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2. KEAP1-driven co-mutations in lung adenocarcinoma unresponsive to immunotherapy despite high tumor mutational burden

Author

Marinelli, D., Mazzotta, M., Scalera, S., Terrenato, I., Sperati, F., D'Ambrosio, L., Pallocca, M., Corleone, G., Krasniqi, E., Pizzuti, L., Barba, M., Carpano, S., Vici, P., Filetti, M., Giusti, R., Vecchione, A., Occhipinti, M., Gelibter, A., Botticelli, A., De Nicola, F., Ciuffreda, L., Goeman, F., Gallo, E., Visca, P., Pescarmona, E., Fanciulli, M., De Maria, R., Marchetti, P., Ciliberto, G., and Maugeri-Saccà, M.

Published
2020
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4. Adjuvant capecitabine in triple negative breast cancer patients with residual disease after neoadjuvant treatment: real-world evidence from CaRe, a multicentric, observational study

Author

Di Lisa, F, Krasniqi, E, Pizzuti, L, Barba, M, Cannita, K, De Giorgi, U, Borella, F, Foglietta, J, Cariello, A, Ferro, A, Picardo, E, Mitidieri, M, Sini, V, Stani, S, Tonini, G, Santini, D, La Verde, N, Gambaro, A, Grassadonia, A, Tinari, N, Garrone, O, Sarobba, G, Livi, L, Meattini, I, D'Auria, G, Vergati, M, Gamucci, T, Pistelli, M, Berardi, R, Risi, E, Giotta, F, Lorusso, V, Rinaldi, L, Artale, S, Cazzaniga, M, Zustovich, F, Cappuzzo, F, Landi, L, Torrisi, R, Scagnoli, S, Botticelli, A, Michelotti, A, Fratini, B, Saltarelli, R, Paris, I, Muratore, M, Cassano, A, Gianni, L, Gaspari, V, Veltri, E, Zoratto, F, Fiorio, E, Fabbri, M, Mazzotta, M, Ruggeri, E, Pedersini, R, Valerio, M, Filomeno, L, Minelli, M, Scavina, P, Raffaele, M, Astone, A, De Vita, R, Pozzi, M, Riccardi, F, Greco, F, Moscetti, L, Giordano, M, Maugeri-Sacca, M, Zennaro, A, Botti, C, Pelle, F, Cappelli, S, Cavicchi, F, Vizza, E, Sanguineti, G, Tomao, F, Cortesi, E, Marchetti, P, Tomao, S, Speranza, I, Sperduti, I, Ciliberto, G, Vici, P, Di Lisa F. S., Krasniqi E., Pizzuti L., Barba M., Cannita K., De Giorgi U., Borella F., Foglietta J., Cariello A., Ferro A., Picardo E., Mitidieri M., Sini V., Stani S., Tonini G., Santini D., La Verde N., Gambaro A. R., Grassadonia A., Tinari N., Garrone O., Sarobba G., Livi L., Meattini I., D'Auria G., Vergati M., Gamucci T., Pistelli M., Berardi R., Risi E., Giotta F., Lorusso V., Rinaldi L., Artale S., Cazzaniga M. E., Zustovich F., Cappuzzo F., Landi L., Torrisi R., Scagnoli S., Botticelli A., Michelotti A., Fratini B., Saltarelli R., Paris I., Muratore M., Cassano A., Gianni L., Gaspari V., Veltri E. M., Zoratto F., Fiorio E., Fabbri M. A., Mazzotta M., Ruggeri E. M., Pedersini R., Valerio M. R., Filomeno L., Minelli M., Scavina P., Raffaele M., Astone A., De Vita R., Pozzi M., Riccardi F., Greco F., Moscetti L., Giordano M., Maugeri-Sacca M., Zennaro A., Botti C., Pelle F., Cappelli S., Cavicchi F., Vizza E., Sanguineti G., Tomao F., Cortesi E., Marchetti P., Tomao S., Speranza I., Sperduti I., Ciliberto G., Vici P., Di Lisa, F, Krasniqi, E, Pizzuti, L, Barba, M, Cannita, K, De Giorgi, U, Borella, F, Foglietta, J, Cariello, A, Ferro, A, Picardo, E, Mitidieri, M, Sini, V, Stani, S, Tonini, G, Santini, D, La Verde, N, Gambaro, A, Grassadonia, A, Tinari, N, Garrone, O, Sarobba, G, Livi, L, Meattini, I, D'Auria, G, Vergati, M, Gamucci, T, Pistelli, M, Berardi, R, Risi, E, Giotta, F, Lorusso, V, Rinaldi, L, Artale, S, Cazzaniga, M, Zustovich, F, Cappuzzo, F, Landi, L, Torrisi, R, Scagnoli, S, Botticelli, A, Michelotti, A, Fratini, B, Saltarelli, R, Paris, I, Muratore, M, Cassano, A, Gianni, L, Gaspari, V, Veltri, E, Zoratto, F, Fiorio, E, Fabbri, M, Mazzotta, M, Ruggeri, E, Pedersini, R, Valerio, M, Filomeno, L, Minelli, M, Scavina, P, Raffaele, M, Astone, A, De Vita, R, Pozzi, M, Riccardi, F, Greco, F, Moscetti, L, Giordano, M, Maugeri-Sacca, M, Zennaro, A, Botti, C, Pelle, F, Cappelli, S, Cavicchi, F, Vizza, E, Sanguineti, G, Tomao, F, Cortesi, E, Marchetti, P, Tomao, S, Speranza, I, Sperduti, I, Ciliberto, G, Vici, P, Di Lisa F. S., Krasniqi E., Pizzuti L., Barba M., Cannita K., De Giorgi U., Borella F., Foglietta J., Cariello A., Ferro A., Picardo E., Mitidieri M., Sini V., Stani S., Tonini G., Santini D., La Verde N., Gambaro A. R., Grassadonia A., Tinari N., Garrone O., Sarobba G., Livi L., Meattini I., D'Auria G., Vergati M., Gamucci T., Pistelli M., Berardi R., Risi E., Giotta F., Lorusso V., Rinaldi L., Artale S., Cazzaniga M. E., Zustovich F., Cappuzzo F., Landi L., Torrisi R., Scagnoli S., Botticelli A., Michelotti A., Fratini B., Saltarelli R., Paris I., Muratore M., Cassano A., Gianni L., Gaspari V., Veltri E. M., Zoratto F., Fiorio E., Fabbri M. A., Mazzotta M., Ruggeri E. M., Pedersini R., Valerio M. R., Filomeno L., Minelli M., Scavina P., Raffaele M., Astone A., De Vita R., Pozzi M., Riccardi F., Greco F., Moscetti L., Giordano M., Maugeri-Sacca M., Zennaro A., Botti C., Pelle F., Cappelli S., Cavicchi F., Vizza E., Sanguineti G., Tomao F., Cortesi E., Marchetti P., Tomao S., Speranza I., Sperduti I., Ciliberto G., and Vici P.

