Lymphatic Embolization Research Articles

Invasive micropapillary carcinoma of urinary bladder: a clinicopathological study.

Micropapillary variant of urothelial carcinoma (MPUC) is a rare but well-recognized tumor of the urinary bladder. Tumors with micropapillary areas accompanying conventional urothelial carcinoma are more aggressive compared to conventional urothelial carcinoma and show variable keratin 7, keratin 20 and human epidermal growth factor receptor 2 (Her 2)neu expression. The aim of the study was to analyze the clinical, morphological and immunohistochemical profile of MPUC. Transurethral resection of bladder tumor (TURBT) chips of seven cases of invasive MPUC with subsequent cystoprostatectomy specimens of five patients was reviewed. Epithelial membrane antigen (EMA), Keratin 7, Keratin 20, and Her 2 immunohistochemistry were performed in all cases. Follow-up information was available for all patients (2-36 months). All seven patients were male, and their ages ranged from 50 to 62 years. All cases presented with hematuria. The micropapillary pattern was seen in 20-95% of the tumor. All cases showed extensive lymphatic emboli with detrusor muscle invasion. Lymph node metastasis was present in all cases undergoing cystoprostatectomy except one. Keratin 7 and abluminal pattern of EMA positivity were seen in all cases. Keratin 20 was positive in five cases (71%), and Her 2neu positivity was seen in four cases. Three patients died 2, 3, and 6 months after initial diagnosis, among which two were Her 2 positive and one was Her 2 negative. There was no clear prognostic significance of Her 2 positivity. (1) MPUC is a rare but highly aggressive tumor. (2) Micropapillary is usually the predominant pattern. (3) Keratin 7 is expressed universally, whereas Keratin 20 expression is variable. (4) Her 2 expression has no clear influence on the survival.

Abstract 2867: EGFR expression in T1/T2 oral tongue and floor of the mouth carcinoma

Abstract Epidermal growth factor receptor (EGFR) is a molecular maker that regulates the cell growth and plays an important role in tumor proliferation, invasion and metastasis formation. Objective: In this study we examined the association of immunohistochemical expression of EGFR with clinicopathological parameters, lymph node metastasis, regional recurrence and survival in selected cases of early squamous cell carcinoma (SCC) of the oral tongue and floor of the mouth. Methods: Patients with early stage SCC of oral tongue and floor of the mouth were treated surgically at a single institution from 1980 to 2010. Specimens from 139 patients were analyzed for EGFR expression using monoclonal antibody. Results: This study included 139 patients, 96 men (69%), with ages ranging from 21 to 85 years old (mean, 58 years). The tumor site was the tongue in 105 cases (75.5%) and the floor of the mouth in 34 (24.5%). With regard to pathological T-stage, 69 cases were pT1 (52.7%) and 62 were pT2 (47.3%). EGFR was overexpressed in 18 cases (13%) and was significantly associated with pT (p=0.017), thickness greater than 4mm (p=0.017), muscular invasion (p=0.014), desmoplastic reaction (p=0.021), inflammatory infiltrate (p=0.029), lymphatic embolization (p=0.016), mode of invasion (p=0.027) and perineural invasion (p=0.007). The overexpression of EGFR was also associated with lymph node metastasis (p=0.038) and regional recurrence (p=0.014). The cancer-specific survival in 5 years decreased from 90% in the group without EGFR expression to 75.3% in the EGFR overexpression group (p=0.019). Conclusion: The EGFR overexpression was associated with more aggressive pathological features, lymph node metastasis and regional recurrence in patients with early oral tongue and floor of the mouth squamous cell carcinoma. Citation Format: Natalie Kelner, Clovis Antonio Lopes Pinto, Luiz Paulo Kowalski, Claudia Malheiros Coutinho-Camillo. EGFR expression in T1/T2 oral tongue and floor of the mouth carcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2867. doi:10.1158/1538-7445.AM2014-2867

Inflammatory breast cancer: high incidence of detection of mixed human cytomegalovirus genotypes associated with disease pathogenesis.

