Advanced Inflammatory Breast Cancer Research Articles

Survival outcomes seen with neoadjuvant chemotherapy in the management of locally advanced inflammatory breast cancer (IBC) versus matched controls

Inflammatory breast cancer (IBC) poses an ongoing challenge as rates of disease recurrence and mortality remain high compared to stage-matched controls. However, frontline therapy has evolved through the years, including the widespread use of neoadjuvant chemotherapy (NAC) given the prognostic importance of pathologic complete response (pCR). Due to these sweeping changes, we need new data to assess current recurrence and survival outcomes for locally advanced IBC in the context of matched non-inflammatory controls. We conducted a retrospective analysis of institutional IBC data from 2010 to 2016 with the primary objective of comparing overall survival (OS), relapse-free survival (RFS), and distant relapse-free survival (DRFS). We matched IBC patients to non-inflammatory controls based on age, receptor status, tumor grade, clinical stage, and receipt of prior NAC. Secondary objectives included assessing pCR rates and identifying prognostic factors. Among NAC recipients, we observed similar pCR rates (47.6 % vs. 49.4 %, p = 0.88) between IBC (n = 84) and matched non-IBC (n = 81) cohorts. However, we noted a significant worsening of OS (p = 0.0001), RFS (p = 0.0001), and DRFS (p = 0.001) in the IBC group. Specifically, 5-year OS in the IBC cohort was 58.9 % vs. 86.7 % for matched controls (p = 0.0003). Older age was a weak negative predictor for OS (HR 1.03, p = 0.001) and RFS (HR 1.02, p = 0.01). For DRFS, older age was also a weak negative predictor (HR 1.02, p = 0.02), whereas the use of NAC was a positive predictor (HR 0.47, p = 0.02). Despite no clear difference in pCR, survival outcomes remain poor for IBC compared to matched non-inflammatory controls.

Abstract P1-03-06: Development of patient-derived xenograft tumor models and 3D spheroid culture from advanced hormone receptor-positive inflammatory breast cancer patients for evaluation of new therapeutics

Abstract Background: Breast cancer (BC) is a heterogeneous disease comprising different clinical, histopathological, and molecular subtypes. Hormone receptor-positive (HR+) advanced BC cancer, in particular the inflammatory BC (IBC) represents a significant clinical challenge because of the development of endocrine resistance during either adjuvant or metastatic treatment translating to poor outcome. We aim to develop unique PDX tumor models and 3D spheroid/organoid cultures that recapture advanced IBC using pleural effusions or/and circulating tumor cells (CTCs) as tumor resource and that can help understand the mechanism of IBC metastasis for new drug development. Methods: Five samples of pleural effusion-derived tumor cells or circulating tumor cells (CTCs) from three advanced IBC patients were obtained from Northwestern Memorial Hospital to establish IBC PDX tumor model in immunodeficient NSG female mice via subcutaneous or breast fat pad xenografting and develop the derived 3D organoid/spheroid cultures for anti-cancer drug evaluation. STR profiling against with original patient tumor DNA was conducted to confirm the tumor authentication. Results: Three developed IBC PDX tumor models (one HR+-IBC and two triple negative (TN)-IBC) were demonstrated by pathology to have highly heterogeneous characteristics and metastatic features similar to the original patient tumor. NSG mice xenografted with original TN-IBC pleural effusion, or derived spheroid cultures with varying passage numbers (<3 passages or >6 passages) manifested different inflammatory clinical symptoms. Mice xenografted with one case of original TN-IBC pleural effusion cells (~40% of tumor-associated macrophages and ~60% of tumor cells) developed palpable tumors and was shown to have the most IBC-like characteristics including reddish skin and ulcerative lesions. They were sacrificed 2 months after xenograft due to declining health. Mice xenografted with >6 passages or <3 passages of spheroid cultures manifested little to moderate skin lesions and developed tumor sizes of ~1 cm within 2-3 months while having a longer life span. Liver and lung metastases were observed in the breast fat pad of xenografted PDX tumor mice with one case of original HR+-IBC pleural effusion. 3D tumor spheroid/organoid cultures were successfully established from original IBC pleural effusion or/and IBC PDX tumor cultures. Spheroid generated from HR+-IBC pleural effusion showed phenotypic plasticity: the HR+-IBC spheroid cells display both tumor and macrophage cell characteristics and spheroid cultures can convert to adhesive cell phenotypes with addition of condition media. These spheroid/organoid cultures are used for evaluation of new drug strategies such as selectively targeting ER degraders (SERDS), CDK4/6 inhibitor, or Tyrosine kinase inhibitors for treatment of HR+-IBC or TN-IBC. Conclusions: Our results suggested 3D spheroid cultures and PDX tumor models from advanced IBC recapture aggressive features of the disease and can be an ideal model for the mechanism study of metastatic advanced IBC and preclinical testing of novel agents in IBC and endocrine resistant disease. Citation Format: Wenan Qiang, Zhangfeng Zhong, Pamela Monahan, Kristy Tse, Youbin Zhang, Qiang Zhang, Lorenzo Gerratana, Andrew Davis, Demirkan Gursel, Reiner Bleher, Jian-Jun Wei, Charles D. James, Thomas V. O’Halloran, Massimo Cristofanilli. Development of patient-derived xenograft tumor models and 3D spheroid culture from advanced hormone receptor-positive inflammatory breast cancer patients for evaluation of new therapeutics [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-03-06.