Abstract

Background: In triple negative breast cancer patients treated with neoadjuvant chemotherapy, residual disease at surgery is the most relevant unfavorable prognostic factor. Current guidelines consider the use of adjuvant capecitabine, based on the results of the randomized CREATE-X study, carried out in Asian patients and including a small subset of triple negative tumors. Thus far, evidence on Caucasian patients is limited, and no real-world data are available. Methods: We carried out a multicenter, observational study, involving 44 oncologic centres. Triple negative breast cancer patients with residual disease, treated with adjuvant capecitabine from January 2017 through June 2021, were recruited. We primarily focused on treatment tolerability, with toxicity being reported as potential cause of treatment discontinuation. Secondarily, we assessed effectiveness in the overall study population and in a subset having a minimum follow-up of 2 years. Results: Overall, 270 patients were retrospectively identified. The 50.4% of the patients had residual node positive disease, 7.8% and 81.9% had large or G3 residual tumor, respectively, and 80.4% a Ki-67 >20%. Toxicity-related treatment discontinuation was observed only in 10.4% of the patients. In the whole population, at a median follow-up of 15 months, 2-year disease-free survival was 62%, 2 and 3-year overall survival 84.0% and 76.2%, respectively. In 129 patients with a median follow-up of 25 months, 2-year disease-free survival was 43.4%, 2 and 3-year overall survival 78.0% and 70.8%, respectively. Six or more cycles of capecitabine were associated with more favourable outcomes compared with less than six cycles. Conclusion: The CaRe study shows an unexpectedly good tolerance of adjuvant capecitabine in a real-world setting, although effectiveness appears to be lower than that observed in the CREATE-X study. Methodological differences between the two studies impose significant limits to comparability concerning ef

Published
2023

5. Clonal KEAP1 mutations with loss of heterozygosity share reduced immunotherapy efficacy and low immune cell infiltration in lung adenocarcinoma

Author

Scalera, S., primary, Ricciuti, B., additional, Mazzotta, M., additional, Calonaci, N., additional, Alessi, J.V., additional, Cipriani, L., additional, Bon, G., additional, Messina, B., additional, Lamberti, G., additional, Di Federico, A., additional, Pecci, F., additional, Milite, S., additional, Krasniqi, E., additional, Barba, M., additional, Vici, P., additional, Vecchione, A., additional, De Nicola, F., additional, Ciuffreda, L., additional, Goeman, F., additional, Fanciulli, M., additional, Buglioni, S., additional, Pescarmona, E., additional, Sharma, B., additional, Felt, K.D., additional, Lindsay, J., additional, Rodig, S.J., additional, De Maria, R., additional, Caravagna, G., additional, Cappuzzo, F., additional, Ciliberto, G., additional, Awad, M.M., additional, and Maugeri-Saccà, M., additional

Published
2023
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7. The prognostic relevance of HER2-positivity gain in metastatic breast cancer in the ChangeHER trial

Author

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, Mirabelli, R, Fabbri, M, 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., 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, Mirabelli, R, Fabbri, M, 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., and Vici P.

