapy response was significantly associated with OS after controlling for covariates (P=0.003). Women not responding to chemotherapy had a significantly higher hazard of death compared with women with complete (hazard ratio [HR]=5.76; 95% CI, 2.09-15.84) or partial (HR=3.40; 95% CI, 1.27-9.10) response. Diagnostic delay was not significantly associated with OS (HR=1.003; 95% CI, 0.999-1.007). OS did not differ significantly between classic and "atypical" IBC cases (P=0.60). Response to standard IBC chemotherapy is a dominant prognostic factor in determining patient outcomes. In our study, with limited statistical power, delay in diagnosis defined as >60 days from the time of first physician contact did not seem to affect patient outcomes. Data support similarities between classic and "atypical" IBC.

Prognostic Value of Lymphocyte Vascular Density and E-Cadherin in Inflammatory Breast Cancer

Background: We recently evaluated four laboratory assays, vascular endothelial growth factor D (VEGF-D), E-cadherin, lymphatic vessel density (LVD) measured by podoplanin, and intra-lymphatic tumor emboli (ILTE), which showed notable differences between inflammatory breast cancer (IBC) and non-inflammatory locally advanced breast cancer (LABC). In this study we investigated the potential of the three most quantitatively measured markers, E-cadherin, LVD and VEGF-D, to predict survival in the IBC patients. Materials and Methods: This study involved the 100 cases identified in the Inflammatory Breast Cancer Registry (IBCR) whose tumors were previously evaluated for the four assays noted above. Living patients were recontacted and survival data were available for up to 17 years. Overall survival (OS) was analyzed through the Kaplan-Meier method stratified by E-cadherin, LVD, VEGF-D, and response to chemotherapy. The differences in OS curves were compared using the log-rank test. Results: The median OS for patients with high LVD was 6.63 years (95% CI: 4.06 to 10.14), compared to median at 10 years not reached in those with low LVD (p = 0.03). There was a trend towards a longer median OS in patients with high E-cadherin (10.14, 95% CI: 6.63 to 11.67), compared with those with low E-cadherin (6.26, 95% CI: 3.42 to undeterminable). VEGF-D levels showed no correlation with survival. Conclusion: Low LVD significantly predicts better survival. High E-cadherin expression, as with non-IBC breast cancer and several other malignancies, tends to be associated with a better prognosis.

Abstract P5-13-06: Seasonal variation in onset of inflammatory breast cancer: Evidence of an infectious trigger

Abstract Introduction: Inflammatory breast cancer (IBC) is a rare but extraordinarily aggressive disease with a number of studies indicating that environmental factors play the most important role. We have identified four reported clusters of IBC and our investigations thus far suggest that local toxic or infectious agents could be involved in the pathogenesis of the disease. IBC, like Burkitt's lymphoma (BL) has been reported to cluster and both have been implicated with infectious agents. Since BL has been reported to have a seasonal variation attributed to acute malaria symptoms as the precipitating agent, we decided to investigate the seasonality of IBC in two populations. Methods: For our analysis we used the datasets of two IBC referral groups. The first group consisted of a series of 163 consecutive cases of patients seen at Fox Chase Cancer Center (FCCC) almost all being from the Northeast U.S. (NE) and Canada. At the time of initial visit a detailed series of questions was specifically directed at identifying the accurate time of the first onset of symptoms/signs including skin rash, swelling, pain, nipple retraction and palpable mass. The second was the IBC registry (IBCR), established at the George Washington University with the purpose of collecting standardized clinical and epidemiologic data (including a detailed interview) and biospecimens from patients with IBC in the U.S and Canada. Complete data on patients in both groups were evaluated, including diagnostic workup, pathologic findings and treatment. Results: Of the 163 FCCC patients, 156 had the month of onset of symptoms clearly delineated. Of the 161 patients in the IBCR, 153 had month of symptomatic onset defined. In the combined groups, 181 NE patients were compared with 63 from the South. A seasonal pattern was noted in the NE patients, a bimodal pattern showing most patients with onset in March and July-Sept. No seasonal pattern was noted in patients from the South. Conclusion: The reports of IBC clusters are consistent with an acute triggering factor, possibly an infection. The seasonality we observed in NE patients but not in southern patients is consistent with this hypothesis. We are currently continuing to investigate clusters of IBC and are testing for specific candidate infectious agents as well as candidate environmental toxic agents to further understand possible triggers for this disease. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P5-13-06.

