Distinct HR expression patterns significantly affect the clinical behavior of metastatic HER2+ breast cancer and degree of benefit from novel anti-HER2 agents in the real world setting

We analyzed data from 738 HER2\u2010positive metastatic breast cancer (mbc) patients treated with pertuzumab\u2010based regimens and/or T\u2010DM1 at 45 Italian centers. Outcomes were explored in relation to tumor subtype assessed by immunohistochemistry (IHC). The median progression free survival at first\u2010line (mPFS1) was 12 months. Pertuzumab as first\u2010line conferred longer mPFS1 compared to other first\u2010line treatments (16 vs 9 months, p=0.0001), regardless of IHC subtype. Median PFS in second\u2010line (mPFS2) was 7 months, with no difference by IHC subtype, but it was more favorable with T\u2010DM1 compared to other agents (7 vs 6 months, p=0.03). There was no PFS2 gain in patients with tumors expressing both hormonal receptors (HRs) (p=0.17), while a trend emerged for tumors with one HR (p=0.05). Conversely, PFS2 gain was significant in HRs\u2010negative tumors (p=0.04). Median overall survival (mOS) was 74 months, with no significant differences by IHC subtypes. Survival rates at 2 and 3 years in patients treated with T\u2010DM1 in second\u2010line following pertuzumab were significantly lower compared to pertuzumab\u2010na\uefve patients(p=0.01). When analyzed by IHC subtype, the outcome was confirmed if both HRs or no HRs were expressed (p=0.02 and p=0.006, respectively). Our results confirm that HRs expression impacts the clinical behavior and novel treatment\u2010related outcomes of HER2\u2010positive tumors when treatment sequences are considered. Moreover, multivariate analysis showed that HRs expression had no effect on PFS and OS. Further studies are warranted to confirm our findings and clarify the interplay between HER2 and estrogen receptor (ER) pathways in HER2\u2010positive (mbc) patients

Cyclophilin C-associated protein (CyCAP) knock-out mice spontaneously develop colonic mucosal hyperplasia and exaggerated tumorigenesis after treatment with carcinogen azoxymethane1

<p>Abstract</p> <p>Background</p> <p>The discovery of a "serrated neoplasia pathway" has highlighted the role of hyperplastic lesions of the colon as the significant precursor of colorectal adenocarcinoma. In mice, hyperplasia of the colonic mucosa is a regular phenomenon after a challenge with colonic carcinogens indicating that mucosal hyperproliferation and thickening, even without cytological dysplasia, represents an early pre-malignant change. Cyclophilin C-associated protein (CyCAP) has been described to down-modulate endotoxin signaling in colorectal murine mucosa and is a murine orthologue of the tumor-associated antigen 90 K (TAA90K)/mac-2-binding protein.</p> <p>Methods</p> <p>Female Balb/c wild-type (WT) and CyCAP knock-out (KO) mice (6–8 weeks old) were administered 2 or 6 weekly subcutaneous injections of azoxymethane. The animals were evaluated post-injection at six weeks for aberrant crypt foci (ACF) study and at five months for colon tumor measurement. The thickness of the colon crypts was measured in microns and the number of colonocytes per crypt was also determined in well-oriented crypts. Morphometric analyses of the colon mucosa were also performed in untreated 6–8 weeks old KO and WT animals. Formalin-fixed/paraffin-embedded colon sections were also studied by immunohistochemistry to determine the Ki-67 proliferation fraction of the colon mucosa, β-catenin cellular localization, cyclin D1, c-myc, and lysozyme in Paneth cells.</p> <p>Results</p> <p>Cyclophilin C-associated protein (CyCAP)^-/-mice, spontaneously developed colonic mucosal hyperplasia early in life compared to wild-type mice (WT) (p < 0.0001, T-test) and crypts of colonic mucosa of the (CyCAP)^-/-mice show higher proliferation rate (p = 0.039, Mann-Whitney Test) and larger number of cyclin D1-positive cells (p < 0.0001, Mann-Whitney Test). Proliferation fraction and cyclin D1 expression showed positive linear association (p = 0.019, Linear-by-Linear Association). The hyperplasia was even more pronounced in CyCAP^-/-mice than in WT after challenge with azoxymethane (p = 0.005, T-test). The length of the crypts (r = 0.723, p = 0.018, Spearman Correlation) and the number of colonocytes per crypt (r = 0.863, p = 0.001, Spearman Correlation) in non-tumorous areas were positively associated with azoxymethane-induced number of tumors. CyCAP^-/-developed larger numbers of tumors than WT animals (p = 0.003, T-Test) as well as overall larger tumor mass (p = 0.016, T-Test). Membranous β-catenin was focally overexpressed in KO mice including proliferative zone of the crypts.</p> <p>Conclusion</p> <p>CyCAP^-/-represent the first described model of spontaneous colonic mucosal hyperplasia. We conclude that CyCAP-deficient mice spontaneously and after challenge with carcinogen develop significantly more colorectal mucosal hyperplasia, an early stage in murine colonic carcinogenesis.</p