Inflammatory breast cancer (IBC) is a highly metastatic, aggressive, and fatal form of breast cancer. Patients presenting with IBC are characterized by a high number of axillary lymph node metastases. Recently, we found that IBC carcinoma tissues contain significantly higher levels of human cytomegalovirus (HCMV) DNA compared to other breast cancer tissues that may regulate cell signaling pathways. In fact, HCMV pathogenesis and clinical outcome can be statistically associated with multiple HCMV genotypes within IBC. Thus, in the present study, we established the incidence and types of HCMV genotypes present in carcinoma tissues of infected non-IBC versus IBC patients. We also assessed the correlation between detection of mixed genotypes of HCMV and disease progression. Genotyping of HCMV in carcinoma tissues revealed that glycoprotein B (gB)-1 and glycoprotein N (gN)-1 were the most prevalent HCMV genotypes in both non-IBC and IBC patients with no significant difference between patients groups. IBC carcinoma tissues, however, showed statistically significant higher incidence of detection of the gN-3b genotype compared to non-IBC patients. The incidence of detection of mixed genotypes of gB showed that gB-1 + gB-3 was statistically significantly higher in IBC than non-IBC patients. Similarly, the incidence of detection of mixed genotypes of gN showed that gN-1 + gN-3b and gN-3 + gN-4b/c were statistically significant higher in the carcinoma tissues of IBC than non-IBC. Mixed presence of different HCMV genotypes was found to be significantly correlated with the number of metastatic lymph nodes in non-IBC but not in IBC patients. In IBC, detection of mixed HCMV different genotypes significantly correlates with lymphovascular invasion and formation of dermal lymphatic emboli, which was not found in non-IBC patients.

Histopathological Review of Male Breast Cancer Cases

Objective: Male breast cancer (MBC) accounts for less than 1% of all breast cancer diagnoses and all cancer cases in men. Methods: We included 33 MBC cases and analyzed histopathological features and survival data. Results: The mean age was 63.5, mean tumor diameter was 3 cm. Central quadrants (69.2%) was most common localization, invasive ductal carcinoma (75.8%) was most common histological subtype. Most of the cases (78.6%) were grade 2. Nipple involvement was noted in 9, tumor necrosis in 9, perineural invasion in 15, dermal lymphatic emboli in 10 cases. Nearly half of the cases (45.5%) showed lymph node metastasis. There was statistically significant relation between lymph node metastasis and stromal lymphocyte response, tumor necrosis (p=0.008, p=0.013) also between grade and dermal lymphatic emboli (p=0.04). Non-tumoral parenchymal findings were columnar cell lesions (CCL), (n: 5) and gynaecomastia (n: 3). Majority of the cases showed estrogen receptor (90.9%) and progesterone receptor (77.2%) positivity. Overall survival analysis showed significant results between grade (p=0.008), lymph node metastasis (p=0.03), dermal lymphatic tumor emboli (p=0.02), nipple involvement (p=0.02) and survival. Conclusions: Our results showed good correlation with literature data in terms of histopathological features and prognostic factors. Confidential data about etiological and prognostic factors will be collected through these reports showing institutional experiences. The significance of CCL in MBC etiology, the impact of intratumoral stromal lymphocyte response, hormone receptor-HER2 status on survival should be clarified in larger series

Carcinoma Erysipelatoides Resulting from Cutaneous Metastasis of Breast Cancer

Cutaneous metastasis of breast cancer is easily misdiagnosed. Herein, we report two such cases. In the first case, a 49-year-old woman received neoadjuvant chemotherapy and underwent modified radical mastectomy for right locally advanced breast cancer (LABC). The erythematous skin lesion on the right chest wall was detected during ongoing trastuzumab treatment after radiotherapy. Radiation recall dermatitis was initially suspected, but the lesion persisted for 7 months, and a biopsy confirmed metastatic carcinoma showing multiple lymphatic tumor emboli. In the second case, a 42-year-old woman underwent breast-conserving surgery with axillary lymph node dissection for right LABC, and then adjuvant chemotherapy followed by trastuzumab treatment and radiotherapy. A localized slightly pruritic erythematous patch on the right breast persisted for 2 months, and allergic dermatitis was suspected. However, a 3-cm mass developed in the right breast during trastuzumab treatment, and a biopsy confirmed a diagnosis of ductal carcinoma with multiple lymphatic tumor emboli.

