Metastatic profiles and survival differences between infiltrating ductal carcinoma and infiltrating lobular carcinoma in invasive breast cancer.

BACKGROUND: In this study, we conducted a comprehensive evaluation of metastatic profiles and survival outcomes in patients with infiltrating ductal carcinoma (IDC) and infiltrating lobular carcinoma (ILC) treated at our university hospital center. METHODS: We collected and analyzed data from all patients diagnosed with invasive breast cancer at our center between January 1, 2007, and 31 December 2014. We specifically compared three subgroups: patients with IDC, patients with ILC and patients with mixed carcinoma, which is a combination of IDC and ILC. RESULTS: Among the 1963 patients treated for invasive breast cancer in our center during the study period, 1435 had IDC, 466 had ILC, and 59 had mixed carcinoma. The incidence of patients with at least one positive axillary lymph node differed significantly: 40 % for IDC, 36 % for ILC, and 45 % for mixed carcinoma (p = 0.001). However, there was no significant difference in the mean number of positive nodes (p = 0.1633). The occurrence of distant metastases was lower in patients with ILC (p = 0.04), particularly in the case of brain metastases (p = 0.01), although there was no difference in bone or visceral metastatic sites. Patients with ILC exhibited a longer mean time to metastasis from the initial diagnosis of invasive breast carcinoma. Overall survival (p = 0.0525) and survival without locoregional recurrence (p = 0.026) were significantly different. Specifically, the 5-year overall survival rates for IDC, ILC, and mixed carcinoma were approximately 95 %. Distance metastatic-free survival at 5 years was 85 % for IDC, 91 % for ILC, and 87 % for mixed carcinoma (p = 0.00506). CONCLUSION: Our findings indicate variations in the distribution of distant metastatic sites among patients with IDC, ILC, and mixed carcinoma, as well as differences in survival outcomes. This study sheds light on the unique characteristics and clinical implications associated with these two distinct subtypes of invasive breast cancer.

Prognostic value of axillary lymph node metastases in invasive lobular breast carcinoma.

BACKGROUND: Axillary lymph node involvement is a well-established prognostic factor for recurrence in breast cancer, specifically the number of nodes affected and the ratio of the number of affected nodes to the number of harvested nodes for non-specific invasive breast cancer (invasive ductal carcinoma). However, there is limited information on the impact of lymph node involvement in the case of invasive lobular carcinoma. OBJECTIVES: our study aimed to evaluate the prognostic impact of lymph node involvement on overall survival and distant metastatic-free survival according to the number of nodes affected and the ratio of positive nodes (LNR) for patients managed for invasive lobular carcinoma. METHODS: This is a monocentre, comparative, observational study of patients managed for invasive lobular carcinoma at the Gynaecology Department of the University Hospital Center of Tours between January 1, 2007 and December 31, 2018. The LNR cut-off values used were: low risk if LNR ≤ 0.2; intermediate risk if LNR > 0.2 and ≤ 0.65, and high risk for LNR >0.659. RESULTS: Our study demonstrated a significant difference in overall survival and distant metastasis free survival (p < 0.0001). The 5-years Overall survival was 94 % for N0 patients, 92.4 % for low-risk patients, 85.6 % for intermediate-risk patients and 58.5 % for high-risk patients. The 5-year distant metastasis-free survival was 98.2 % for N0 patients, 95.9 % for low-risk patients, 80.1 % for intermediate-risk patients, and 60.3 % for high-risk patients. Multivariate analysis identified age, invasive lobular histologic type, presence of clinical inflammation, and intermediate and high risk classes of LNR ratio as independent factors affecting overall survival. For metastatic-free survival, the presence of clinical inflammation, the presence of LVSI and the low, intermediate, or high-risk classes of LNR ratio were identified as independent factors. However, age and invasive lobular histologic type did not appear to be independent factors affecting metastatic-free survival. CONCLUSION: Our study highlights the significant prognostic impact of lymph node involvement in patients with invasive lobular carcinoma. The LNR ratio can be used as a reliable predictor of overall survival and metastatic-free survival in these patients.

