Inflammatory breast cancer: Epidemiologic data and therapeutic results.

Since the early description more than a century ago, inflammatory breast cancer (IBC) remains an aggressive disease, with a different geographic repartition, with the highest ones incidence reported in the North of Africa (Tunisia, Algeria, Morocco, and Egypt), and the lowest incidence in Western countries (USA, Europe…). In this study, we reviewed the literature using the Surveillance, Epidemiology, and End Results (SEER) database compared to other published series. We observed that in the high incidence areas (North of Africa) when compared to "classical" breast cancer, IBC was associated to younger age (less than 50 years) with rapid evolution of signs and symptoms (in less than 3 up to 6 months), and more aggressive clinical and histopathological-molecular parameters, due to the predominance of triple-negative and HER2+ subtypes in around 60% of cases. An epidemiologic trend was observed in both high and low incidence areas since the eighties are towards reduction of IBC prevalence. Concerning Tunisia, in comparison with the historical series of the 1980s, the incidence decreased in part by applying more stringent diagnostic criteria but also probably due to a slight improvement of the socio-economic level (SEL). This trend was also observed in the US, due to the efforts of collaborative IBC groups from MD Anderson Cancer Center (MDACC), Duke and IBC patient advocacy groups. Therapeutic results are slightly better due to the standardization of a multidisciplinary approach and the use of combined primary chemotherapy and/or targeted therapies (especially in HER2 positive patients), followed by mastectomy plus radiotherapy. The 5-year overall and disease-free survival is at more than 60%, related to an IBC mortality decrease observed in the cohorts of patients treated in the last decade.

Inflammatory breast cancer: As surgical oncologists, what can we do?

Breast cancer surgery is the primary treatment for early-stage breast cancer. However, inflammatory breast cancer (IBC), with its specific presentation characterized by skin invasion, is unfit for primary surgery. According to the different guidelines, the management of IBC is trimodal with the coordination of oncologists, surgeons, and radiation therapists. Advances in breast cancer imaging and the development of more targeted therapies make new challenges for this aggressive cancer. This chapter aims to provide an update on the role of surgery in IBC. Radical surgery is still considered the standard surgical treatment in IBC. Some authors suggest a conservative surgery in patients with a clinical response to chemotherapy without affecting survival. For lymph node surgery, the sentinel lymph node biopsy (SLNB) is not feasible in IBC patients, according to the existing studies. However, prospective studies on SLNB are needed to verify its reliability after chemotherapy for a specific group of patients. In the metastatic IBC, surgery can be considered if there is a good response after chemotherapy or for uncontrolled symptoms. Existing studies showed that surgery may impact survival for these patients. Prospective studies are mandatory to optimize IBC management, considering factors such as tumor's molecular profile.

TBCRC 039: a phase II study of preoperative ruxolitinib with or without paclitaxel for triple-negative inflammatory breast cancer.

BACKGROUND: Patients with inflammatory breast cancer (IBC) have overall poor clinical outcomes, with triple-negative IBC (TN-IBC) being associated with the worst survival, warranting the investigation of novel therapies. Preclinical studies implied that ruxolitinib (RUX), a JAK1/2 inhibitor, may be an effective therapy for TN-IBC. METHODS: We conducted a randomized phase II study with nested window-of-opportunity in TN-IBC. Treatment-naïve patients received a 7-day run-in of RUX alone or RUX plus paclitaxel (PAC). After the run-in, those who received RUX alone proceeded to neoadjuvant therapy with either RUX + PAC or PAC alone for 12 weeks; those who had received RUX + PAC continued treatment for 12 weeks. All patients subsequently received 4 cycles of doxorubicin plus cyclophosphamide prior to surgery. Research tumor biopsies were performed at baseline (pre-run-in) and after run-in therapy. Tumors were evaluated for phosphorylated STAT3 (pSTAT3) by immunostaining, and a subset was also analyzed by RNA-seq. The primary endpoint was the percent of pSTAT3-positive pre-run-in tumors that became pSTAT3-negative. Secondary endpoints included pathologic complete response (pCR). RESULTS: Overall, 23 patients were enrolled, of whom 21 completed preoperative therapy. Two patients achieved pCR (8.7%). pSTAT3 and IL-6/JAK/STAT3 signaling decreased in post-run-in biopsies of RUX-treated samples, while sustained treatment with RUX + PAC upregulated IL-6/JAK/STAT3 signaling compared to RUX alone. Both treatments decreased GZMB+ T cells implying immune suppression. RUX alone effectively inhibited JAK/STAT3 signaling but its combination with PAC led to incomplete inhibition. The immune suppressive effects of RUX alone and in combination may negate its growth inhibitory effects on cancer cells. CONCLUSION: In summary, the use of RUX in TN-IBC was associated with a decrease in pSTAT3 levels despite lack of clinical benefit. Cancer cell-specific-targeting of JAK2/STAT3 or combinations with immunotherapy may be required for further evaluation of JAK2/STAT3 signaling as a cancer therapeutic target. TRIAL REGISTRATION: www. CLINICALTRIALS: gov , NCT02876302. Registered 23 August 2016.