Abstract

In 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.

Published
2021

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

Author

Bon, G, Pizzuti, L, Laquintana, V, Loria, R, Porru, M, Marchio, C, Krasniqi, E, Barba, M, 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, Barchiesi, G, Mazzotta, M, Marinelli, D, Tomao, S, Marchetti, P, Valerio, M, Mirabelli, R, Russo, A, Fabbri, M, D'Ostilio, N, Veltri, E, Corsi, D, Garrone, O, Paris, I, Sarobba, G, Giotta, F, Garufi, C, Cazzaniga, M, Del Medico, P, Roselli, M, Sanguineti, G, Sperduti, I, Sapino, A, De Maria, R, Leonetti, C, Di Leo, A, Ciliberto, G, Falcioni, R, Vici, P, Bon G., Pizzuti L., Laquintana V., Loria R., Porru M., Marchio C., Krasniqi E., Barba M., 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., Barchiesi G., Mazzotta M., Marinelli D., Tomao S., Marchetti P., Valerio M. R., Mirabelli R., Russo A., Fabbri M. A., D'Ostilio N., Veltri E., Corsi D., Garrone O., Paris I., Sarobba G., Giotta F., Garufi C., Cazzaniga M., Del Medico P., Roselli M., Sanguineti G., Sperduti I., Sapino A., De Maria R., Leonetti C., Di Leo A., Ciliberto G., Falcioni R., Vici P., Bon, G, Pizzuti, L, Laquintana, V, Loria, R, Porru, M, Marchio, C, Krasniqi, E, Barba, M, 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, Barchiesi, G, Mazzotta, M, Marinelli, D, Tomao, S, Marchetti, P, Valerio, M, Mirabelli, R, Russo, A, Fabbri, M, D'Ostilio, N, Veltri, E, Corsi, D, Garrone, O, Paris, I, Sarobba, G, Giotta, F, Garufi, C, Cazzaniga, M, Del Medico, P, Roselli, M, Sanguineti, G, Sperduti, I, Sapino, A, De Maria, R, Leonetti, C, Di Leo, A, Ciliberto, G, Falcioni, R, Vici, P, Bon G., Pizzuti L., Laquintana V., Loria R., Porru M., Marchio C., Krasniqi E., Barba M., 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., Barchiesi G., Mazzotta M., Marinelli D., Tomao S., Marchetti P., Valerio M. R., Mirabelli R., Russo A., Fabbri M. A., D'Ostilio N., Veltri E., Corsi D., Garrone O., Paris I., Sarobba G., Giotta F., Garufi C., Cazzaniga M., Del Medico P., Roselli M., Sanguineti G., Sperduti I., Sapino A., De Maria R., Leonetti C., Di Leo A., Ciliberto G., Falcioni R., and Vici P.