Mutational studies on single circulating tumor cells isolated from the blood of inflammatory breast cancer patients

PurposeThe molecular characterization of circulating tumor cells (CTCs) is critical to identify the key drivers of cancer metastasis and devising therapeutic approaches, particularly for inflammatory breast cancer (IBC) which is usually diagnosed at advance stages and progresses rapidly.MethodsGenomic alterations in tumor tissue samples were studied using Foundation One™. Single CTCs were isolated using CellSearch followed by single-cell isolation by DEPArray™. Samples with 20 or more CTCs were chosen to isolate single CTCs using the DEPArray™.ResultsGenomic alterations were studied in primary tumor or metastatic sites from 32 IBC patients. Genes with high-frequency mutations were as follows: TP53 (69%), RB1 (16%), PIK3CA (13%), and also ErbB2 (3%). At least once during treatment, CTCs were detected in 26 patients with metastatic IBC, in two patients with locally advanced IBC, and four patients had no detectable CTCs. Per 7.5 mL of blood, fifteen patients (47%) had ≥20 CTCs and six of them were chosen at random to isolate single CTCs. These cells were tested for the presence of TP53, RB1, PIK3CA, and/or ErbB2 mutations previously found in matching tissue biopsies. The isolated CTCs showed the same mutations as primary or metastatic tumor samples. Intra-patient CTC heterogeneity was found by the presence of different CTC subclones, with some CTCs harboring different combinations of mutated and wild-type genes.ConclusionsOur results indicate that CTCs could represent a non-invasive source of cancer cells from which to determine genetic markers as the disease progresses and identify potential therapeutic targets in IBC patients.

Late pulmonary metastasis of inflammatory breast cancer 26 years after initial radiation therapy alone

A 64-year-old woman underwent cobalt-60 radiation therapy 26 years ago because of advanced inflammatory breast cancer. The initial stage was T4N0M0. During the course of cobalt-60 therapy, the patient presented severe chest wall necrosis. Her chest wall wound healed very slowly and she decided to stop radiation therapy and declined both surgery as well as chemotherapy. After chronic wound healing, the patient did not come back for follow-up. Twenty-six years later, she came back for mild dyspnea. Subsequent study showed suspicious lung metastasis. Later, she underwent thoracoscopic biopsy, with which lung metastasis was confirmed. She recovered well and currently receives oral chemotherapy for disease control.

Abstract P4-13-18: A phase I study of romidepsin in combination with nab-paclitaxel in patients with metastatic HER-2 negative inflammatory breast cancer (IBC)