Clinical outcomes after 1 versus 2-3 lines of neoadjuvant therapy in stage III inflammatory breast cancer.

PURPOSE: Many stage III inflammatory breast cancer (IBC) patients experience a sufficient response to first-line (1L) neoadjuvant chemotherapy (NAC) to allow surgery, while some require additional NAC. We evaluated the pathologic complete response (pCR), breast cancer-free survival (BCFS) and overall survival (OS) among patients requiring 1 vs. 2-3 lines (L) of NAC prior to surgery. METHODS: Stage III IBC patients from 2 institutions who received 1L or 2-3L of NAC prior to surgery were identified. Hormone receptor and HER2 status, grade, and pCR were evaluated. BCFS and OS were evaluated by the Kaplan-Meier method. Multivariable Cox models were utilized to estimate the hazard ratio (HR). RESULTS: 808 eligible patients (1997-2020) were identified (median age 51 years, median follow-up 69 months). 733 (91%) had 1L and 75 (9%) had 2-3L of NAC. Grade III, triple-negative and HER2-positive disease were more prevalent in 2-3L patients. 178 (24%) 1L and 14 (19%) 2-3L patients had pCR. 376 1L patients and 41 2-3L patients had recurrences. The 5-year BCFS was worse for the 2-3L group (33 vs. 46%, HR = 1.37; 95% CI 0.99-1.91). However, in 192 patients with a pCR, BCFS was similar (76 vs. 83% in 1L vs. 2-3L, respectively). There were 308 deaths (276 among 1L and 32 among 2-3L patients). The 5-year OS in 1L vs. 2-3L was 60 vs. 53% (HR = 1.32, 95% CI 0.91-1.93). CONCLUSIONS: Among stage III IBC patients, pCR rates were similar, irrespective of the NAC lines number, and BCFS and OS were comparable with pCR after 1L and 2-3L.

Inflammatory Breast Cancer: Understanding the Patient Experience.

BACKGROUND: Inflammatory breast cancer (IBC) is an aggressive, locally advanced cancer with a 5-year survival rate of approximately 40%. Although patients with IBC likely experience significant and variable symptom burden from diagnosis through survivorship, the description of the symptom burden in this population is limited. OBJECTIVES: The purpose of this study was to describe the experience of patients with IBC and define the content domain for a patient-reported outcome measure of IBC symptom burden. METHODS: Twenty patients with IBC described their experience in single qualitative interviews. Content analysis was used to define the symptom burden content domain. Relevance ratings by a panel of experts reduced the number of items for a preliminary patient-reported outcome symptom burden measure. RESULTS: The mean (SD) participant age was 52.8 (12.0) years; 50.0% had distant metastatic disease, and 85.0% were currently receiving treatment. Content analysis revealed 45 symptoms, with 20 symptoms reported by greater than or equal to 20% of participants. All participants described localized disease-related symptoms. Treatment-related symptoms varied among participants based on the modalities received. CONCLUSION: Patients with IBC experience symptom burden that is distinct from the symptom burden experienced by patients with non-IBC. IMPLICATIONS FOR PRACTICE: Differentiating the disease-related symptoms of IBC may assist clinicians in making timely and accurate diagnoses for IBC. A disease- and treatment-specific measure of the symptom burden of IBC should be incorporated in clinical practice to allow for regular assessment and evaluation of symptom burden and implementation of evidence-based interventions for symptom management.

Treatment Response, Tumor Infiltrating Lymphocytes and Clinical Outcomes in Inflammatory Breast Cancer-Treated with Neoadjuvant Systemic Therapy.