Authors’ reply

We would like to thank Dr Garg for his thoughtful reading of our case report.(1) Although the main subject of our article was not inflammatory breast cancer (IBC), we fully agree with his concern about the need for a set of worldwide uniform diagnostic criteria for IBC. This is because the varying definitions used by clinicians and researchers can delay the understanding of the biology, clinical behaviour and treatment outcome of the disease.(2) However, there has been some disagreement on whether IBC is a clinical, histopathological or a combined diagnosis. In the past, the National Cancer Institute’s Surveillance Epidemiology and End Results (SEER) Programme introduced histopathological and clinical features as diagnostic criteria for IBC, while the American Joint Committee on Cancer (AJCC), and more recently, the consensus of a panel of recognised international experts in the First International Conference on Inflammatory Breast Cancer, based the diagnosis mainly on clinical features.(2,3) As the presence of dermal lymphatic emboli can be documented in only about 75% of cases of IBC,(4,5) Dr Garg has correctly pointed out that IBC cannot be ruled out based solely on the absence of dermal lymphatic emboli in histological examination in our case. Yours sincerely,

Tumor sprouting in papillary thyroid carcinoma is correlated with lymph node metastasis and recurrence.

BackgroundIdentification of poor prognostic factors in papillary thyroid carcinoma (PTC) patients is important for the patients' care and follow-up. We can sometimes see small tumor clusters without desmoplasia and no evidence of lymphatic emboli around the main tumor mass of PTC. We termed this form of tumor clustering, 'tumor sprouting,' and determined whether these tumors correlate with lymphovascular invasion, lymph node metastasis, and recurrence.MethodsWe analyzed a total of 204 cases of papillary thyroid macrocarcinoma. Number, size and distance from the main tumor of the tumor sprouting were observed and analyzed with clinicopathologic characteristics.ResultsTumor sprouting was observed in 101 patients. Presence of tumor sprouting was significantly associated with positive resection margin (p=.002), lymphovascular invasion (p=.001), lymph node metastasis (p<.001), and recurrence (p=.004). Univariate analysis of recurrence-free survival revealed that tumor multiplicity (p=.037), positive resection margin (p=.007), lymphovascular invasion (p=.004), lymph node metastasis (p<.001), and tumor sprouting (p=.004) were poor prognostic factors. In multivariate analysis, positive resection margin was an independent poor prognostic factor of recurrence.ConclusionsIn conclusion, tumor sprouting is significantly correlated with lymph node metastasis and recurrence. Evaluation of tumor sprouting in PTC patients could be helpful in predicting tumor recurrence or lymph node metastasis.

Initial Management of Testicular Cancer: Practice Survey Among Urologists and Pathologists

IntroductionThe objective of this study was to conduct a declarative professional practices survey among urologists of the French Association of Urology (AFU) and French pathologists concerning their management of testicular cancer. Materials and MethodsA questionnaire was sent to all urologists, members of the AFU, and another questionnaire was sent to French pathologists, members of the International Academy of Pathology, French Division, in June 2010. A total of 289 urologists (29%) and 84 pathologists (19%) returned the questionnaires. ResultsFifty-seven percent of urologists declared that they performed fewer than 5 orchidectomies per year. Pathologists declared that they examined less than 5 orchidectomy specimens per year in 24% of cases. The laboratory work-up (only alpha fetoprotein [AFP], lactate dehydrogenase [LDH], and total human chorionic gonadotropin [hCG]) and the radiological work-up (only testicular ultrasound and chest, abdomen, and pelvis computed tomography [CT] scan) were performed strictly according to guidelines in 15.9% and 65.7% of cases, respectively. A total of 31.8% of urologists declared that they performed the minimum assessment required by guidelines (AFP, LDH, total hCG, testicular ultrasound and chest, abdomen, and pelvis CT scan plus other examinations not recommended). Prognostic factors of stage I tumors, to define the indications for adjuvant therapy, were correctly declared in 7.3% of nonseminomatous germ cell tumors (vascular and/or lymphatic emboli) and in 13.8% of seminomas (tumor size >4 cm and rete testis invasion). ConclusionThis survey demonstrated that clinical practice did not comply with guidelines, which raises the question of the measures that can be taken to ensure better application of guidelines or how to develop expert centers for the management of these rare tumors.