Integrated conservative-peritoneal dialysis in CKD-stage5 (ICOPE) study: rationale, design and methods

INTRODUCTION: Increasing dialysis use is expected in the next future due to the growing population of CKD patients referred to renal clinics. The high cost, morbidity and mortality of full-dose dialysis, as its negative impact on quality of life, call for new therapeutic strategy to postpone standard dialysis treatment. Adding a low dose of peritoneal dialysis (PD) on the top of usual conservative therapy (CT) in nondialysis CKD-stage 5 may delay the onerous full-dose dialysis; however, no solid evidence has been provided on effectiveness of this combined therapy because the few previous studies on incremental dialysis were limited by retrospective nature, small sample size, absence of control group and undefined selection criteria. Therefore, we designed the ICOPE study to validate safety and efficacy of integrated therapy METHODS: Prospective multicenter controlled study evaluating the effects of add-on therapy with PD at low dose (CAPD 1-2 exchanges/24h or APD ≤4 sessions/week) in adult CKD-stage 5 patients with complications poorly responsive to nephrology treatment (diet and/or drugs). Key inclusion criteria are: age &gt;18 years, CT in the renal clinic from at least three months, eGFR-MDRD 5-15 mL/min/1.73m2. Furthermore, according to current guidelines on dialysis start, presence of ≥2 risk factors uncontro led by CT was required for enrolment. Key exclusion criteria are kidney transplantation and uremic symptoms that make mandatory full-dose dialysis. Patients unwilling to start PD constitute the control group (treated by CT only). Patients are followed according to best clinical practice with data collected every three months. Primary endpoint is time to renal death (full-dose dialysis or death whichever occurs first); secondary endpoints are hypertension status, metabolic abnormalities and nutritional/functional status after six months of integrated therapy. Estimated sample size is 440 RESULTS: Twenty Italian renal clinics have so far recruited 100 patients in the ICOPE arm and 15 controls. Twelve patients have been excluded as they did not meet selection criteria. The analysis planned at 25% recruitment to verify appropriateness of selection criteria, shows the following main basal features: age 63±15 y, males 61%, prior nephrology care 53 months [13-124], diabetes 29%, history of CV disease 36%, eGFR-MDRD 8.4±2.2 and mean of 24-h urea and creatinine clearance 7.8±2.6 mL/min/1.73m2, urinary output 2098±663 ml/24h. Median number of uncontrolled factors is 3 [2-4] and ≥3 in 64% patients; more prevalent complications are: fatigue in 88% patients, hypertension (BP&gt;140/90 mmHg) 52%, worsening of nutritional status 34%, and uncontroled Mineral Bone Disease (30%), anemia (16%), hyperkalemia (14%) and acidosis (11%). These complications have occurred despite multifactorial CT: dietary protein restriction 74%, anti-hypertensive drugs 3/pt [2-4]; diuretics 70%; anti-RAS 46%; antianemic drugs (epoietin and/or iron) 66%; P-binders and/or Vitamin D 78% CONCLUSIONS: ICOPE will be able to verify for the first time effectiveness of combined low PD dose+CT and to provide useful insights for the choice of the best candidate to this integrated therap