Abstract Inflammatory breast carcinoma (IBC) is the most aggressive form of breast cancer. The hallmark of IBC is regional extension into dermal lymphatics as tumor emboli causing breast edema and erythema. Pathologic characteristics of IBC include high grade, negative hormone receptor status and overexpression of HER2 and E-cadherin. The latter is the most attractive therapeutic target in IBC. In preclinical studies the histone deacetylase inhibitor, romidepsin targeted E-cadherin, affecting tumor emboli and increasing taxane sensitivity. Rationale: In vitro studies show that histone deacetylase inhibitors (HDACi) with taxanes provide synergy to enhance cell death. HDACi alter expression of AIRH1, a regulator of autophagy, typically silenced in breast cancer. In vitro treatment with HDACi induces expression of AIRH1, resulting in enhanced cell death with taxanes. In vitro studies of IBC have demonstrated the utility of HDACi and romidepsin in IBC cell lines. SAHA and romidespin, HDACis, inhibited self-renewal of IBC tumor spheroids from IBC cell lines. This trial combines romidepsin with a taxane proven in metastatic breast cancer to explore whether the combination will be effective in IBC. Design: This is a phase I trial to assess the safety of romidepsin plus nab-paclitaxel in patients with recurrent or metastatic IBC. The maximum tolerated dose (MTD) of romidepsin + weekly nab-paclitaxel was determined to define the dose for the phase II trial. Secondary objectives included describing the adverse event profile and assessing the overall response rate (ORR) and Clinical Benefit Rate (CBR). This study employed a 3+3 design. DLTs included febrile neutropenia or non-hematologic grade 3 or 4 toxicities. Patients were treated with nab-paclitaxel 100 mg/m2 iv with romidepsin, 7 mg/m2 iv (1st cohort) and 10 mg/m2 iv (2nd cohort), on days 1, 8, 15 of a 28 day cycle. Results: Nine patients were treated. The median age was 52. Three patients were treated in the first cohort. Two patients showed progressive disease (PD). One patient has had stable disease (SD) over 10 cycles and continues treatment. DLT was not reached at 7 mg. Toxicities related to romidepsin included neutropenia, anemia and fatigue. Six patients were treated in the 2nd cohort. Grade 3 hypophosphatemia, a DLT, was reached. One patient had complete response (CR). One patient had SD; four patients had PD. Toxicities related to romidepsin were anemia, neutropenia, GI upset, edema, hyperglycemia, fatigue, hypophosphatemia, pruritis, dry mouth, and increased lab values. The overall response rate (ORR) was 33% (3/9). The table below shows results. CohortResponse# Prior TherapiesMetastatic Sites# Cycles on study1PD2pleura, nodes51PD0lung31SD2lung, nodes102PD2pleura, nodes, soft tissue42PD0liver, nodes, bone22CR2 chemotherapy, 2 endocrinebone, nodes72SD0nodes52PD0lung,liver, nodes22PD0liver, bone, nodes2 Conclusions: This phase I trial shows that romidepsin and nab-paclitaxel are well-tolerated in patients with advanced IBC. The MTD and recommended dose of romidepsin is 10 mg/m2 with nab-paclitaxel 100 mg/ m2 days 1, 8, 15 of a 28 day cycle. A phase II trial is planned in recurrent HER negative IBC patients. Citation Format: Avery TP, Jaslow R, Basu-Mallick A, Zibelli A, Fellin F, Cristofanilli M. A phase I study of romidepsin in combination with nab-paclitaxel in patients with metastatic HER-2 negative inflammatory breast cancer (IBC). [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 P4-13-18.

Abstract OT1-1-15: A phase II study of dovitinib as salvage therapy in patients with stage IV inflammatory breast cancer HER2-negative with local or distant relapse

Abstract Background: Inflammatory breast cancer (IBC) is an aggressive form of breast cancer that accounts for 3 to 5% of all invasive breast tumors in the United States. IBC possesses an increase of proangiogenic factors including vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and platelet derived growth factor (PDGF) as compared with non-IBC. In particular, FGF family receptors play a critical role in tumorigenesis, morphogenesis, and inducers of angiogenesis. Dovitinib (TKI258) is an oral tyrosine kinase inhibitor with in vitro IC50 values of approximately 10 nmol/L against FGFR1-3, VEGFR1-3, and PDGFR. These structurally related receptors are important for the growth and survival of endothelial cells during tumor angiogenesis. Trial Design: This is a single institution, single arm phase II study. Patients receive a single daily oral dose of dovitinib 500 mg for 5 consecutive days, followed by a 2-day rest period (5 days on/2 days off schedule). Eligibility: Patients have histological confirmation of breast carcinoma with a clinical diagnosis of IBC based on presence of inflammatory changes in the involved breast, including diffuse erythema and edema (peau d’orange). Pathological evidence of dermal lymphatic invasion should be noted but is not required for diagnosis. HER2-negative. ECOG PS 0-2. Baseline MUGA or echocardiogram scans with LVEF of > 50%. Normal hematology, liver and kidney function laboratory studies. Patients must have received at least 2 chemotherapy lines for metastatic disease and have relapsed. Research Hypothesis: Dovitinib has antitumor activity in patients with HER2-negative advanced IBC. Specific Aims: Primary objective: to determine the disease control rate (CR, PR, and SD). Secondary objective: to evaluate safety profile. Exploratory biomarkers: circulating tumor cells (CTC), CTC undergoing EMT, and cancer stem cells Statistical Methods: The primary endpoint is the six-month disease control rate (ORR) as defined by RECIST 1.1. A response is anyone who experiences SD, CR or PR in the first 6 months. We will conduct this study with Simon’s two-stage design using the mini-max criterion and the response rate will be estimated accordingly. It is assumed that dovitinib will have a target ORR of 30%. An ORR of 10% or lower is considered a failure based on the typical ORR with a second line regimen for IBC and the new regimen will be rejected under this circumstance. When the probability of accepting a "bad" regimen (i.e. response rate < 10%) is 0.05 and the probability of rejecting a "good" regimen (i.e. response rate > 30%) is also 0.10, Simon’s design to minimize the maximum sample size requires 22 patients in the first stage. If two or less patients respond to the treatment, the trial will be stopped and the regimen will be declared as ineffective. If at least three of the first 22 patients respond to the treatment, 11 additional patients will be entered in the study to reach a total of 33 patients. By the end of the study, the new regimen will be rejected if response rate is less than or equal to 6 out of 33 patients and will be accepted otherwise. Present Accrual and Target Accrual: A total of 22 patients were accrued. Target accrual is 33 patients. Citation Format: Ricardo H Alvarez, Mariana Chavez-MacGregor, Joe Ensor, James L Murray, Kimberly Koenig, Savitri Krishnamurty, Antony Lucci, Gildy V Babiera, Wendy Woodward, Gary J Whitman, Summer A Jackson, Michael Shi, Kenneth Culver, James L Reuben, Naoto T Ueno, Vicente Valero. A phase II study of dovitinib as salvage therapy in patients with stage IV inflammatory breast cancer HER2-negative with local or distant relapse [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr OT1-1-15.