Abstract

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 f

Published
2020

9. 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

Author

Pizzuti, L, Krasniqi, E, Barchiesi, G, Della Giulia, M, Izzo, F, Sanguineti, G, Marchetti, P, Mazzotta, M, Giusti, R, Botticelli, A, Gamucci, T, Natoli, C, Grassadonia, A, Tinari, N, Iezzi, L, Tomao, S, Tomao, F, Tonini, G, Santini, D, Astone, A, Michelotti, A, De Angelis, C, Mentuccia, L, Vaccaro, A, Magnolfi, E, Gelibter, A, Magri, V, Cortesi, E, D'Onofrio, L, Cassano, A, Rossi, E, Cazzaniga, M, Moscetti, L, Omarini, C, Piacentini, F, Fabbri, M, Scinto, A, Corsi, D, Carbognin, L, Bria, E, La Verde, N, Samaritani, R, Garufi, C, Barni, S, Mirabelli, R, Sarmiento, R, Veltri, E, D'Auria, G, Paris, I, Giotta, F, Lorusso, V, Cardillo, F, Landucci, E, Mauri, M, Ficorella, C, Roselli, M, Adamo, V, Ricciardi, G, Russo, A, Berardi, R, Pistelli, M, Fiorio, E, Cannita, K, Sini, V, D'Ostilio, N, Foglietta, J, Greco, F, Zamagni, C, Garrone, O, Di Cocco, B, Baldini, E, Livi, L, Desideri, I, Meattini, I, Sarobba, G, Del Medico, P, De Tursi, M, Generali, D, De Maria, R, Risi, E, Ciliberto, G, Sperduti, I, Villa, A, Barba, M, Di Leo, A, Vici, P, Pizzuti L., Krasniqi E., Barchiesi G., Della Giulia M., Izzo F., Sanguineti G., Marchetti P., Mazzotta M., Giusti R., Botticelli A., Gamucci T., Natoli C., Grassadonia A., Tinari N., Iezzi L., Tomao S., Tomao F., Tonini G., Santini D., Astone A., Michelotti A., De Angelis C., Mentuccia L., Vaccaro A., Magnolfi E., Gelibter A., Magri V., Cortesi E., D'Onofrio L., Cassano A., Rossi E., Cazzaniga M., Moscetti L., Omarini C., Piacentini F., Fabbri M. A., Scinto A. F., Corsi D., Carbognin L., Bria E., La Verde N., Samaritani R., Garufi C., Barni S., Mirabelli R., Sarmiento R., Veltri E. M., D'Auria G., Paris I., Giotta F., Lorusso V., Cardillo F., Landucci E., Mauri M., Ficorella C., Roselli M., Adamo V., Ricciardi G. R. R., Russo A., Berardi R., Pistelli M., Fiorio E., Cannita K., Sini V., D'Ostilio N., Foglietta J., Greco F., Zamagni C., Garrone O., Di Cocco B., Baldini E., Livi L., Desideri I., Meattini I., Sarobba G., Del Medico P., De Tursi M., Generali D., De Maria R., Risi E., Ciliberto G., Sperduti I., Villa A., Barba M., Di Leo A., Vici P., Pizzuti, L, Krasniqi, E, Barchiesi, G, Della Giulia, M, Izzo, F, Sanguineti, G, Marchetti, P, Mazzotta, M, Giusti, R, Botticelli, A, Gamucci, T, Natoli, C, Grassadonia, A, Tinari, N, Iezzi, L, Tomao, S, Tomao, F, Tonini, G, Santini, D, Astone, A, Michelotti, A, De Angelis, C, Mentuccia, L, Vaccaro, A, Magnolfi, E, Gelibter, A, Magri, V, Cortesi, E, D'Onofrio, L, Cassano, A, Rossi, E, Cazzaniga, M, Moscetti, L, Omarini, C, Piacentini, F, Fabbri, M, Scinto, A, Corsi, D, Carbognin, L, Bria, E, La Verde, N, Samaritani, R, Garufi, C, Barni, S, Mirabelli, R, Sarmiento, R, Veltri, E, D'Auria, G, Paris, I, Giotta, F, Lorusso, V, Cardillo, F, Landucci, E, Mauri, M, Ficorella, C, Roselli, M, Adamo, V, Ricciardi, G, Russo, A, Berardi, R, Pistelli, M, Fiorio, E, Cannita, K, Sini, V, D'Ostilio, N, Foglietta, J, Greco, F, Zamagni, C, Garrone, O, Di Cocco, B, Baldini, E, Livi, L, Desideri, I, Meattini, I, Sarobba, G, Del Medico, P, De Tursi, M, Generali, D, De Maria, R, Risi, E, Ciliberto, G, Sperduti, I, Villa, A, Barba, M, Di Leo, A, Vici, P, Pizzuti L., Krasniqi E., Barchiesi G., Della Giulia M., Izzo F., Sanguineti G., Marchetti P., Mazzotta M., Giusti R., Botticelli A., Gamucci T., Natoli C., Grassadonia A., Tinari N., Iezzi L., Tomao S., Tomao F., Tonini G., Santini D., Astone A., Michelotti A., De Angelis C., Mentuccia L., Vaccaro A., Magnolfi E., Gelibter A., Magri V., Cortesi E., D'Onofrio L., Cassano A., Rossi E., Cazzaniga M., Moscetti L., Omarini C., Piacentini F., Fabbri M. A., Scinto A. F., Corsi D., Carbognin L., Bria E., La Verde N., Samaritani R., Garufi C., Barni S., Mirabelli R., Sarmiento R., Veltri E. M., D'Auria G., Paris I., Giotta F., Lorusso V., Cardillo F., Landucci E., Mauri M., Ficorella C., Roselli M., Adamo V., Ricciardi G. R. R., Russo A., Berardi R., Pistelli M., Fiorio E., Cannita K., Sini V., D'Ostilio N., Foglietta J., Greco F., Zamagni C., Garrone O., Di Cocco B., Baldini E., Livi L., Desideri I., Meattini I., Sarobba G., Del Medico P., De Tursi M., Generali D., De Maria R., Risi E., Ciliberto G., Sperduti I., Villa A., Barba M., Di Leo A., and Vici P.