Intradermal melanocytic nevus with lymphatic nevus cell embolus: A case report

The current study presents a rare case of intradermal melanocytic nevus with lymphatic nevus cell embolus. A 26-year-old male presented with a slowly enlarging, pigmented nodule on the back, measuring 1 cm in diameter. Histological observations of the lesion were typical of an intradermal melanocytic nevus. The most notable feature of this nevus, however, was an aggregate of nevus cells within a lymphatic vessel of the upper dermis. The nevus cells observed within the lymphatic lumen demonstrated characteristic morphological features of type A nevus cells. The cells were round-to-cuboidal, exhibited abundant cytoplasm with well-defined cell borders and formed nests. In addition, the nevus cell aggregate was lined by flattened endothelial cells. Nevus cell aggregates occur in the collagenous framework of lymph nodes, however, the mechanism by which nevus cells are deposited in lymph nodes has been a source of interest and controversy. The histological observation presented may be regarded as support for the mechanical transport or benign metastasis theories, which posit transfer of nevus cell emboli, via lymphatics, from a cutaneous nevus to the draining regional lymph node. Due to its rarity, a lymphatic nevus cell embolus creates diagnostic and management issues for pathologists and clinicians. This observation must not be interpreted as evidence of malignancy, but must be assessed in context with the associated histological features of the lesion.

Immunohistochemical Vascular Factor Expression in Canine Inflammatory Mammary Carcinoma

Human inflammatory breast carcinoma (IBC) and canine inflammatory mammary carcinoma (IMC) are considered the most malignant types of breast cancer. IMC has similar characteristics to IBC; hence, IMC has been suggested as a model to study the human disease. To compare the angiogenic and angioinvasive features of IMC with non-IMC, 3 canine mammary tumor xenograft models in female SCID mice were developed: IMC, comedocarcinoma, and osteosarcoma. Histopathological and immunohistochemical characterization of both primary canine tumors and xenografts using cellular markers pancytokeratin, cytokeratin 14, vimentin, and α-smooth muscle actin and vascular factors (VEGF-A, VEGF-D, VEGFR-3, and COX-2) was performed. Tumor cell proliferation index was measured by the Ki-67 marker. The xenograft models reproduced histological features found in the primary canine tumor and preserved the original immunophenotype. IMC xenografts showed a high invasive character with tumor emboli in the dermis, edema, and occasional observations of ulceration. In addition, compared with osteosarcoma and comedocarcinoma, the IMC model showed the highest vascular factor expression associated with a high proliferation index. Likewise, IMC xenografts showed higher COX-2 expression associated with VEGF-D and VEGFR-3, as well as a higher presence of dermal lymphatic tumor emboli, suggesting COX-2 participation in IMC lymphangiogenesis. These results provide additional evidence to consider vascular factors, their receptors, and COX-2 as therapeutic targets for IBC.

Pancreaticoduodenectomy following chemoradiotherapy for locally advanced adenocarcinoma of the pancreatic head

ObjectivesThe aim of this study was to assess oncological outcomes in patients treated with pancreaticoduodenectomy for advanced pancreatic head adenocarcinoma after preoperative chemoradiotherapy and to compare these with outcomes in patients treated with surgery alone. MethodsFrom 2004 to 2009, patients treated with pancreaticoduodenectomy for pancreatic head adenocarcinoma were included in a retrospective comparative study. Patients with locally advanced adenocarcinoma were treated with preoperative chemoradiotherapy (CRT group) and were compared with those treated with surgery alone (SURG group). ResultsA total of 111 patients were included; these comprised 72 patients in the SURG group and 39 patients in the CRT group. The median follow‐up was 21 months. Patients in the CRT group presented with a more advanced tumoral status. Microscopic resection rates were similar in both groups, but nodal status and vascular or lymphatic emboli were lower in the CRT group. At 3 years, the SURG and CRT groups exhibited similar overall (36% and 51%, respectively) and disease‐free (35% and 37%, respectively) survival (P = 0.10). ConclusionsIn patients with advanced pancreatic head adenocarcinoma, a good response after preoperative chemoradiotherapy results in a survival rate similar to that in patients treated with surgery alone in whom the initial prognosis is better.

Breast carcinoma en Cuirasse - case report

Cutaneous metastasis is a phenomenon that results from a tumor spreading via lymphatic or vascular embolization, direct implant during surgery or skin involvement by contiguity. The primary malignant tumor that most commonly metastasizes to the skin in women is breast cancer, which can be manifested through papulonodular lesions, erysipeloid or sclerodermiform infiltration, en cuirasse. We report the case of a female patient, 78 years old, with papular, scaly and confluent lesions in the right breast for one year, progressing to edema and skin infiltration, reduction of breast volume and plaque en cuirasse, and similar lesions in the contralateral breast and abdomen for four months. The pathological diagnosis was invasive ductal breast carcinoma with Paget-like foci, epidermal skin metastases and lymphatic embolization.