O1-11-4 - Sox2 in Inflammatory Breast Cancer: Did We Eventually Have an Answer?

Background: inflammatory breast cancer (IBC) is the most aggressive type of breast cancer and continuous research to identify its nature is of utmost importance.Patients and methods: This is a retrospective case control study including all eligible cases of advanced IBC compared to a control group of stage comparable locally advanced breast cancer (LABC) cases presenting to the National Cancer Institute (NCI), Cairo University in the period between November 2007 and February 2011. SOX2, as a stem cell marker, was assessed in both arms by quantitative RT-PCR. All patients received standard FEC10. Assessment of clinical response (CR) was done after 4 cycles. Primary endpoints were 1-assessment of SOX2 expression in IBC and LABC. 2-Assessment of correlation between SOX2 expression and CR in both arms. Secondary endpoints were assessment of correlation between SOX2 expression and PFS & OS in both arms.Results: 30 cases of IBC and 19 cases of LABC were included with a median follow up period of 31.3 months.SOX2 was highly expressed in IBC compared to LABC (p-values: 0.03). SOX2 expression was significantly correlated with clinical response in IBC where 100% of the SOX2 –ve cases had good overall clinical response (Complete and partial remission) compared to 64.7% of the SOX2 +ve cases (P-value: 0.042). SOX2 expression was significantly correlated with PFS in IBC where 1 and 2 year PFS were 72.7% and 45.5% in SOX2 negative versus 36.8% and 5.3% in SOX2 positive (p-value = 0.045). SOX2 expression showed a trend towards significant correlation with OS in IBC where 1 and 2 year OS were 100% and 90.4% in SOX2 negative versus 95.2% and 73.7% in SOX2 positive (p-value = 0.087).Conclusion: SOX2 expression, as a Stem cell marker, is significantly expressed in IBC and is well correlated with clinical outcome.Key words: SOX2 – stem cell phenotype- Inflammatory breast cancer

Abstract P4-04-12: Identification of a common genotype in patients (pts) with HER2-positive, ER-negative, inflammatory breast cancer (IBC) that was primary-refractory to trastuzumab who have had 5+ years of disease control with lapatinib therapy

Abstract Background: HER2-amplified inflammatory breast cancer (IBC) that is primary-refractory to trastuzumab has a poor prognosis. The objective of this study was to describe the genotypes of the IBC obtained from 3 pts with high grade, ER-negative, HER2+ classical IBC, primary-refractory to trastuzumab, with chest wall disease, who remain with no evidence of disease (NED) on lapatinib for 5+ years. The 3 postmenopausal pts presented with locally advanced IBC, 2 with disease extending onto the chest wall, and the third with chest wall recurrence while on adjuvant trastuzumab. Two pts were treated with preoperative trastuzumab with multiple chemotherapy agents with no response. They were then treated with preoperative lapatinib and had a clinical partial response. They underwent salvage mastectomy showing extensive residual disease, followed by chest wall/regional radiotherapy (RT), continuing on lapatinib. The third patient received preoperative AC followed by docetaxel and had extensive residual disease at mastectomy. She underwent chest wall/regional RT and then had chest wall recurrence while on adjuvant trastuzumab. She was treated with lapatinib and resection of residual chest wall disease. All 3 pts remain NED on 1250mg lapatinib daily. The 3 pts have a strong family history of breast cancer; two have known wild type germline BRCA1/2. Methods: Following IRB-approved informed consent, targeted next generation DNA sequencing (NGS) was performed using HiSeq-2000 (Illumina) on pts’ FFPE primary IBC at a CLIA-certified laboratory, to characterize all classes of genomic alterations across 4,604 exons of 287 cancer-related genes. Phosphoprotein analysis was performed using a proprietary Reverse Phase Protein Microarray (RPMA) platform on pts's FFPE IBC to characterize the activity of the targets of anti-HER2 therapy, and their downstream pathways. Results: In 2 pts’ IBCs NGS identified a common genotype with amplified ERBB2, mutant p53 and PIK3CA (c.3140A>G_p.H1047R), homozygous deletions of both CDKN2A and CDKN2B, and truncated BRCA2 (1 pt) or PALB2 (1 pt). The third pt's FFPE residual disease from her mastectomy did not yield sufficient DNA from invasive tumor cells for sequencing and we plan to sequence DNA from her original diagnostic core biopsy. Phosphoprotein analysis of one pt's trastuzumab-refractory, lapatinib-naive IBC showed 3+ expression of HER1 (but not pHER1 Y1068 nor pHER2 Y1248), pAkt S473, pS6 ribosomal S235-236 protein (2+), p4E-BP1 S65 and Notch1. The second pt's lapatinib-treated IBC showed 3+ overexpression of only p4E-BP1 S65. Conclusions: Pts with a common tumor phenotype who have highly durable responses with a targeted therapy may share a common tumor genotype. Two pts’ trastuzumab-refractory HER2+ IBCs that have been very durably responsive to lapatinib share p53, PIK3CA, p16 and BRCA2-related mutations, potentially enabling the prospective identification of trastuzumab-refractory IBC pts who may benefit substantially from lapatinib. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-04-12.