Abstract

We analyzed data from 738 HER2-positive metastatic breast cancer (mbc) patients treated with pertuzumab-based regimens and/or T-DM1 at 45 Italian centers. Outcomes were explored in relation to tumor subtype assessed by immunohistochemistry (IHC). The median progression-free survival at first-line (mPFS1) was 12 months. Pertuzumab as first-line conferred longer mPFS1 compared to other first-line treatments (16 vs. 9 months, p = 0.0001), regardless of IHC subtype. Median PFS in second-line (mPFS2) was 7 months, with no difference by IHC subtype, but it was more favorable with T-DM1 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-negative 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-DM1 in second-line after pertuzumab were significantly lower compared to pertuzumab-naïve 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-related outcomes of HER2-positive 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 pathways in HER2-positive (mbc) patients

Published
2020

10. Additional file 14 of MicroRNA-based signatures impacting clinical course and biology of ovarian cancer: a miRNOmics study

Author

Krasniqi, E., Sacconi, A., Marinelli, D., Pizzuti, L., Mazzotta, M., Sergi, D., Capomolla, E., Donzelli, S., Carosi, M., Bagnato, A., Gamucci, T., Tomao, S., Natoli, C., Marchetti, P., Grassadonia, A., Tinari, N., De Tursi, M., Vizza, E., Ciliberto, G., Landi, L., Cappuzzo, F., Barba, M., Blandino, G., and Vici, P.

Abstract

Additional file 14: Figure S6. Principal component analysis of 88 normal samples from GTEx dataset and 499 tumor samples from TCGA RNA sequencing-based dataset, using all the target genes negatively correlated to the 9 miRNA signature and significantly modulated between normal samples and tumor samples.

Published
2021
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11. Data-driven stratification of Parkinson's disease patients based on the progression of motor and cognitive disease markers

Author

Krasniqi, E, Schramm, W, Reichenbach, A, Krasniqi, E, Schramm, W, and Reichenbach, A

Abstract

Parkinson's disease (PD) is a progressive neurodegenerative movement disorder with a complex set of motor and non-motor symptoms and a diverse disease progression. Subtyping PD patients is required for personalized therapies but stratification approaches based on intermediate phenotypes such as clinical assessment scores lack reproducibility and stability, which is at least partially due to the broad spectrum of methods that can be applied during different steps of data processing. We propose a novel approach that considers the progression of detailed clinical assessment scores in different domains over a period of five years. Furthermore, we confirm the robustness of our subtypes with comparisons to subtypes that emerge when using different data pre-processing or another clustering algorithm. Three subtypes were found with differentiable symptoms: The motor-dominant subtype has the fastest progression and is most severely affected in daily life, closely followed by the sleep-dominant non-tremor subtype. The mild-motor subtype, in contrast, is characterized by moderate progression. These subtypes emerge from their progression pattern rather than from a snapshot during one time point. Hence we advocate for stratification approaches for PD subtyping that take longitudinal data over several years into account., Die Parkinson-Krankheit ist eine fortschreitende, neurodegenerative Erkrankung, die sich durch komplexe motorische und nicht-motorische Symptome sowie einen vielfältigen Krankheitsverlauf auszeichnet. Subtypisierung der Patienten ist für personalisierte Therapien notwendig, jedoch fehlt es an Stratifizierungsansätzen, die auf Zwischenphänotypen wie z.B. klinischen Tests aufsetzen, an Reproduzierbarkeit und Stabilität. Dies bedingt sich teilweise durch die vielen methodischen Möglichkeiten bei der Datenprozessierung. Wir schlagen einen neuen Ansatz vor, bei dem die Entwicklung detaillierter klinischer Kennwerte aus unterschiedlichen Domänen über einen Zeitraum von fünf Jahren betrachtet wird. Die Robustheit der so erhaltenen Subtypen untermauern wir mit Vergleichen zu Subtypen, die wir mit abweichender Datenprozessierung oder einem anderen Clustering-Algorithmus gewonnen hätten. Wir finden hier drei Subtypen mit differenzierbarer Symptomatik: Der motorisch-dominante Subtyp ist gekennzeichnet durch den raschesten Verfall und ist im täglichen Leben am stärksten betroffen, eng gefolgt vom Schlaf-dominanten non-Tremor Subtyp. Im Gegensatz dazu ist der Krankheitsverlauf des mild-motorischen Subtyps eher moderat. Diese Subtypen erwachsen aus den Verläufen ihrer komplexen Symptomatik und nicht aus Gruppenunterschieden während eines einzelnen Zeitpunkts. Deswegen plädieren wir dafür, für die Subtypisierung von Parkinson-Patienten Längsschnittdaten mehrerer Jahre zu verwenden.