Inflammatory breast cancer (IBC) is a rare (1%-5%), aggressive form of breast cancer, accounting for approximately 10% of breast cancer mortality. In the localized setting, standard of care is neoadjuvant chemotherapy (NACT) ± anti-HER2 therapy, followed by surgery. Here we investigated associations between clinicopathologic variables, stromal tumor-infiltrating lymphocytes (sTIL), and pathologic complete response (pCR), and the prognostic value of pCR. We included 494 localized patients with IBC treated with NACT from October 1996 to October 2021 in eight European hospitals. Standard clinicopathologic variables were collected and central pathologic review was performed, including sTIL. Associations were assessed using Firth logistic regression models. Cox regressions were used to evaluate the role of pCR and residual cancer burden (RCB) on disease-free survival (DFS), distant recurrence-free survival (DRFS), and overall survival (OS). Distribution according to receptor status was as follows: 26.4% estrogen receptor negative (ER-)/HER2-; 22.0% ER-/HER2+; 37.4% ER+/HER2-, and 14.1% ER+/HER2+. Overall pCR rate was 26.3%, being highest in the HER2+ groups (45.9% for ER-/HER2+ and 42.9% for ER+/HER2+). sTILs were low (median: 5.3%), being highest in the ER-/HER2- group (median: 10%). High tumor grade, ER negativity, HER2 positivity, higher sTILs, and taxane-based NACT were significantly associated with pCR. pCR was associated with improved DFS, DRFS, and OS in multivariable analyses. RCB score in patients not achieving pCR was independently associated with survival. In conclusion, sTILs were low in IBC, but were predictive of pCR. Both pCR and RCB have an independent prognostic role in IBC treated with NACT. SIGNIFICANCE: IBC is a rare, but very aggressive type of breast cancer. The prognostic role of pCR after systemic therapy and the predictive value of sTILs for pCR are well established in the general breast cancer population; however, only limited information is available in IBC. We assembled the largest retrospective IBC series so far and demonstrated that sTIL is predictive of pCR. We emphasize that reaching pCR remains of utmost importance in IBC.

Dysregulated Stem Cell Markers Musashi-1 and Musashi-2 are Associated with Therapy Resistance in Inflammatory Breast Cancer.

BACKGROUND AND AIM: While preliminary evidence points to pro-tumorigenic roles for the Musashi (MSI) RNA-binding proteins Musashi-1 (MSI1) and Musashi-2 (MSI2) in some breast cancer subtypes, no data exist for inflammatory breast cancer (IBC). METHODS: MSI gene expression was quantified in IBC SUM149PT cells. We then used small interfering RNA-based MSI1 and MSI2 double knockdown (DKD) to understand gene expression and functional changes upon MSI depletion. We characterized cancer stem cell characteristics, cell apoptosis and cell cycle progression via flow cytometry, mammospheres via spheroid assays, migration and proliferation via digital holographic microscopy, and cell viability using BrdU assays. Chemoresistance was determined for paclitaxel and cisplatin with MTT assays and radioresistance was assessed with clonogenic analyses. In parallel, we supported our in vitro data by analyzing publicly available patient IBC gene expression datasets. RESULTS: MSI1 and MSI2 are upregulated in breast cancer generally and IBC specifically. MSI2 is more commonly expressed compared to MSI1. MSI DKD attenuated proliferation, cell cycle progression, migration, and cell viability while increasing apoptosis. Stem cell characteristics CD44(+)/CD24(-), TERT and Oct4 were associated with MSI expression in vivo and were decreased in vitro after MSI DKD as was ALDH expression and mammosphere formation. In vivo, chemoresistant tumors were characterized by MSI upregulation upon chemotherapy application. In vitro, MSI DKD was able to alleviate chemo- and radioresistance. CONCLUSIONS: The Musashi RNA binding proteins are dysregulated in IBC and associated with tumor proliferation, cancer stem cell phenotype, chemo- and radioresistance. MSI downregulation alleviates therapy resistance and attenuates tumor proliferation in vitro.

Implementation of a Multidisciplinary Inflammatory Breast Cancer Program for Quality Improvement.