Abstract P6-02-05: A novel culturing 3-D model to evaluate the role of tumor microenvironment in IBC.

Abstract Introduction: Inflammatory breast cancer (IBC) is a highly aggressive form of breast cancer associated with extremely poor outcomes. The clinical and pathological characteristics of the disease are the peculiar invasion of the dermal lymphatics as tumor emboli and the development of early recurrences. We aimed to establish a 3D model to evaluate the role of tumor microenvironment. Methods: We used human tumor-associated fibroblasts (or fibroblasts derived from metastatic skin) from IBC patients to build a multilayer extracellular matrix structure which effectively mimics aspects of the mesenchymal microenvironment of IBCs. Using this in vivo-like microenvironment we proceeded to test both matrix effects upon IBC's phenotypes and IBC modifications upon the cell-derived 3D matrices. We seeded the IBC cells into the matrix and cultured for 3 days, then tested the characterization markers cancer cells and ECM e.g. Phalloidin, E-cadherin, Ki67, α5β1 integrin and fibronectin by immunofluorescence and the expression of E-cadherin and vimentin as marker of epithelial-mesenchymal transition (EMT) by western blot. Results: We divided six IBC cell lines into 2 groups depending on the phenotypes acquired when cultured in the IBC fibroblast-derived ECM. SUM149 (EGF receptor positive and aggressive phenotype), BR016 and LG018 (harvested from patient's pleural effusions) presented a single cell organization with a spindle-like or mesenchymal type (as opposed to cluster) morphology. In comparison, SUM190 (HER2 positive and non aggressive tumorigenesis), MDA-IBC-3 and FC-IBC-02 (abstracted from patient's pleural effusion) presented a phenotype resembling mammospheres or in vivo emboli. Moreover, this last group of cells showed a peculiar capability for ECM modifications which greatly differed from the ECM modifications that were apparent following 3 day culturing of the above mentioned group represented by SUM149. In addition, proliferation measurements by Ki67 expression demonstrated a significant increased in 3D culture for SUM149, BR016 and LG018 compared with that in 2D culture, while no differences in proliferation were observed in the other three cell lines. Moreover, the expression of E-cadherin known to be upregulated in IBC tumors was increased in all cancer cells when seeded into the human fibroblast-derived 3D matrix indicating a potential role of the microenvironment in promoting proliferation, growth and invasion. Conclusion: The present study demonstrated the establishment of a novel IBC stromal 3D model using extracellular matrix produced from human fibroblasts of patients with advanced IBC. We showed a dynamic interaction between cancer cells and the microenvironment and potential sorting of IBC cells into two discrete groups which also correlate with their aggressive behaviors in vivo. We believe that these system may serve to predict levels of IBC tumorigenesis. We will proceed to further study the two identified responsive phenotypes with the goal of uncovering mechanisms of IBC tumor-stromal interactions and better understand ECM influences upon IBC development and progression. The ultimate goal will be to use the system to study IBC biology and better design drugs that will specifically affect the newly identified phenotypes. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-02-05.

Abstract PD05-01: Next generation genomic sequencing (NGS) identifies molecular targets in inflammatory breast cancer (IBC)