Differential effect on TCR:CD3 stimulation of a 90-kD glycoprotein (gp90/Mac-2BP), a member of the scavenger receptor cysteine-rich domain protein family

We studied the effects of a 90-kD glycoprotein (gp90/Mac-2BP) belonging to the scavenger receptor family, present in normal serum and at increased levels in inflammatory disease and cancer patients, on some T cell function parameters. Whereas the lymphocyte proliferative response to non-specific mitogens such as phytohaemagglutinin (PHA) and concanavalin A (Con A), but not pokeweed mitogen (PWM), was strongly reduced, probably due to the lectin-binding properties of gp90/Mac-2BP, the response to T cell receptor (TCR) agonists such as superantigens and allogeneic cells was potentiated. When lymphocytes were stimulated with different anti-TCR:CD3 MoAbs, both in soluble and solid-phase form, gp90/Mac-2BP was able to down-regulate the proliferative response to anti-CD3 MoAb, whereas the response to anti-TCR αβ MoAb was enhanced. A similar differential effect was observed when a MoAb against CD5 (another member of the scavenger receptor superfamily) was added to anti-CD3 or anti-TCR-stimulated cells; anti-CD5 MoAb strongly down-modulated the CD3-mediated response, whereas its presence in culture was associated with potentiation of the response to TCR αβ agonists. gp90/Mac-2BP was able per se to up-regulate Ca2+ levels in freshly isolated lymphocytes; moreover, its presence in culture was associated with increased Ca2+ mobilization following stimulation with anti-TCR αβ, but not anti-CD3 MoAb. These data indicate that gp90/Mac-2BP could be able to influence some immune responses, possibly through multiple homologous interactions with other members of the scavenger receptor family; moreover, our findings suggest that signalling through the different components of the TCR:CD3 complex may follow distinct activation pathways into the cells

The prognostic relevance of HER2-positivity gain in metastatic breast cancer in the ChangeHER trial

none56noIn metastatic breast cancer (mBC), the change of human epidermal growth factor receptor 2 (HER2) status between primary and metastatic lesions is widely recognized, however clinical implications are unknown. Our study address the question if relevant differences exist between subjects who preserve the HER2 status and those who gain the HER2 positivity when relapsed. Data of patients affected by HER2-positive mBC, treated with pertuzumab and/or trastuzumab-emtansine (T-DM1) in a real-world setting at 45 Italian cancer centers were retrospectively collected and analyzed. From 2003 to 2017, 491 HER2‐positive mBC patients were included. Of these, 102 (20.7%) had been initially diagnosed as HER2-negative early BC. Estrogen and/or progesterone receptor were more expressed in patients with HER2-discordance compared to patients with HER2-concordant status (p < 0.0001 and p = 0.006, respectively). HER2-discordant tumors were characterized also by a lower rate of brain metastases (p = 0.01) and a longer disease free interval (p < 0.0001). Median overall survival was longer, although not statistically significant, in the subgroup of patients with HER2-discordant cancer with respect to patients with HER2-concordant status (140 vs 78 months, p = 0.07). Our findings suggest that patients with HER2-positive mBC with discordant HER2 status in early BC may have different clinical, biological and prognostic behavior compared to HER2-concordant patients.nonePizzuti L.; Barba M.; Mazzotta M.; Krasniqi E.; Maugeri-Sacca M.; Gamucci T.; Berardi R.; Livi L.; Ficorella C.; Natoli C.; Cortesi E.; Generali D.; La Verde N.; Cassano A.; Bria E.; Moscetti L.; Michelotti A.; Adamo V.; Zamagni C.; Tonini G.; Sergi D.; Marinelli D.; Paoletti G.; Tomao S.; Botticelli A.; Marchetti P.; Tinari N.; Grassadonia A.; Valerio M.R.; Mirabelli R.; Fabbri M.A.; D'Ostilio N.; Veltri E.; Corsi D.; Garrone O.; Paris I.; Sarobba G.; Meattini I.; Pistelli M.; Giotta F.; Lorusso V.; Garufi C.; Russo A.; Cazzaniga M.; Del Medico P.; Roselli M.; Vaccaro A.; Perracchio L.; di Benedetto A.; Daralioti T.; Sperduti I.; De Maria R.; Di Leo A.; Sanguineti G.; Ciliberto G.; Vici P.Pizzuti, L.; Barba, M.; Mazzotta, M.; Krasniqi, E.; Maugeri-Sacca, M.; Gamucci, T.; Berardi, R.; Livi, L.; Ficorella, C.; Natoli, C.; Cortesi, E.; Generali, D.; La Verde, N.; Cassano, A.; Bria, E.; Moscetti, L.; Michelotti, A.; Adamo, V.; Zamagni, C.; Tonini, G.; Sergi, D.; Marinelli, D.; Paoletti, G.; Tomao, S.; Botticelli, A.; Marchetti, P.; Tinari, N.; Grassadonia, A.; Valerio, M. R.; Mirabelli, R.; Fabbri, M. A.; D'Ostilio, N.; Veltri, E.; Corsi, D.; Garrone, O.; Paris, I.; Sarobba, G.; Meattini, I.; Pistelli, M.; Giotta, F.; Lorusso, V.; Garufi, C.; Russo, A.; Cazzaniga, M.; Del Medico, P.; Roselli, M.; Vaccaro, A.; Perracchio, L.; di Benedetto, A.; Daralioti, T.; Sperduti, I.; De Maria, R.; Di Leo, A.; Sanguineti, G.; Ciliberto, G.; Vici, P