Expression of Decoy Receptor 3 in Diffuse Sclerosing Variant of Papillary Thyroid Carcinoma: Correlation with M2 Macrophage Differentiation and Lymphatic Invasion

The diffuse sclerosing variant of papillary thyroid carcinoma (DSV-PTC) is a unique variant of PTC that is characterized by extensive lymphovascular invasion of tumor cells in a background of lymphocytic thyroiditis. The lymphatic emboli contain tumor cells as well as macrophages, but the recruitment of these macrophages is not well understood. The aim of this study was to determine the relationship between the expression of Decoy receptor 3 (DcR3), the recruitment of tumor-associated macrophages (TAMs), and lymphatic invasion in DSV-PTC. We retrospectively examined 14 cases of DSV-PTC using immunohistochemistry studies. The density of TAMs, lymphatic vessel density, lymphatic invasion, tumor emboli area, and DcR3 expression were assessed. Statistical analyses were performed using Fisher's exact test, unpaired t-test, and linear regression. The lymphatic tumor emboli contained a relatively higher density of TAMs than stroma and classical PTC (CPTC) areas. In addition, the number of lymphatic invasions and the size of the tumor emboli area were positively correlated with the number of M2 TAMs. A higher density of M2 TAMs was associated with older patients and larger tumor size. Moreover, DcR3 was expressed only in lymphatic tumor cells and squamous metaplastic tumor cells, but not in macrophages and CPTC. In addition, the preferential expression of DcR3 in tumors was associated with higher levels of M2 TAMs and lymphatic invasion. Despite the fact that the exact relationship between DcR3, M2 macrophages, and lymphatic invasion in DSV-PTC remains to be elucidated, our findings suggest that DcR3 expression in DSV-PTC tumor cells may promote the polarized macrophage differentiation toward the M2 phenotype. This phenomenon may further promote lymphatic invasion of DSV-PTC tumor cells.

Chemotherapy with irradiation in salivary gland carcinomas (SGC): A Rare Cancer Network study (RCN).

e17019 Background: To report the role of combined chemotherapy in SGT. Methods: 251 patients with SGC treated in 2001-2011 were included in a collaborative IRB-approved retrospective RCN study. Chemotherapy is empirically administered based on extrapolation from conventional head and neck squamous cell carcinoma (Ca) (SCC) and data on systemic treatment in localized SGC are lacking. Results: Median age was 60 yo with 2/5 females/males. Tumor sites were the parotid 74.9%, submandibular 16%, sublingual 2.8% or minor gland 4%. Histologic findings were adenoid cystic (ACC) 17.3%, mucoepidermoid (MEC) 19.8%, adenoCa 15.6%, salivary duct (SDC) 10.3%, acinic cell (Aci) 6.2%, ex-pleomorphic 7.8%, undifferentiated 4.9%, myoepithelial 3.3%, epithelial myoepithelial 1.6%, basal cell 1.2%, lymphoepithelial 1.2%, others 4.0%. Surgery was performed in 95.1% (complete resection 38.1%). T stages 1, 2, 3 and 4 were 17.2%, 41.2%, 18.1% and 23.5% respectively. N stages were N0 61%, N1 13%, N2 24%, N3 2%. Perineural, vascular or lymphatic emboli were present in 47%, 24%, 27% respectively. Irradiation was performed postoperatively 96% or exclusively 4% (unilateral 84%, performed w/ photons only 78%, IMRT 41%). Chemotherapy was administered in 18%, dependent on grade, N stage, and emboli (p ≤ .05). None of 17 ex-pleomorphic, 25% of undifferentiated, 36% of SDC, and 66.7% of lymphoepithelial Ca received chemotherapy (p NS). With a median follow-up of 42 months for living patients, crude local, regional, metastatic relapse rates were 112% (in field 85%), 10%, 25%, respectively. Crude death rate was 28% including 77% from SGC. 5-year survival (5y OS) was 63%. The only prognostic factor was nodal involvement (p .002). However, 5y OS differed by histology: ACC 79%, MEC 84%, Aci 67%, SCC 43%, adenoCa NOS 40%, SDC 37%. Chemotherapy did not improve survival whatever histology. Conclusions: Further prospective studies are warranted to define the role of chemotherapy by histology in the setting of localized SGT. Also molecular profile-driven systemic treatments should be investigated.