Abstract BACKGROUND: Inflammatory breast cancer (IBC) is the most aggressive form of invasive breast cancer and is associated with poor outcome in spite of optimal multidisciplinary management. The disease is associated poor response to neoadjuvant chemotherapy and a peculiar pattern of recurrence (chest wall, nodes, CNS). There currently few distinct molecular alterations for effective therapeutic targeting in the advance setting. The availability of comprehensive cancer genomic testing using Next-Generation Sequencing (NGS) technology may identify a number of genomic alterations not assessed by traditional methods and provide opportunities for more effective treatment selection particularly in aggressive and uncommon diseases such as IBC. METHODS: Twenty-three patients with refractory metastatic IBC were included in this analysis. All patients underwent confirmatory biopsy and/or tissue collection. Tissue from metastastic lesions of patients with recurrent IBC was submitted as slides or FFPE blocks. NGS was performed by Foundation Medicine, Cambridge, MA. The entire coding sequence of 182 cancer-related genes (3,230 exons) plus 37 introns from 14 genes often rearranged in cancer were sequenced to high depth (>500X) All classes of genomic alterations were detected. RESULTS: The site distribution and frequency of disease recurrence included: soft tissue (19) lung (4), bone and liver (3), and brain (2). The disease subtype classification based on the expression of ER, PR and HER-2 were as follow: ER−, PR−, Her-2−, Basal-like or TN (65%); ER+ and/or PR+, HER-2− (grade3) or HER-2+, Luminal B (22%); ER−, PR−, HER2+ (13%). Genomic alterations were identified in all patients with various frequencies. Genetic mutations included: P53 (DNA-binding domain, splice site), PI3KCA (H1047R, R441N, E545K, K111E,); RB1; PTEN (D107Y); EGFR (L858R); ERBB2 (V777L, S310F) in a patient with TN disease; ESR1 D538G. Gene amplifications included: MYC (26%); CCND1 (22%); ERBB2 (in a patient with TN disease), MLC-1, CCNE1, CK4, K-RAS. One patient had evidence of discordant genomic abnormalities in two simultaneous sites of recurrence (skin and pleura) suggesting disease heterogeneity. Three patients were effectively treated with genomic alterations-guided therapies. CONCLUSIONS: Genomic sequencing of advanced IBC is feasible, identifies potential therapeutic targets and can advance our understanding of the molecular alterations of this aggressive disease. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr PD05-01.

Malignant change in a massive pleomorphic adenoma resembling the presentation of advanced inflammatory breast cancer

Massive tumours of the parotid are uncommon as due to their site, they are usually removed at an earlier stage. We present a bizarre case of a carcinoma ex-pleomorphic adenoma which mimicked an advanced breast cancer, complete with a ‘nipple-like’ extension and peau d’orange changes in the overlying skin as a result of a dense dermal inflammatory response. A procedure akin to a mastectomy with facial nerve preservation was carried out for removal. To our knowledge, peau d’orange has not been reported before in parotid tumours.

Lapatinib ditosylate: Expanding therapeutic options for receptor tyrosine-protein kinase erbB-2-positive breast cancer

Receptor tyrosine-protein kinase erbB-2 (HER2)-positive breast cancer is a specific entity with an aggressive behavior. Trastuzumab, a monoclonal antibody targeting erbB-2 (HER2) deeply transformed the outcome in patients. Nevertheless, resistance to trastuzumab is still a major concern. Lapatinib ditosylate is an orally available, small molecule targeting the tyrosine activity of the HER2 receptor. Lapatinib as a single agent and in combination therapy showed interesting activity in trastuzumab-resistant advanced tumors. In addition, lapatinib use seemed suitable in recurrent locally advanced inflammatory breast cancer and brain metastases. More recently, the Neo-ALTTO (NeoAdjuvant Lapatinib and/or Trastuzumab Treatment Optimisation) trial showed that lapatinib in combination with trastuzumab and paclitaxel significantly improved the pathological complete response in a neoadjuvant setting. Several clinical trials are still ongoing and data that may change current clinical practice are awaited with much interest.

A case of HER-2-positive advanced inflammatory breast cancer with invasive micropapillary component showing a clinically complete response to concurrent trastuzumab and paclitaxel treatment

We report a case of HER-2-positive advanced inflammatory breast cancer with invasive micropapillary component showing a complete response to trastuzumab and paclitaxel treatment. A 37-year-old woman was referred to our hospital for right breast swelling with broad skin redness and right axillary tumor. Ipsilateral infraclavicular and contralateral axillary lymph nodes swelling were also recognized. The histopathological findings of core-needle biopsy specimens from primary breast tumor and ipsilateral axillary lymph node were invasive ductal carcinoma with a micropapillary component. Immunohistochemical examination gave a negative result for estrogen receptor (ER)/progesterone receptor (PgR), and overexpression of HER-2 (Hercep Test 3+). Advanced inflammatory breast cancer with an invasive micropapillary component was diagnosed (T4d N3 M1 (LYM), stage IV). The patient was treated with combination chemotherapy using weekly paclitaxel and trastuzumab. After administration of three courses, the breast swelling, skin redness, and lymph node swelling disappeared completely. She maintained complete remission of disease for 12 months and was judged to have a clinically complete response by the RECIST criteria. Invasive micropapillary carcinoma is known to be an aggressive histological type associated with a high incidence of lymph node metastasis and poor prognosis. This is the first reported case of advanced inflammatory breast cancer with an invasive micropapillary component showing a clinically complete response to trastuzumab-containing treatment. This report suggests trastuzumab-containing chemotherapy is a promising therapy for HER-2-positive advanced invasive micropapillary carcinoma.