Oncological Safety of Autologous Fat Grafting in Breast Reconstruction after Mastectomy for cancer: A case-control study.

OBJECTIVE: The use of autologous fat grafting in the context of breast reconstruction is still a matter of controversy. The objective of this study was to compare the local relapse rate in women who had a fat grafting session in the context of breast reconstruction after breast cancer management, to those who had breast reconstruction without fat grafting. METHODS: We performed a retrospective, monocentric, case-control study from January 2007 to December 2017 in our hospital. The cases included women who underwent breast reconstruction with autologous fat grafting and controls, undergoing breast reconstruction without fat grafting. We compared survival and local recurrence between the two groups. RESULTS: 412 women were included: 109 (26.5%) in the lipofilling group and 303 women (73.5%) in the "no lipofilling" group. In the overall study population, lipofilling did not appear to be a predictive factor for recurrence, HR = 1.39 [0.63 - 3.06], p = 0.41; or a predictive factor for overall survival, HR = 0.84 [0.23 - 3.02], p = 0.79, or for distant metastases, HR = 1.10 [0.43 - 2.79], p = 0.84. In contrast, in the subgroup of women treated for invasive cancer, the multivariate analysis showed that lipofilling in this context was an independent predictive factor for local recurrence (HR= 5.06 [1.97 - 10.6], p = 0.04). CONCLUSION: we found an increased risk of local recurrence after lipofilling in women who were managed for invasive breast cancer. This suggests that special consideration should be given to women who have had invasive breast cancer before lipofilling.

Susceptibility of rat colon carcinoma cells to lymphokine activated killer-mediated cytotoxicity is decreased by alpha1,2-fucosylation.

The presence of alpha1,2-fucosylated glycans at the surface of rat colon carcinoma cells has been associated with an increased tumorigenicity and resistance to natural killer/lymphokine activated killer (NK/LAK) cytotoxicity. We now report that transfection of rat alpha1,2-fucosyltransferases cDNA (FTA and FTB) into REG cells, which are spontaneously devoid of this enzymatic activity, allows expression of histo-blood group H antigen and increases their resistance to LAK, but not NK cell lysis. Conversely, transfection of PRO cells, which spontaneously express alpha1, 2-fucosyltransferase activity, with the FTA cDNA in the antisense orientation decreases expression of the H antigen together with their resistance to LAK cell lysis, but again, not to NK cell lysis. Furthermore, REG cells that are rejected by immunocompetent syngeneic rats are similarly rejected by rats depleted of NK cells by antibody 3.2.3, directed against the NKR-P1 molecule. Thus, the rejection of REG cells by immunocompetent rats and their earlier reported increased tumorigenicity after transfection with an alpha1, 2-fucosyltransferase cDNA cannot be ascribed to NK cell sensitivity or resistance, respectively. The increased resistance to LAK cell lysis, however, may be relevant to tumor progression.

alpha1,2Fucosyltransferase increases resistance to apoptosis of rat colon carcinoma cells.

Accumulation of histo-blood group antigens such as Lewis b, Lewis Y and H in colon cancer is indicative of poor prognosis. It is accompanied by increase in alpha1,2fucosyl-transferase activity, a key enzyme for synthesis of these antigens. Using a model of colon carcinoma, we previously showed that alpha1,2fucosylation increases tumorigenicity. We now show that tumorigenicity inversely correlates with the cells' sensitivity to apoptosis. In addition, poorly tumorigenic REG cells independently transfected with three different alpha1,2fucosyltransferase cDNAs, the human FUT1, the rat FTA and FTB were more resistant than control cells to apoptosis induced in vitro by serum deprivation. Inversely, PRO cells, spontaneously tumorigenic in immunocompetent syngeneic animals and able to synthesize alpha1,2fucosylated glycans, became more sensitive to apoptosis after transfection with a fragment of the FTA cDNA in the antisense orientation. Expression of alpha1,2fucosyl-transferase in poorly tumorigenic REG cells dramatically enhanced their tumorigenicity in syngeneic rats. However, in immunodeficient animals, both control and alpha1,2fuco-syltransferase transfected REG cells were fully tumorigenic and metastatic, indicating that the presence of alpha1,2fucosylated antigens allowed REG tumor cells to escape immune control. Taken together, the results show that increased tumorigenicity mediated by alpha1,2fucosyl-ation is associated to increased resistance to apoptosis and to escape from immune control.