A case of male inflammatory breast cancer

This report describes the case of an 85-year-old male with inflammatory breast cancer. The patient presented with diffuse erythema and induration over the right anterior chest wall. Ultrasonography and mammography demonstrated an ill-defined small mass, 8 mm in diameter, in the right breast with skin thickening. A core needle biopsy of the breast mass confirmed the presence of invasive ductal carcinoma. A skin biopsy revealed a diffuse tumor cell infiltration with dermal lymphatic emboli. These findings were compatible with the diagnosis of inflammatory breast cancer. The tumor cells were triple negative for estrogen receptor, progesterone receptor, and HER2/neu. His bone scintigraphy showed multiple bone metastases. Systemic chemotherapy using capecitabine was introduced, but it failed to control the disease. TS-1, as second-line systemic chemotherapy, also resulted in treatment failure. Third-line chemotherapy using docetaxel and cyclophosphamide was then administered and was effective. However, he developed pneumonia due to febrile neutropenia after two cycles of treatment and the chemotherapy was discontinued. The patient died of carcinomatous lymphangiosis 2 years and 3 months after the initial onset of the disease. Male inflammatory breast cancer is challenging because of its rarity, biological uncertainness, diagnostic difficulty, and the fact that it is associated with a very poor prognosis. The establishment of a reliable diagnostic and treatment strategy for male inflammatory breast cancer is therefore needed.

Prognostic Significance of Vascular and Lymphatic Emboli in Resected Pulmonary Adenocarcinoma

The incidence of vascular and lymphatic emboli in a specimen of resected non-small cell lung cancer is variable according to different authors' experience as well as prognostic significance in patients treated by surgery. We aimed at evaluating these factors in an unselected population of patients with primary pulmonary adenocarcinoma treated by major surgical resection. Clinical and pathology records of all patients treated by lobectomy or pneumonectomy and nodal dissection for pulmonary adenocarcinoma between June 2001 and June 2006 were retrospectively reviewed. Impact on survival of age, sex, tobacco use, history of chronic obstructive pulmonary disease, extent of resection, pathologic stage, and presence of vascular and lymphatic emboli was studied by univariate analysis and multivariate analysis (for factors significantly associated with survival at univariate analysis). Five hundred three patients underwent lobectomy or pneumonectomy with nodal dissection for pathologically proven lung adenocarcinoma. There were 355 men and 148 women; mean age was 61.1 years, and 181 patients were 65 years old or older; 87% were current or former smokers; 90.3% had pulmonary lobectomy; and 9.7% had pneumonectomy. Pathologic stages were I, II, and III/IV in 45%, 17.9%, and 37.1%, respectively. Vascular emboli and lymphatic emboli were found in 183 of 503 patients (36.4%) and 149 of 503 (29.6%), respectively. Overall 5-year survival for the whole population was 50.7%. At univariate analysis, age more than 65 years (p=0.0019), chronic obstructive pulmonary disease (p=0.042), extent of resection (p=0.047), pathologic stage (p<0.0000001), T size (p=0.0020), T and N variables (p=0.0000016 and p<0.0000001, respectively), presence of vascular emboli (p=0.026), and presence of lymphatic emboli (p=0.000021) were associated with worse prognosis. At multivariate analysis, age more than 65 years (p=0.0047, relative risk 1.5), stage I versus II versus III versus IV (p=0.00000032), and presence of lymphatic emboli (p=0.05, relative risk 1.34) were identified as independent negative prognostic factors. In an unselected population of patients with pulmonary adenocarcinoma treated by lobectomy or pneumonectomy, the presence of lymphatic emboli is an independent negative prognostic factor.