BACKGROUND: Inflammatory Breast Cancer (IBC) is a rare but aggressive subtype of breast cancer accounting for only 1% to 5% of cases but comprising 7% to 10% of breast cancer deaths. Diagnosis of IBC can be challenging which can lead to delays in diagnosis and treatment. We formed a multidisciplinary IBC program to address the unique challenges of diagnosing and treating patients with IBC. MATERIALS AND METHODS: We retrospectively identified patients with an IBC CPT code and collected data on the date of the first visit with medical oncology, surgical oncology, or radiation oncology, date of biopsy, and initiation of neoadjuvant chemotherapy. In 2020, as part of the IBC program at The Ohio State University, the decision tree (DT) was revised to help identify potential IBC patients. These patients were prioritized with a multidisciplinary appointment within 3 days. RESULTS: After adjusting the call center DT, there was a significant decline in the median and mean time from initial contact to chemotherapy initiation and an insignificant decrease in the mean time from contact to biopsy (P = .71884). The median time of contact to chemotherapy was 10 days (range 9-14) in 2020, a decrease of 43% compared to 3 prior years (P = .0068). After initiation of the IBC program, 100% of patients underwent trimodality therapy-neoadjuvant systemic therapy, modified radical mastectomy, and post mastectomy radiation therapy. CONCLUSION: A multidisciplinary IBC program that included scheduling DT with specific questions about IBC symptoms helped identify potential patients and significantly decrease time to treatment and assured completion of trimodality therapy.

Preoperative Radiation Therapy for Chemorefractory Localized Inflammatory Breast Cancer.

PURPOSE: Inflammatory breast cancer (IBC) is a rare breast cancer subtype. Chemorefractory nonmetastatic IBC, defined by locoregional progression under neoadjuvant chemotherapy, is a rare situation with few therapeutic options. Owing to the rarity of this clinical presentation and the lack of specific data, no specific management guidelines exist. We evaluated whether preoperative radiation therapy/chemoradiotherapy could achieve locoregional control after first-line neoadjuvant chemotherapy in patients with IBC. METHODS AND MATERIALS: Patients with chemorefractory disease receiving preoperative radiation therapy were identified from a retrospective multicenter cohort of consecutive patients with IBC diagnosed between 2010 and 2017 at 7 oncology centers in France. RESULTS: Overall, 18 patients among the 364 patients (5%) treated for IBC had progressive disease during neoadjuvant chemotherapy. These patients had aggressive tumors with lymph node involvement at diagnosis (n = 17; 94.4%), triple-negative subtype (n = 11; 61.1%), Scarff Bloom and Richardson grade 3 (n = 10; 55.6%), and high Ki67 (median, 56.0%). After preoperative radiation therapy, all patients had a complete (n = 1; 5.6%) or partial (n = 17; 94.4%) locoregional response. One patient (5.6%) experienced acute grade 3 dermatitis. Twelve (66.7%) patients underwent surgery as planned. The estimated median follow-up was 31 months. The median overall survival, disease-free survival, distant metastases-free survival, and locoregional recurrence-free survival were 19 months, 4.5 months, 5 months, and 6 months, respectively. Ultimate locoregional control was obtained for 11 patients (61.1%), and 13 patients (72.2%) experienced metastatic progression. Triple-negative subtype (hazard ratio [HR], 15.54; P = .011) and surgery (HR, 0.23; P = .030) were significantly associated with overall survival in the univariate analysis. In multivariate analyses, the triple-negative subtype remained a significant prognostic factor (HR, 13.04; P = .021) for overall survival. CONCLUSIONS: Preoperative radiation therapy is a feasible approach with acceptable toxicities. It allowed surgery and ultimate locoregional control in a majority of patients. The lack of translation into better survival has been a challenge, in part owing to the metastatic propensity of patients with chemorefractory IBC, especially in the overrepresented triple-negative population in this series.

Clinical outcomes of curative-intent multimodal management of chemorefractory nonmetastatic inflammatory breast cancer.