Role for alpha1,2-fucosyltransferase and histo-blood group antigen H type 2 in resistance of rat colon carcinoma cells to 5-fluorouracil.

5-Fluorouracil (5-FU) is a drug of standard use in chemotherapy of colon carcinoma. However, its efficacy is limited by inherent and acquired cell resistance. Major changes in histo-blood group antigenic expression, at times associated with poor prognosis, occur on colon cancer cells. To assess whether these antigens might play a role in the resistance to 5-FU, a rat model of colon carcinoma was used. We observed that in vivo treatment of tumors with the drug increased expression of antigen H type 2. The increase was also observed after in vitro short-term exposure to 5-FU, as well as on a cell-resistant variant selected by continuous exposure to the drug, and was accompanied by an increase in alpha1,2-fucosyltransferase activity, the key enzyme involved in synthesis of H antigens. Transfection of cells devoid of this enzymatic activity by an alpha1, 2-fucosyltransferase cDNA allowed expression of H type 2 antigen and increased resistance to 5-FU. Inversely, transfection of cells which possess enzymatic activity by a cDNA in anti-sense orientation reduced both H type 2 cell-surface antigen and resistance to the drug. These results demonstrate that, in this experimental model, alpha1,2-fucosyltransferase and H type 2 antigen are involved in cellular resistance to 5-FU.

Increased tumorigenicity of rat colon carcinoma cells after alpha1,2-fucosyltransferase FTA anti-sense cDNA transfection.

Accumulation of histo-blood group antigens such as Lewis b, Lewis Y and H increases tumor cell motility and tumorigenesis. Alpha1,2-fucosylation is a key step in the synthesis of these antigens. Two alpha1,2-fucosyltransferases, expressed in colorectal carcinomas, have been characterized (FUT1 and FUT2 in humans, FTA and FTB in rats). To define the relative contribution of each of these enzymes in tumor cell behavior, we have used an anti-sense transfection approach in rat colon carcinoma PROb cells, which synthesize mRNA encoding for both enzymes. We have previously reported that anti-sense transfection of a cDNA fragment of the FTB enzyme decreased H antigenic cell-surface levels and concomitantly decreased tumorigenicity. H antigens, detected by antibodies specific for H type 1, 3 or 4, were detected only on a splice variant of CD44 containing the product of exon v6. We now report the anti-sense transfection of an FTA cDNA fragment into PROb cells, which resulted in decreased enzymatic activity on a type 2 precursor and decreased cell-surface H type 2 antigen exclusively. Compared to controls, FTA anti-sense-transfected cells were significantly more tumorigenic in syngeneic animals but not in immunodeficient SCID mice. The UEA-I lectin, specific for H type 2, revealed that these structures were present on the CD44v6 variant and on an uncharacterized 80-kDa glycoprotein. Our results indicate that FTA and FTB fucosylate distinct glycan chains in the same cell, leading to opposite effects, under control of the immune system.

A rat experimental model for the design of vaccines against tumor associated antigens Tn and Sialyl-Tn.

Clones either strongly or barely expressing the Tn and Sialyl-Tn antigens were isolated from a rat colon carcinoma cell line. Expression of the antigens in normal rat tissues was very restricted and vaccination using Ovine Submaxillary Mucin as the immunogen could delay growth of the Sialyl-Tn positive cells, but not of the Sialyl-Tn negative cells in syngeneic rats. The model should be useful for testing new anti-Tn or Sialyl-Tn vaccination protocols.

Detection of a potential receptor for the H-blood-group antigen on rat colon-carcinoma cells and normal tissues.