A Tool to Strengthen the Doctor-Patient Relationship

Though Congress passed the American Recovery and Reinvestment Act earlier this year, debate continues to swirl around the provision of funds for comparative effectiveness research. Critics warn that government bodies could use such research to dictate appropriate care and impose third-party oversight so intrusive it would impinge upon the interaction between doctors and their patients. On the contrary, I believe that comparative effectiveness has the potential to strengthen the patient-doctor relationship. How? By keeping all of us from being blindsided by our own best intentions. Dr. G was a senior surgeon and teacher of mine. What set Dr. G apart from his colleagues was an extraordinary ability to sympathize--empathize, even--with his patients. As I trailed him on rounds, I watched him, a former college football player, fold his body into a small bedside chair in order to better listen as patients spoke. With certain patients he seemed so moved that his emotions reflected theirs perfectly. He smiled when they did; his eyes welled up as great tears fell from theirs; his face flushed with anger when they spoke of mistreatment by another clinician. Once outside the room and unlike some of his other colleagues, Dr. G's sentiments did not evaporate. Instead, he translated them into care so conscientious that he routinely put the efforts of younger and more energetic doctors to shame. For a young surgeon who wanted more than anything to retain all of my compassionate ideals beyond my training, Dr. G was a beacon of light at the end of a very long tunnel. He represented what I someday hoped to be. Until I saw him care for Carolyn. Carolyn was stay-at-home mother who had been diagnosed with inflammatory breast cancer, a rare but extremely aggressive tumor. Her primary care doctor had used the term locally in his referral note; but his descriptor, we would soon learn, put it mildly. Carolyn's left breast was covered with fungating, necrotic tumors. One of the tumors extended upwards, throwing off pebble-sized satellite lesions that burrowed into her left shoulder. Left uncovered, the tumors reeked of rotting flesh, an odor so strong that the doctors and nurses in the clinic's hallway donned surgical masks. In Carolyn's room, the other resident and I tried to keep our breathing shallow. Dr. G, however, remained unphased, sitting next to Carolyn for half an hour and touching her tumors with ungloved hands. He asked questions and listened quietly as she responded. He nodded when she talked about her children and frowned when she recounted her failed attempts at radiation therapy and the less-than-fruitful discussions with medical oncologists who had thrown up their hands. I watched Dr. G begin to lean forward as he heard about the other doctors who had turned their backs on Carolyn. I could see lines appear on his forehead as his lips pursed together in deep thought. Then I heard Carolyn's final entreaties. Could he as a surgeon do something? Could he operate and take all the tumor away? Dr. G stood silent, looking for a moment like a man suddenly thrown in turbulent waters and struggling to keep afloat. The look soon passed, his brow smoothed over, and, looking straight into Carolyn's eyes, he answered quietly, Yes, we can. He passed his hand once more over the tumorous terrain of her left chest and shoulder. We would have to do a mastectomy and a forequarter amputation. That is, we would need to amputate your arm and your shoulder because the tumor extends all the way there. He paused again, then added, You would lose your arm, but we would take all that tumor away. I looked at the other resident. The muscles along his mandible had tightened; this was the only thing that prevented his jaw from dropping. Both of us knew that such radical surgery was unheard of in patients with advanced inflammatory breast cancer. But we also knew that there was no comparative effectiveness research available on aggressive surgical therapy with this disease. …

Phase II Study of Predictive Biomarker Profiles for Response Targeting Human Epidermal Growth Factor Receptor 2 (HER-2) in Advanced Inflammatory Breast Cancer With Lapatinib Monotherapy

Inflammatory breast cancer (IBC) is one of the most aggressive forms of breast cancer. Lapatinib, an oral reversible inhibitor of epidermal growth factor receptor (EGFR) and human EGFR 2 (HER-2), demonstrated clinical activity in four of five IBC patients in phase I trials. We conducted a phase II trial to confirm the sensitivity of IBC to lapatinib, to determine whether response is HER-2 or EGFR dependent, and to elucidate a molecular signature predictive of lapatinib sensitivity. Our open-label multicenter phase II trial (EGF103009) assessed clinical activity and safety of lapatinib monotherapy in patients with recurrent or anthracycline-refractory IBC. Patients were assigned to cohorts A (HER-2-overexpressing [HER-2+]) or B(HER-2-/EGFR+) and fresh pretreatment tumor biopsies were collected. Forty-five patients (30 in cohort A; 15 in cohort B) received lapatinib 1,500 mg once daily continuously. Clinical presentation and biomarker analyses demonstrated a tumor molecular signature consistent with IBC. Lapatinib was generally well tolerated, with primarily grade 1/2 skin and GI toxicities. Fifteen patients (50%) in cohort A had clinical responses to lapatinib in skin and/or measurable disease (according to Response Evaluation Criteria in Solid Tumors) compared with one patient in cohort B. Within cohort A, phosphorylated (p) HER-3 and lack of p53 expression predicted for response to lapatinib (P < .05). Tumors coexpressing pHER-2 and pHER-3 were more likely to respond to lapatinib (nine of 10 v four of 14; P = .0045). Prior trastuzumab therapy and loss of phosphate and tensin homolog 10 (PTEN) did not preclude response to lapatinib. Lapatinib is well tolerated with clinical activity in heavily pretreated HER-2+, but not EGFR+/HER-2-, IBC. In this study, coexpression of pHER-2 and pHER-3 in tumors seems to predict for a favorable response to lapatinib. These findings warrant further investigation of lapatinib monotherapy or combination therapy in HER-2+ IBC.