INTRODUCTION: Chemorefractory nonmetastatic inflammatory breast cancer (IBC) which progresses under neoadjuvant chemotherapy poses specific therapeutic challenges: either pursuing a curative-intent treatment with a salvage combination of radiotherapy and surgery or switching to second-line systemic treatments despite the absence of metastasis. Due to the rarity of this situation, no specific management guidelines exist and the outcomes of these patients remain uncertain. In this retrospective observational study, we aimed to report the clinical outcomes of patients treated in a curative intent for chemorefractory nonmetastatic IBC, with a multimodal salvage treatment combining radiotherapy and surgery. MATERIALS AND METHODS: This single-center retrospective observational study included all chemorefractory nonmetastatic IBC treated at the Institut Curie (Paris, France). Overall survival (OS), disease-free survival (DFS), and locoregional relapse-free survival (LRRFS) were calculated from the time of diagnosis and from the time of neoadjuvant chemotherapy interruption. RESULTS: Between January 2010 and January 2018, 7 patients presented with chemorefractory nonmetastatic IBC with a progressive disease during neoadjuvant chemotherapy. Overall, chemorefractory IBC patients were young (median age of 50 years), had a good performance status, and usually presented with node-positive tumors characterized by a combination of adverse histological factors such as triple-negative breast cancer (TNBC), grade III, and high proliferation index. From the date of pathological diagnosis, 1­year OS, DFS, and LRRFS were 64.3%, 53.6%, and 71.4%, respectively. From the date of neoadjuvant chemotherapy interruption, 1­year OS, DFS, and LRRFS were 47.6%, 19.0%, and 45.7%, respectively, and median OS, DFS, and LRRFS were 8.3, 5.0, and 5.0 months, respectively. CONCLUSION: The prognosis of chemorefractory nonmetastatic IBC treated with a multimodal approach combining surgery and radiotherapy is particularly reserved, despite the curative intent of the salvage treatment and the lack of distant metastasis at the time of treatment. Optimal treatment modalities are still to be defined in this rare but critical presentation of IBC.

Prognostic value of a modified systemic inflammation score in breast cancer patients who underwent neoadjuvant chemotherapy.

BACKGROUND AND PURPOSE: The modified systemic inflammation score (mSIS) system, which is constructed based on the neutrophil to lymphocyte ratio (NLR) and albumin (Alb), has not been applied to evaluate the prognosis of malignant breast cancer patients who underwent neoadjuvant chemotherapy (NAC). The present study aimed to explore the relationship between the mSIS and overall survival (OS), disease-free survival (DFS) and pathological complete response (pCR). METHODS: A total of 305 malignant breast tumor patients who underwent NAC were incorporated into this retrospective analysis. We determined OS and DFS using K-M survival curves and the log-rank test. The relationship between the mSIS and OS and DFS was evaluated by a Cox regression model. A nomogram was constructed based on Cox regression analysis. RESULTS: Patients in the mSIS low-risk group had better 5- and 8-year OS rates than those in the mSIS high-risk group (59.8% vs. 77.0%; 50.1% vs. 67.7%; X2 = 8.5, P = 0.0035, respectively). Patients in the mSIS (1 + 2 score) + pCR subgroup had the highest 5- and 8-year OS and disease-free survival (DFS) rates (OS: 55.0% vs. 75.7% vs. 84.8, 42.8% vs. 65.7% vs. 79.8%, X2 = 16.6, P = 0.00025; DFS: 38.8% vs. 54.7% vs. 76.3%, 33.3% vs. 42.3 vs. 72.1%, X2 = 12.4, P = 0.002, respectively). Based on the mSIS, clinical T stage and pCR results, the nomogram had better predictive ability than the clinical TNM stage, NLR and Alb. CONCLUSIONS: mSIS is a promising prognostic tool for malignant breast tumor patients who underwent NAC, and the combination of mSIS and pCR is helpful in enhancing the ability to predict a pCR.

EGFR is a master switch between immunosuppressive and immunoactive tumor microenvironment in inflammatory breast cancer.

Inflammatory breast cancer (IBC), the most aggressive breast cancer subtype, is driven by an immunosuppressive tumor microenvironment (TME). Current treatments for IBC have limited efficacy. In a clinical trial (NCT01036087), an anti-EGFR antibody combined with neoadjuvant chemotherapy produced the highest pathological complete response rate ever reported in patients with IBC having triple-negative receptor status. We determined the molecular and immunological mechanisms behind this superior clinical outcome. Using novel humanized IBC mouse models, we discovered that EGFR-targeted therapy remodels the IBC TME by increasing cytotoxic T cells and reducing immunosuppressive regulatory T cells and M2 macrophages. These changes were due to diminishing immunosuppressive chemokine expression regulated by transcription factor EGR1. We also showed that induction of an immunoactive IBC TME by an anti-EGFR antibody improved the antitumor efficacy of an anti-PD-L1 antibody. Our findings lay the foundation for clinical trials evaluating EGFR-targeted therapy combined with immune checkpoint inhibitors in patients with cancer.