Published
2021

12. KEAP1 and TP53 Frame Genomic, Evolutionary, and Immunologic Subtypes of Lung Adenocarcinoma With Different Sensitivity to Immunotherapy

Author

Scalera, S., Mazzotta, M., Corleone, G., Sperati, F., Terrenato, I., Krasniqi, E., Pizzuti, L., Barba, Marta, Vici, P., Gallo, E., Buglioni, S., Visca, P., Pescarmona, E., Marinelli, D., De Nicola, F., Ciuffreda, L., Goeman, F., Fanciulli, M., Giusti, R., Vecchione, Andrea, De Maria Marchiano, Ruggero, Cappuzzo, F., Marchetti, P., Ciliberto, G., Maugeri-Sacca, M., Barba M. (ORCID:0000-0001-6084-7666), Vecchione A., De Maria R. (ORCID:0000-0003-2255-0583), Scalera, S., Mazzotta, M., Corleone, G., Sperati, F., Terrenato, I., Krasniqi, E., Pizzuti, L., Barba, Marta, Vici, P., Gallo, E., Buglioni, S., Visca, P., Pescarmona, E., Marinelli, D., De Nicola, F., Ciuffreda, L., Goeman, F., Fanciulli, M., Giusti, R., Vecchione, Andrea, De Maria Marchiano, Ruggero, Cappuzzo, F., Marchetti, P., Ciliberto, G., Maugeri-Sacca, M., Barba M. (ORCID:0000-0001-6084-7666), Vecchione A., and De Maria R. (ORCID:0000-0003-2255-0583)

Abstract

Introduction: The connection between driver mutations and the efficacy of immune checkpoint inhibitors is the focus of intense investigations. In lung adenocarcinoma (LUAD), KEAP1/STK11 alterations have been tied to immunoresistance. Nevertheless, the heterogeneity characterizing immunotherapy efficacy suggests the contribution of still unappreciated events. Methods: Somatic interaction analysis of top-ranking mutant genes in LUAD was carried out in the American Association for Cancer Research (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE) (N = 6208). Mutational processes, intratumor heterogeneity, evolutionary trajectories, immunologic features, and cancer-associated signatures were investigated, exploiting multiple data sets (AACR GENIE, The Cancer Genome Atlas [TCGA], TRAcking Cancer Evolution through therapy [Rx]). The impact of the proposed subtyping on survival outcomes was assessed in two independent cohorts of immune checkpoint inhibitor–treated patients: the tissue-based sequencing cohort (Rome/Memorial Sloan Kettering Cancer Center/Dana-Farber Cancer Institute, tissue-based next-generation sequencing [NGS] cohort, N = 343) and the blood-based sequencing cohort (OAK/POPLAR trials, blood-based NGS cohort, N = 304). Results: Observing the neutral interaction between KEAP1 and TP53, KEAP1/TP53-based subtypes were dissected at the molecular and clinical levels. KEAP1 single-mutant (KEAP1 SM) and KEAP1/TP53 double-mutant (KEAP1/TP53 DM) LUAD share a transcriptomic profile characterized by the overexpression of AKR genes, which are under the control of a productive superenhancer with NEF2L2-binding signals. Nevertheless, KEAP1 SM and KEAP1/TP53 DM tumors differ by mutational repertoire, degree of intratumor heterogeneity, evolutionary trajectories, pathway-level signatures, and immune microenvironment composition. In both cohorts (blood-based NGS and tissue-based NGS), KEAP1 SM tumors had the shortest survival; the KEAP1/TP53 DM subgroup

Published
2021

13. Cdk4/6 inhibitor treatments in patients with hormone receptor positive, her2 negative advanced breast cancer: Potential molecular mechanisms, clinical implications and future perspectives

Author

Roberto, M., Astone, Antonio, Botticelli, A., Carbognin, L., Cassano, Alessandra, D'Auria, G., Fabbri, A., Fabi, A., Gamucci, T., Krasniqi, E., Minelli, M., Orlandi, Armando, Pantano, F., Paris, Ida, Pizzuti, L., Portarena, I., Salesi, N., Scagnoli, S., Scavina, P., Tonini, G., Vici, P., Marchetti, P., Astone A. (ORCID:0000-0001-9572-309X), Cassano A. (ORCID:0000-0002-3311-7163), Orlandi A. (ORCID:0000-0001-5253-4678), Paris I., Roberto, M., Astone, Antonio, Botticelli, A., Carbognin, L., Cassano, Alessandra, D'Auria, G., Fabbri, A., Fabi, A., Gamucci, T., Krasniqi, E., Minelli, M., Orlandi, Armando, Pantano, F., Paris, Ida, Pizzuti, L., Portarena, I., Salesi, N., Scagnoli, S., Scavina, P., Tonini, G., Vici, P., Marchetti, P., Astone A. (ORCID:0000-0001-9572-309X), Cassano A. (ORCID:0000-0002-3311-7163), Orlandi A. (ORCID:0000-0001-5253-4678), and Paris I.