Loss of HER2 and decreased T-DM1 efficacy in HER2 positive advanced breast cancer treated with dual HER2 blockade: the SePHER Study

Background: HER2-targeting agents have dramatically changed the therapeutic landscape of HER2+ advanced breast cancer (ABC). Within a short time frame, the rapid introduction of new therapeutics has led to the approval of pertuzumab combined with trastuzumab and a taxane in first-line, and trastuzumab emtansine (T-DM1) in second-line. Thereby, evidence of T-DM1 efficacy following trastuzumab/pertuzumab combination is limited, with data from some retrospective reports suggesting lower activity. The purpose of the present study is to investigate T-DM1 efficacy in pertuzumab-pretreated and pertuzumab naïve HER2 positive ABC patients. We also aimed to provide evidence on the exposure to different drugs sequences including pertuzumab and T-DM1 in HER2 positive cell lines. Methods: The biology of HER2 was investigated in vitro through sequential exposure of resistant HER2 + breast cancer cell lines to trastuzumab, pertuzumab, and their combination. In vitro experiments were paralleled by the analysis of data from 555 HER2 + ABC patients treated with T-DM1 and evaluation of T-DM1 efficacy in the 371 patients who received it in second line. Survival estimates were graphically displayed in Kaplan Meier curves, compared by log rank test and, when possibile, confirmed in multivariate models. Results: We herein show evidence of lower activity of T-DM1 in two HER2+ breast cancer cell lines resistant to trastuzumab+pertuzumab, as compared to trastuzumab-resistant cells. Lower T-DM1 efficacy was associated with a marked reduction of HER2 expression on the cell membrane and its nuclear translocation. HER2 downregulation at the membrane level was confirmed in biopsies of four trastuzumab/pertuzumab-pretreated patients. Among the 371 patients treated with second-line T-DM1, median overall survival (mOS) from diagnosis of advanced disease and median progression-free survival to second-line treatment (mPFS2) were 52 and 6 months in 177 patients who received trastuzumab/pertuzumab in first-line, and 74 and 10 months in 194 pertuzumab-naïve patients (p = 0.0006 and 0.03 for OS and PFS2, respectively). Conclusions: Our data support the hypothesis that the addition of pertuzumab to trastuzumab reduces the amount of available plasma membrane HER2 receptor, limiting the binding of T-DM1 in cancer cells. This may help interpret the less favorable outcomes of second-line T-DM1 in trastuzumab/pertuzumab pre-treated patients compared to their pertuzumab-naïve counterpart