Abstract OT1-1-14: Open-label, Phase II trial of afatinib, with or without vinorelbine, for the treatment of HER2-overexpressing inflammatory breast cancer (IBC)*

Abstract Background: IBC is a rare but aggressive form of BC accounting for 1–5% of all BC. Despite recent treatment advances, prognosis remains poor, with 3-year survival rate of 40% vs. 85% in non-IBC. IBC commonly lack ER/PR and more frequently harbor HER2 gene amplification (∼40%), and EGFR overexpression (∼30%) that are associated with poor prognosis. Recent data reported clinical efficacy of lapatinib, a reversible EGFR/HER2 inhibitor, in trastuzumab naïve/resistant HER2-positive IBC. Afatinib is an oral irreversible ErbB Family Blocker that blocks signaling through activated EGFR (ErbB1), HER2 (ErbB2), ErbB4 receptors, and transphosphorylation of ErbB3. Afatinib demonstrated preclinical activity in trastuzumab-resistant cell lines, HER2-positive tumor xenografts and HER2-negative SUM149 xenograft model derived from an IBC cell line. Its clinical efficacy was shown in heavily pretreated, HER2-positive metastatic BC patients (pts) who progressed after trastuzumab, with a partial response in 10% and a clinical benefit in 46% of pts. The combination of afatinib and vinorelbine has been shown to be more effective than either compound alone in reducing tumor volume in the SUM190 xenograft model. The purpose of this biomarker-driven trial is to investigate the efficacy and safety of afatinib alone and in combination with vinorelbine following progression on afatinib monotherapy and the genomic changes that occur during treatment in pts with trastuzumab pretreated or naïve HER2-positive IBC. Methods: Pts are recruited in two parallel cohorts of 20 pts each – trastuzumab-naïve and trastuzumab failure cohorts. Key eligibility criteria: Histologically-confirmed HER2-positive BC; investigator-confirmed IBC characterized by diffuse erythema and edema (peau d'orange) – dermal lymphatic emboli or palpable mass are not necessary for diagnosis; no prior anti-HER2 therapy except trastuzumab in the trastuzumab failure cohort; no prior vinorelbine; ECOG performance status 0–2; disease must be biopsiable. All pts start afatinib monotherapy (40 mg/day oral) in 4-week cycles (Part A). Following disease progression, pts may receive afatinib (40 mg/day) + vinorelbine (i.v. 25 mg/m2/week) (Part B). Primary endpoint: Clinical benefit defined as stable disease (for ≥6 months), partial response or complete response (RECIST 1.1). Secondary endpoints: Objective response, duration of objective response and progression-free survival. Other endpoints include overall survival and safety. Endpoints are assessed separately for Part A and Part B. In Part A (afatinib monotherapy) fresh tumor biopsies are taken pretreatment and following progressive disease, and blood samples are taken pretreatment to explore predictive markers of response/resistance to afatinib, to describe the IBC population that may benefit most and for tumor DNA next-generation sequencing and proteomic analysis. This is one of the first prospective clinical trials to integrate deep exome sequencing into trial design to assess proof of principle of a personalized cancer medicine approach to improve individualized pt treatment. The trial is planned to accrue 40 pts worldwide and recruitment is ongoing since August 2011. *Updated abstract from ASCO 2012. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr OT1-1-14.

FGFR4 Profile as a Prognostic Marker in Squamous Cell Carcinoma of the Mouth and Oropharynx

BackgroundFibroblast growth factor receptor 4 (FGFR4) is a member of a receptor tyrosine kinase family of enzymes involved in cell cycle control and proliferation. A common single nucleotide polymorphism (SNP) Gly388Arg variant has been associated with increased tumor cell motility and progression of breast cancer, head and neck cancer and soft tissue sarcomas. The present study evaluated the prognostic significance of FGFR4 in oral and oropharynx carcinomas, finding an association of FGFR4 expression and Gly388Arg genotype with tumor onset and prognosis.Patients and MethodsDNA from peripheral blood of 122 patients with oral and oropharyngeal squamous cell carcinomas was used to determine FGFR4 genotype by PCR-RFLP. Protein expression was assessed by immunohistochemistry (IHC) on paraffin-embedded tissue microarrays.ResultsPresence of allele Arg388 was associated with lymphatic embolization and with disease related premature death. In addition, FGFR4 low expression was related with lymph node positivity and premature relapse of disease, as well as disease related death.ConclusionOur results propose FGFR4 profile, measured by the Gly388Arg genotype and expression, as a novel marker of prognosis in squamous cell carcinoma of the mouth and oropharynx.