Abstract

Hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer is the most common breast cancer subtype, and endocrine therapy (ET) remains its therapeutic backbone. Although anti-estrogen therapies are usually effective initially, approximately 50% of HR+ patients develop resistance to ET within their lifetime, ultimately leading to disease recurrence and limited clinical benefit. The recent addition of cyclin-dependent kinase 4 (CDK4) and CDK6 inhibitors (palbociclib, ribociclib, abemaciclib) to ET have remarkably improved the outcome of patients with HR+ advanced breast cancer (ABC) compared with anti-estrogens alone, by targeting the cell-cycle machinery and overcoming some aspects of endocrine resistance. However, egies to enhance their efficacy in improving survival and quality of life of patients affected whichHR+, HER2−,patients areABC.the better candidates for these drugs, which are the main characteristics for a better selection of patients or if there are predictive biomarkers of response, is still unknown. In this review we reported the mechanism of action of CDK4/6 inhibitors as well as their potential mechanism Keywords: CDK4/6 inhibitors; breast cancer; endocrine therapy (ET); advanced breast cancer (Aof resistance, their implications in clinical practice and the forthcoming strategies to enhance their endocrine resistance efficacy in improving survival and quality of life of patients affected with HR+, HER2−, ABC.

Published
2021

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

Author

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, Emilio, 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, Domenico Cristiano, Garrone, O., Paris, Ida, 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 Marchiano, Ruggero, Di Leo, A., Sanguineti, G., Ciliberto, G., Vici, P., Bria E. (ORCID:0000-0002-2333-704X), Corsi D., Paris I., De Maria R. (ORCID:0000-0003-2255-0583), 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, Emilio, 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, Domenico Cristiano, Garrone, O., Paris, Ida, 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 Marchiano, Ruggero, Di Leo, A., Sanguineti, G., Ciliberto, G., Vici, P., Bria E. (ORCID:0000-0002-2333-704X), Corsi D., Paris I., and De Maria R. (ORCID:0000-0003-2255-0583)

Abstract

In 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.

Published
2021

15. Impact of BMI on HER2+ metastatic breast cancer patients treated with pertuzumab and/or trastuzumab emtansine. Real-world evidence