Up-regulation of the synthesis of carbohydrate tumor-associated antigens terminated by the disaccharide Fucalpha1-2Gal is frequent in colon carcinoma and associated with poor prognosis. There is evidence that Fucalpha1-2Gal (H-disaccharide) structures increase cancer-cell motility and tumorigenicity by as-yet unknown mechanisms. Using polyacrylamide-based neoglycoconjugates, we looked for a potential receptor for this disaccharide, and observed that a neoglycoconjugate probe containing the H-disaccharide could bind rat colon-carcinoma cells in a dose-dependent manner, whereas very little binding was evidenced when a probe containing glucose was used. Binding of the H-disaccharide probe could be inhibited by the free H-disaccharide as well as by unlabeled neoglycoconjugates containing a terminal H-disaccharide. The best inhibitor was the H-type-1 trisaccharide neoglycoconjugate. Histochemical detection of the potential H-receptor was performed on rat normal tissues and in situ 1,2-dimethylhydrazine-induced colon carcinomas. A strong binding of the H-disaccharide probe was evidenced on most tumors that could be partly inhibited by the trisaccharide Fucalpha1-2Galbeta1-4Glc and by the unlabeled H-disaccharide neoglycoconjugate, indicating carbohydrate specificity of the binding. Staining of normal colonic mucosa was much weaker. Strong staining was also observed on some normal tissues, such as the spleen or lymph nodes, while others, such as lungs or liver, were negative. Probes containing glucose or the Lewis-a trisaccharide did not stain tumors or normal tissues. These results provide preliminary evidence for the existence of H-specific binding sites, the number of which increases in colon carcinoma.

Increase of rat colon carcinoma cells tumorigenicity by alpha(1-2) fucosyltransferase gene transfection.

Fucosylated histo-blood group antigens such as Lewis b, Lewis Y, and H accumulate in colon carcinoma and this is accompanied by a clear increase in alpha(1-2)fucosyltransferase activity, a key enzyme for the biosynthesis of these antigens. Yet the biological significance of alpha(1-2) fucosylated structures is not well defined. We have transfected a poorly tumorigenic rat colon carcinoma cell line with the human H blood group alpha(1-2)fucosyltransferase cDNA. This resulted in cell surface expression of H antigens with a concomitant decrease of sialic acid substituted and free beta-galactosides. Immunoprecipitation experiments showed that H antigens were essentially borne by variants of CD44 carrying amino acid sequences encoded by exon v6. The transfected cells showed increased motility in a wound healing assay, without changing their proliferation rates. Parental and control cells transfected with an empty vector formed small tumors that always regressed after 30 days when injected subcutaneously to syngeneic rats. In contrast, alpha(1-2)fucosyltransferase transfectants were able to form progressive tumors. Increased tumorigenicity was also visible in nude mice. These results demonstrate that alpha(1-2)fucosylated antigens contribute directly to aggressiveness of colon carcinoma cells. This could occur by altering a function of CD44 variants.

Expression of A and H blood-group and of CD44 antigens during chemical rat colonic carcinogenesis.

Using an experimental model of rat colon adenocarcinoma, we have recently shown that the presence of H blood-group antigen on variants of the CD44 adhesion molecule carrying amino acids encoded by exon v6 (CD44v6), increased the cells' tumorigenicity. In the present study, colon adenocarcinomas were induced by 1,2-dimethylhydrazine treatment in rats. Using immunohistochemistry, biopsies of normal, precancerous and carcinomatous colon mucosa were evaluated for expression A and H blood group antigens and CD44s and CD44v6 antigens. Normal rat colon showed strong and homogeneous expression of blood-group antigen A, but weak expression of H antigen. Several weeks before the appearance of tumours, dysplastic glands were strongly stained with anti-H reagents, while their A antigen was lost. Expression of CD44v6 was weak and restricted to some cells at the bottom of normal crypts. No obvious change was observed before appearance of severe dysplasia. In carcinomas, a strong but irregular expression of A, H and CD44v6 antigens was observed. In moderately differentiated carcinomas, A and H antigens were present at the apical surface of cells, whereas CD44v6 was found at the basolateral side. Only carcinomatous cells with loss of polarity, found in poorly differentiated cancers or infiltrated in the muscularis mucosae, were found to coexpress blood-group H or A and CD44v6 antigens at their surface.