MARCKS as a Potential Therapeutic Target in Inflammatory Breast Cancer.

Inflammatory breast cancer (IBC) is the most pro-metastatic form of breast cancer (BC). We previously demonstrated that protein overexpression of Myristoylated Alanine-Rich C Kinase Substrate (MARCKS) protein was associated with shorter survival in IBC patients. MARCKS has been associated with the PI3K/AKT pathway. MARCKS inhibitors are in development. Our objective was to investigate MARCKS, expressed preferentially in IBC that non-IBC (nIBC), as a novel potential therapeutic target for IBC. The biologic activity of MPS, a MARCKS peptide inhibitor, on cell proliferation, migration, invasion, and mammosphere formation was evaluated in IBC (SUM149 and SUM190) and nIBC (MDA-MB-231 and MCF7) cell lines, as well as its effects on protein expression in the PTEN/AKT and MAPK pathways. The prognostic relevance of MARCKS and phosphatase and tensin homolog (PTEN) protein expression as a surrogate marker of metastasis-free survival (MFS) was evaluated by immunohistochemistry (IHC) in a retrospective series of archival tumor samples derived from 180 IBC patients and 355 nIBC patients. In vitro MPS impaired cell proliferation, migration and invasion, and mammosphere formation in IBC cells. MARCKS inhibition upregulated PTEN and downregulated pAKT and pMAPK expression in IBC cells, but not in nIBC cells. By IHC, MARCKS expression and PTEN expression were negatively correlated in IBC samples and were associated with shorter MFS and longer MFS, respectively, in multivariate analysis. The combination of MARCKS-/PTEN+ protein status was associated with longer MFS in IBC patient only (p = 8.7 × 10-3), and mirrored the molecular profile (MARCKS-downregulated/PTEN-upregulated) of MPS-treated IBC cell lines. In conclusion, our results uncover a functional role of MARCKS implicated in IBC aggressiveness. Associated with the good-prognosis value of the MARCKS-/PTEN+ protein status that mirrors the molecular profile of MPS-treated IBC cell lines, our results suggest that MARCKS could be a potential therapeutic target in patients with MARCKS-positive IBC. Future preclinical studies using a larger panel of IBC cell lines, animal models and analysis of a larger series of clinical samples are warranted in order to validate our results.

Forecasting factors and outcomes in hawkish inflammatory breast carcinoma - A single center data exploration.

INTRODUCTION: Inflammatory breast carcinoma (IBC) is an aggressive clinical syndrome of invasive breast carcinoma. There is paucity of data regarding the outcomes in IBC. OBJECTIVES: Analyses of OS and Event-free survival (EFS) in nonmetastatic and metastatic IBC and to find prognostic factors influencing them. METHODOLOGY: In this single center, retrospective study the data of patients fulfilling the clinical criteria of IBC were retrieved from 2016 to 2021. The impact of prognostic factors on OS and EFS were analysed by log rank test (univariate analysis). The OS and EFS were depicted as Kaplan Meier survival curves. RESULTS: There were 22 patients with IBC. Median follow-up was 17 months. The median OS was significantly better in non-metastatic(M0) compared to metastatic IBC (25 months vs 6 months) with 3year OS rate of 50% vs 0% respectively. The post-menopausal status, grade 2 histology and trimodality treatment showed better outcome while N3 stage at diagnosis had worse outcome in M0 group. The lesser HR expression, lesser pCR rates, higher N3 proportion, liver metastasis and multiple metastatic site involvement contributed to the worse outcome observed in this study. CONCLUSION: The aggressive clinicopathological features of IBC in the present study resulted in less favourable outcome compared to literature review. Improved outcome with trimodality highlights the emergent need for additional targeted therapy to improve pCR and operability.

Inflammatory breast cancer with excellent response to pembrolizumab-chemotherapy combination: A case report.