Phase II study of postperative radiotherapy (RT), cisplatin (Ci), and cetuximab (Ce) in resected bad prognostic head and neck squamous cell carcinoma (HNSCC): Toxicity analysis.

e16051 Background: Despite toxic multimodal about 60% of resected HNSCC relapse. The addition of both Ce or Ci to RT improved overall survival of patients with HNSCC. Consequently, we designed a prospective phase II study, to evaluate the feasibility and efficacy of concomitant RT-Ci and Ce in bad prognostic resected HNSCC. Methods: Patients have resected HNSCC of the oral cavity , oropharynx, larynx or hypopharynx, and at least one of the following adverse prognostic factors: microscopically incomplete resection, &gt;2 metastatic lymph nodes and/or &gt;1 lymph node with extracapsular spread, vascular and/or lymphatic emboli, &gt;2 perineural invasion, positive margins and pT4. All patients received: RT 70-72Gy in 7 weeks concurrent with Ce 250mg/m² weekly (6-7 weeks), after a loading dose of 400mg/m², and Ci 75mg/m² every 3 weeks x3 cycles. The primary endpoint is the 2 years disease-free survival. Results: 45 patients (35 Male) were enrolled, and 44 were evaluable for toxicity. Median age was 56 years (27-70). The tumor site was oral cavity (21), oropharynx (17), hypopharynx (3) and larynx (4). 39% of the patients had stage T2, 14% stage T3 and 27% stage T4. The nodal status was 0-2b in 80% of cases. The main adverse prognostic factors were the nodal involvement and microscopical positive resection (80% of patients). The RT-Ce-Ci regimen was discontinued in 11 cases including 7 due to toxicity. Among the 352 cycles (ie Ce+/-Ci) initially planned, 301 were delivered. Cutaneous and mucosal toxicity were the most common grade 3/4 side effects, accounting for 35% and 33%, respectively, and remained manageable. Grade 3 lymphopenia has been noted in 25% of cases. No treatment-related death was recorded. Conclusions: The triple association of RT-Ce-Ci appears to be safe and feasible in patients with bad prognostic resected HNSCC. The toxicity profile is comparable to that reported for RT-Ci or RT-Ce alone. Longer follow-up is required to evaluate the impact of addition of Ce to RT-Ci on survival.

Open-label, phase II trial of afatinib, with or without vinorelbine (V), for the treatment of HER2-overexpressing inflammatory breast cancer (IBC).

TPS650 Background: IBC is an aggressive and rare form of BC (1–6% cases). Despite recent treatment advances, prognosis remains poor, with 3-yr survival rate of 40 vs 85% in non-IBC. IBC commonly lack ER/PR and more frequently harbour HER2 gene amplification (~40%), and EGFR overexpression (~30%) associated with poor prognosis. Recent data reported clinical efficacy of lapatinib, a reversible EGFR/HER2 inhibitor, in trastuzumab (T) naïve/resistant HER2 positive IBC. Afatinib is an irreversible ErbB Family Blocker with preclinical activity in T-resistant cell lines, HER2-positive tumor xenografts and HER2-negative SUM 149 xenograft model derived from an IBC cell line. Its clinical efficacy was shown in heavily pre-treated, HER2-positive metastatic BC pts who progressed after T, with PR in 10% and clinical benefit in 46% of pts. The purpose of this biomarker-driven study is to investigate efficacy and safety of afatinib alone and in combination with V upon progression on afatinib monotherapy and the genomic changes that occur through treatment in pts with T pretreated or naïve HER2-positive IBC. Methods: Pts are recruited in 2 parallel cohorts of 20 pts each: T-naïve and T failure. Key eligibility criteria: histologically-confirmed HER2-positive BC; investigator-confirmed IBC characterized by diffuse erythema and oedema (peau d’orange) while dermal lymphatic emboli or palpable mass are not necessary for diagnosis; no prior anti-HER2 therapy except T in the T failure cohort; no prior V; ECOG 0–2. All pts start afatinib monotherapy (40 mg/d oral) in 4-week cycles (Part A). Upon disease progression, pts may receive afatinib (40 mg/d) + V (IV 25 mg/m2/week) (Part B). Primary endpoint: Clinical Benefit Rate (CR, PR or SD) for ≥6 months. Secondary endpoints: objective response rate, PFS, OS and safety. Endpoints are assessed separately for Part A and Part B. Fresh biopsy and blood samples are taken prior to treatment and upon progression in Part A, to explore predictive markers of response/resistance to afatinib, to describe the IBC population which may benefit most, and for next generation sequencing and proteomic analysis. Enrollment ongoing since Aug 2011.