Primary systemic chemotherapy with sequential, dose-dense epirubicin and docetaxel for inoperable, locally advanced inflammatory breast cancer: A phase II study

Sequential, dose-dense epirubicin plus docetaxel was evaluated as primary systemic therapy for women with inoperable, locally advanced breast cancer (LABC) or inflammatory breast cancer (IBC). Patients (LABC n=27; IBC n=7) received 3 cycles of epirubicin 120 mg/m2 every 2 weeks followed by 3 cycles of docetaxel 100 mg/m2 every 2 weeks, with granulocyte colony-stimulating factor. Grade 3–4 toxicities were observed in 21 of 195 cycles (10.8%). Grade 3 anemia and leukopenia each occurred in 1% of cycles. Following chemotherapy, all patients underwent surgery. Eight patients (23.5%) had a clinical complete response and 15 (44.1%) had a partial response. In patients with IBC, median skin thickness decreased from 5.85 mm (range: 3.1–6.2 mm) to 4 mm (range: 2.7–5.1 mm) (p<0.005). Sequential, dose-dense epirubicin plus docetaxel achieved a high response rate among patients with LABC or IBC with only moderate toxicity.

High level of EGF-R expression in carcinomatous skin invasion: Does it reflect the tissue characteristics of the breast carcinoma aggressiveness?

Background: The normal function and distribution of EGF-R and its role in breast cancer aggressiveness, prognosis and prediction, have become extremely important in the light of the recently developed methods of EGF-R targeting. In the aim to investigate the relationship between EGF-R and the aggressive tumor behavior, the EGF-R content was analyzed as related to the presence of inflammatory breast skin involvement. Methods: EGF-R, ER and PR content was determined at diagnosis, using the biochemical methods, in the group of 103 unselected breast cancer patients, either in primary tumors (TU), lymph nodes (LN) or skin tissue samples (65, 27 and 11 cases respectively). In 10 patients with inflammatory breast cancers, TU/LN tissue was sampled from 3, and skin from 7 patients. Results: ER and PR content was significantly higher in tumor and LN tissue, compared to the invaded skin the EGF-R content was, on the contrary, significantly higher in skin than in TU or LN tissue. However, no difference was found between TU and LN in all three receptors' content. When the receptor content was analyzed in 10 patients with inflammatory breast cancer, higher levels of both ER and PR were found in tumor biopsies than in skin biopsies, while for the EGF-R the result was opposite. Significantly lower ER content and a trend towards higher EGF-R content was found in the inflammatory breast cancers in comparison to the non-inflammatory ones. Conclusion: Although we examined a small number of patients, our results suggest that the EGF-R could be a marker of breast cancer aggressiveness. However, the influence of the normal skin cells contaminating the biopsied tumor tissue cannot be ruled out. The predictive role of EGF-R deserves to be further investigated especially in locally advanced inflammatory breast cancer patients.

A CASE OF ADVANCED INFLAMMATORY MALE BREAST CANCER

A case of advanced inflammatory breast cancer with complete response of primary lesion to combination therapy in a 84-year-old male is reported.The patient was admitted to our hospital with a 21×13 cm rubor in the left chest wall and a 8×7 cm subareolar tumor. On admission, it passed about 5 years after he first noticed these changes, and the left chest wall was entirely thicked and inflammed. From minute examinations, the tumor was found to be left breast cancer, T4cN3M1 in stage IV. Curative resection was impossible. Diagnostic modalities showed liver and bone metastases. The biopsy of the chest wall revealed breast cancer with positive estrogen receptor. Combination therapy (Pirarubicin, THP and Medroxoprogesteron, MPA was started. His breast cancer was gradually improved and completely disappeared 23 weeks after treatment, when histological evaluation was of complete effect (grade IV). However, distant metastases did not responed. Combination therapy may be an alternative, useful strategy for advavced breast cancer in males.