A Comparison of Epidemiology, Biology, and Prognosis of Inflammatory Breast Cancer in Japanese and US Populations

BackgroundThe epidemiology of inflammatory breast cancer (IBC) in East Asia has not been fully investigated. We hypothesized the epidemiologic factors associated with IBC in Japanese populations are different from other populations. To determine this, we conducted a comparison study assessing multiple clinically relevant risk factors. Patients and MethodsPatients diagnosed with IBC at St. Luke's International Hospital (SLIH) in Tokyo, Japan, and at the University of Texas MD Anderson Cancer Center (MDA) in Houston, Texas, from 2003 to 2009 were identified via the electronic medical records. Stage IV patients were excluded. Epidemiological, biological, and overall survival (OS) data were collected and compared. After all patient populations were combined, Cox proportional hazard regression analysis was performed. ResultsTwenty-two patients at SLIH and 384 patients at MDA were identified. No differences were found for IBC between SLIH and MDA regarding age at diagnosis (P = .898), hormone receptor status (P = .144), overexpression of HER2 (P = .136), or OS (P = .323), however, BMI (P < .01) and nuclear grade (NG) (P < .01) in Japanese patients were lower than those of US patients. Cox proportional hazard regression analysis revealed ER status and race were associated with OS. ConclusionDespite the small number of patients enrolled, IBC in a Japanese population demonstrated lower BMI and lower NG than IBC in a US population with no difference in survival. ER status and race were prognostic factors when the 2 populations were combined. To more robustly define IBC among East Asian individuals, we have started to register Japanese patients with an International IBC Registry.

Nomogram for predicting development of brain metastasis in patients with inflammatory breast cancer.

243 Background: Inflammatory breast cancer (IBC) is associated with poor prognosis and high rates of distant metastasis. Brain metastasis is particularly important due to its morbidity and mortality. The purpose of this study was to construct a nomogram from clinicopathological factors that could predict the risk of occurrence of brain metastasis in patients with IBC. Methods: We performed a retrospective analysis of 406 patients with IBC, who were seen at the University of Texas M. D. Anderson Cancer Center between 1991 and 2009. Data was collected from IBC registry. Patients were divided in a randomized manner into a training cohort (n = 206) and a validation (n = 200) cohort. A multivariate cox proportional hazards regression analysis of selected prognostic features was performed on the training cohort. The model estimated in the training cohort was cross-validated with the validation cohort. Based on this model a nomogram was constructed to assess 5- and 10-year risk of developing brain metastasis. Results: A total of 115 (28%) patients developed brain metastasis. Univariate analysis identified menopausal status, progesterone receptor expression, number of distant metastasis, adjuvant taxane-based therapy and age at diagnosis as significant factors associated with brain metastasis (p &lt; 0.05). Subsequent multivariate analysis showed menopausal status and number of metastasis were independently associated with development of brain metastasis (p &lt; 0.05). Nomogram constructed using above model was evaluated for its ability to discriminate among likelihood of occurrence of brain metastasis in patients, using the validation set. The validation set showed good discrimination with the area under the receiver operating characteristic curve of 0.68. Conclusions: We have formulated a distinct predictive tool to evaluate 5 and 10-year risk for developing brain metastasis in patients with IBC. This nomogram can be potentially helpful for designing risk adapted therapeutic trials. Identifying patients at high risk for brain metastasis in IBC can help personalize therapy, surveillance, and prognostication. [Table: see text]

Abstract 889: Evaluating the case definition of inflammatory breast cancer

Abstract Background: Inflammatory breast cancer (IBC) is recognized as an aggressive form of breast cancer requiring neoadjuvant chemotherapy. Although IBC affects only a small percentage of breast cancer patients, the estimated 4,810 new cases for 2009 exceeds the number of women diagnosed with other cancers, such as acute lymphocytic leukemia and chronic myelocytic leukemia (as reported by the American Cancer Society). Research on IBC is hampered by the absence of an agreed upon case definition. While the American Joint Committee on Cancer (AJCC) relies on clinical features (more than half of the breast being involved with redness, warmth and edema), the National Cancer Institute's Surveillance, Epidemiology and End Results (SEER) Program focuses on pathologic confirmation. This study was undertaken to determine whether the outcome of IBC differs among patients who meet IBC criteria by AJCC, SEER, and private practitioners to try to improve the case definition for research purposes. Methods: This is a retrospective study of 121 patients in The George Washington University Medical Center IBC Registry who were classified as an IBC case by AJCC, SEER or private practitioners. We grouped these IBC cases into four epidemiological categories: (1) clinical-pathologic presentation of disease involving more than half of the breast, (2) clinical-only presentation of disease involving more than half of the breast, (3) clinical-pathologic presentation of disease involving less than half of the breast, and (4) clinical-only presentation of disease involving less than half of the breast. Note that Categories 1 and 2 meet AJCC criteria, while Categories 1 and 3 meet SEER criteria for IBC. We used an unadjusted Cox proportional hazards model to test the homogeneity of the progression-free survival (PFS) curves among these four epidemiological categories. Results: Of the 121 IBC cases, 33.1% (n=40) were classified as Category 1, 16.5% (n=20) were Category 2, 25.6% (n=31) were Category 3, and 24.8% (n=30) were Category 4. Using Category 4 as the reference group, the Cox proportional hazards model yielded insignificant hazard ratios (95% CI) of 1.69 (0.82, 3.51), 0.80 (0.28, 2.28), and 1.98 (0.95, 4.12) for Categories 1, 2, and 3, respectively. Applying the Score test, we found no significant difference in the PFS curves among the four epidemiological categories (χ2=5.87, p=0.12). Conclusions: The case definitions of IBC as proposed by the AJCC and SEER are inadequate. This study suggests that IBC as identified by private practitioners not meeting these criteria have the same poor prognosis as those meeting the case definitions of these national organizations. Preliminary laboratory studies support the conclusion that women with clinical evidence of IBC not involving half of the breast and with no documentation of involvement of the dermal lymphatics have the same disease as those meeting AJCC and SEER diagnostic criteria. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 889.