Inflammatory breast cancer (IBC) is a rare variety of breast cancer accounting for two percent of breast cancer diagnoses in the United States. It is characterized by peau d'orange, breast edema and erythema on physical examination and dermal lymphatic invasion by tumor emboli on histological examination. Micrometastases to lymphatics and bone marrow at the time of diagnosis and angiogenic properties of IBC explain the high propensity of this cancer to relapse and metastasize, its aggressiveness and poor prognosis. Preoperative sequential anthracycline and taxane (plus trastuzumab and pertuzumab if HER2-positive) based chemotherapy is the current standard of care for IBC. We herein report a case of stage IIIC triple-negative IBC treated with pembrolizumab plus chemotherapy based neoadjuvant therapy with a complete clinical and complete pathological response. This is the first case of triple-negative IBC treated with this regimen reported in the literature, thereby providing clinical data on the tolerability and efficacy of pembrolizumab plus chemotherapy based neoadjuvant regimen for the treatment of IBC.

Changes in Ki-67 in Residual Tumor and Outcome of Primary Inflammatory Breast Cancer Treated With Trimodality Therapy.

BACKGROUND: Limited data are available on the prognostic role of Ki-67 changes in residual tumors after neoadjuvant chemotherapy in primary inflammatory breast cancer (IBC) patients treated with trimodality therapy. This study aims to evaluate changes in Ki-67 associated with disease-free survival (DFS) and overall survival (OS) in IBC patients without pathological complete response. PATIENTS AND METHODS: We identified a cohort of primary IBC patients with matched pre- and posttreatment samples treated with anthracycline and taxane-based regimen. All patients had a pathological evaluation, including ER, PR, HER2 status, and Ki-67 expression performed both at diagnostic core biopsy and at final surgery. Kaplan-Meier and Cox proportional hazards methods were used to assess DFS and OS rates and their relationship with clinicopathological features. RESULTS: Two hundred and ten patients with stage III IBC were included. Sixty-three percent of residual tumors showed a decrease in Ki-67 positivity by at least 1%. The decrease of Ki-67 significantly correlated with better DFS (p = .001) and OS (P = .010) compared with no decrease, particularly in the luminal B-like and HER2-positive subgroups. The multivariate analysis showed that the decrease in Ki-67 level had a significant positive predictive value on DFS (HR = 0.47, 95% CI: 0.33-0.67; P< .001) and OS (HR = 0.59, 95% CI: 0.36-0.82; P= .004) in all IBC patients. CONCLUSION: The decrease of Ki-67 expression after neoadjuvant chemotherapy has a prognostic significance in IBC patients with residual disease. Evaluation of Ki-67 changes may help to identify subgroups of patients with worse outcome to receive novel treatment in this setting.

A Phase II Study Evaluating the Safety and Efficacy of Sunitinib Malate in Combination With Weekly Paclitaxel Followed by Doxorubicin and Daily Oral Cyclophosphamide Plus G-CSF as Neoadjuvant Chemotherapy for Locally Advanced or Inflammatory Breast Cancer.

INTRODUCTION: Neoadjuvant chemotherapy is standard treatment for locally advanced breast cancer (LABC) or inflammatory breast cancer (IBC). We hypothesized that adding sunitinib, a tyrosine kinase inhibitor with antitumor and antiangiogenic activity, to an anthracycline and taxane regimen would improve pathologic complete response (pCR) rates to a prespecified endpoint of 45% in patients with HER2-negative LABC or IBC. METHODS: We conducted a multicenter, phase II trial of neoadjuvant sunitinib with paclitaxel (S+T) followed by doxorubicin and cyclophosphamide plus G-CSF for patients with HER2-negative LABC or IBC. Patients received sunitinib 25 mg PO daily with paclitaxel 80 mg/m2 IV weekly ×12 followed by doxorubicin 24 mg/m2 IV weekly + cyclophosphamide 60 mg/m2 PO daily with G-CSF support. Response was evaluated using pCR in the breast and the CPS + EG score (clinical-pathologic scoring + estrogen receptor [ER] and grade). RESULTS: Seventy patients enrolled, and 66 were evaluable for efficacy. Eighteen patients (27%) had pCR in the breast (10 had ER+ disease and 8 had triple-negative disease). When defining response as pCR and/or CPS + EG score ≤2, 31 (47%) were responders. In pateints with ER positive disease, 23 (64%) were responders. The most common toxicities were cytopenias and fatigue. CONCLUSIONS: Neoadjuvant S+T followed by AC+G-CSF was safe and tolerable in LABC and IBC. The study did not meet the prespecified endpoint for pCR; however, 47% were responders using pCR and/or CPS + EG score ≤2. ER positive patients had the highest response rate (64%). The addition of sunitinib to neoadjuvant chemotherapy may provide promising incremental benefit for patients with ER positive LABC.