Clinical Outcomes in Two Different Cohorts of Patients with Inflammatory Breast Cancer (IBC) Treated at the MD Anderson Cancer Center: The Experience of the Morgan Welch IBC Research Program and Clinic.

Abstract BACKGROUND: Inflammatory Breast Cancer (IBC) is a rare but aggressive manifestation of primary breast cancer. Survival in patients with IBC is significantly lower than for non-IBC breast cancer patients. Appropriate diagnostic and treatment strategies provided by a specialized multidisciplinary team could impact the overall prognosis of the disease. We recently established an IBC research program and clinic including investigators from various disciplines solely dedicated to this disease. We sought to compare the characteristics and clinical outcomes of newly diagnosed IBC patients evaluated and treated using novel diagnostic and therapeutic approaches with an historical cohort of IBC patients treated at our institution.METHODS: We included 240 IBC patients treated at MD Anderson Cancer Center between January 1970 and August 2000. In this analysis we compared characteristics, 1 year progression free survival (PFS) and 1 year survival between the historic cohort and 47 patients diagnosed with IBC and seen at our IBC clinic between August 2007 and September 2008. The new patients are part of a prospective IBC registry. All of them had staging and monitoring with breast MRI and FDG-PET/CT. When indicated, they were treated with targeted therapies (e.g. trastuzumab and tipifarnib), that were not available for the patients in the old cohort. Descriptive statistics were used. Kaplan Meier product-limit method was used to calculate survival outcomes, groups were compare by log-rank test.RESULTS: Median age was similar in both cohorts (53 vs 51). In the new cohort 40% of the patients had evidence of distant metastasis at presentation. The most common sites were contralateral lymph nodes (26%), pleura (16%), bone (16%) and liver (11%). In the old cohort only 17% presented with stage IV. 38.7% of the new patients had Her2-neu amplified and 34%, triple receptor negative IBC. There was no difference in 1-year survival between the two groups (92.4% vs. 93.8%, p=0.637). For patients with stage III disease, the 1-year survival was 95% for both groups. The 1 year-PFS was 86.4% in the new cohort compared to 77.9% (p=0.43) in the old cohort. With a median follow up of 13 months, 51%of the patients in the new cohort are disease free and 87% are still alive.CONCLUSIONS: IBC is an aggressive but rare disease with poor prognosis. We have established a specialized IBC research program and clinic that introduces novel concepts and strategies in laboratory, imaging diagnostics and targeted therapies. This approach may accelerate our understanding of the biology, develop new therapeutic strategies and finally improve the outcome of IBC. Early results of this multidisciplinary approach show a modest, but not significant difference in outcome. We hope that with additional patients and longer follow-up a significant improvement in outcomes will become apparent. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5119.

Delay in Treatment Does Not Predict Outcome in Inflammatory Breast Cancer.

Abstract Aim: Inflammatory breast cancer (IBC) is an extremely aggressive form of breast cancer that fortunately has proven to be increasingly controlled by modern multimodal chemotherapy. Many doctors consider the immediate use of chemotherapy as critical to the outcome, and delays in treatment due to diagnostic issues have on occasion led to law suits. One such law suit led us to examine the relative importance of delay in diagnosis and other potential prognostic factors in a series of well documented IBC patients.Methods: 134 patients reported to the North American IBC Registry were evaluated for prognostic factors related to disease outcome. Relevant information included the time intervals between onset of symptoms and first medical visit, first medical visit to onset of chemotherapy, and progression free survival (PFS). Other parameters included initial response to chemotherapy, cell surface receptors and extent of disease at diagnosis. Patients were categorized according to the extent of clinical breast involvement and the presence or absence of dermal lymphatic invasion (DLI).Results: Patients with a delay of diagnosis of 60 days or less had a mean PFS of 4.41 years (N=62) while those with a delay &amp;gt;60 days had a mean PFS of 4.58 years (N=58). Initial response to chemotherapy was an important predictor of outcome: 31 patients with a complete clinical response had a median PFS of 5.12 years vs. 4.38 years for 71 patients that had a partial clinical response and 4.01 years for 15 patients with no significant response or progression of disease. The detection of dermal lymphatic invasion (RR: 2.77; 95%CI: 1.4-5.46) and clinical metastases at diagnosis (RR 2.81. 95% CI:1.16-6.80) were also significantly associated with a poorer outcome. The presence or absence of hormone receptors and HER2-neu markers were not predictive of outcome.Conclusion: Delay in initiating chemotherapy was not a significant factor in determining outcome of IBC. Initial extent of disease and response to chemotherapy were the two most imnportant factors in predicitng outcome of treated patients. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2012.