Author

Krasniqi, E, Pizzuti, L, Barchiesi, G, Sergi, D, Carpano, S, Botti, C, Kayal, R, Sanguineti, G, Marchetti, P, Botticelli, A, Marinelli, D, Gamucci, T, Natoli, C, Grassadonia, A, Tinari, N, Tomao, S, Tonini, G, Santini, D, Michelotti, A, Mentuccia, L, Vaccaro, A, Magnolfi, E, Gelibter, A, Magri, V, Cortesi, E, D'Onofrio, L, Cassano, A, Cazzaniga, M, Moscetti, L, Fabbri, A, Scinto, A, Corsi, D, Carbognin, L, Bria, E, La Verde, N, Garufi, C, Di Stefano, P, Mirabelli, R, Veltri, E, Paris, I, Giotta, F, Lorusso, V, Landucci, E, Ficorella, C, Roselli, M, Adamo, V, Ricciardi, G, Russo, A, Valerio, M, Berardi, R, Pistelli, M, Cannita, K, Zamagni, C, Garrone, O, Baldini, E, Livi, L, Meattini, I, Del Medico, P, Generali, D, De Maria, R, Risi, E, Ciliberto, G, Villa, A, Sperduti, I, Mazzotta, M, Barba, M, Giordano, A, Vici, P, Krasniqi, Eriseld, Pizzuti, Laura, Barchiesi, Giacomo, Sergi, Domenico, Carpano, Silvia, Botti, Claudio, Kayal, Ramy, Sanguineti, Giuseppe, Marchetti, Paolo, Botticelli, Andrea, Marinelli, Daniele, Gamucci, Teresa, Natoli, Clara, Grassadonia, Antonino, Tinari, Nicola, Tomao, Silverio, Tonini, Giuseppe, Santini, Daniele, Michelotti, Aandrea, Mentuccia, Lucia, Vaccaro, Aangela, Magnolfi, Emanuela, Gelibter, Alain, Magri, Valentina, Cortesi, Enrico, D'Onofrio, Loretta, Cassano, Alessandra, Cazzaniga, Marina, Moscetti, Luca, Fabbri, Agnese, Scinto, Angelo Fedele, Corsi, Domenico, Carbognin, Luisa, Bria, Emilio, La Verde, Nicla, Garufi, Carlo, Di Stefano, Pia, Mirabelli, Rossana, Veltri, Enzo, Paris, Ida, Giotta, Francesco, Lorusso, Vito, Landucci, Elisa, Ficorella, Corrado, Roselli, Mario, Adamo, Vincenzo, Ricciardi, Giuseppina, Russo, Antonio, Valerio, Maria Rosaria, Berardi, Rossana, Pistelli, Mirco, Cannita, Katia, Zamagni, Claudio, Garrone, Ornella, Baldini, Editta, Livi, Lorenzo, Meattini, Icro, Del Medico, Pietro, Generali, Daniele, De Maria, Ruggero, Risi, Emanuela, Ciliberto, Gennaro, Villa, Alice, Sperduti, Isabella, Mazzotta, Marco, Barba, Maddalena, Giordano, Antonio, Vici, Patrizia, Krasniqi, E, Pizzuti, L, Barchiesi, G, Sergi, D, Carpano, S, Botti, C, Kayal, R, Sanguineti, G, Marchetti, P, Botticelli, A, Marinelli, D, Gamucci, T, Natoli, C, Grassadonia, A, Tinari, N, Tomao, S, Tonini, G, Santini, D, Michelotti, A, Mentuccia, L, Vaccaro, A, Magnolfi, E, Gelibter, A, Magri, V, Cortesi, E, D'Onofrio, L, Cassano, A, Cazzaniga, M, Moscetti, L, Fabbri, A, Scinto, A, Corsi, D, Carbognin, L, Bria, E, La Verde, N, Garufi, C, Di Stefano, P, Mirabelli, R, Veltri, E, Paris, I, Giotta, F, Lorusso, V, Landucci, E, Ficorella, C, Roselli, M, Adamo, V, Ricciardi, G, Russo, A, Valerio, M, Berardi, R, Pistelli, M, Cannita, K, Zamagni, C, Garrone, O, Baldini, E, Livi, L, Meattini, I, Del Medico, P, Generali, D, De Maria, R, Risi, E, Ciliberto, G, Villa, A, Sperduti, I, Mazzotta, M, Barba, M, Giordano, A, Vici, P, Krasniqi, Eriseld, Pizzuti, Laura, Barchiesi, Giacomo, Sergi, Domenico, Carpano, Silvia, Botti, Claudio, Kayal, Ramy, Sanguineti, Giuseppe, Marchetti, Paolo, Botticelli, Andrea, Marinelli, Daniele, Gamucci, Teresa, Natoli, Clara, Grassadonia, Antonino, Tinari, Nicola, Tomao, Silverio, Tonini, Giuseppe, Santini, Daniele, Michelotti, Aandrea, Mentuccia, Lucia, Vaccaro, Aangela, Magnolfi, Emanuela, Gelibter, Alain, Magri, Valentina, Cortesi, Enrico, D'Onofrio, Loretta, Cassano, Alessandra, Cazzaniga, Marina, Moscetti, Luca, Fabbri, Agnese, Scinto, Angelo Fedele, Corsi, Domenico, Carbognin, Luisa, Bria, Emilio, La Verde, Nicla, Garufi, Carlo, Di Stefano, Pia, Mirabelli, Rossana, Veltri, Enzo, Paris, Ida, Giotta, Francesco, Lorusso, Vito, Landucci, Elisa, Ficorella, Corrado, Roselli, Mario, Adamo, Vincenzo, Ricciardi, Giuseppina, Russo, Antonio, Valerio, Maria Rosaria, Berardi, Rossana, Pistelli, Mirco, Cannita, Katia, Zamagni, Claudio, Garrone, Ornella, Baldini, Editta, Livi, Lorenzo, Meattini, Icro, Del Medico, Pietro, Generali, Daniele, De Maria, Ruggero, Risi, Emanuela, Ciliberto, Gennaro, Villa, Alice, Sperduti, Isabella, Mazzotta, Marco, Barba, Maddalena, Giordano, Antonio, and Vici, Patrizia

Abstract

Body mass index (BMI) is a main indicator of obesity and its association with breast cancer is well established. However, little is known in the metastatic setting, especially in HER2-positive patients. We assessed the influence of BMI on clinical outcomes of patients treated with pertuzumab and/or trastuzumab emtansine (T-DM1) for HER2+ metastatic breast cancer (mBC). BMI was addressed as a categorical variable, being classified on the basis of the following ranges, that is, 18.5–24.9, 25–29.9, and 30.0–34.9, namely, normal weight, overweight, and Class I obesity. The outcomes chosen were progression-free survival to first-line chemotherapy (PFS1) and overall survival (OS). Overall (N = 709), no impact of BMI was observed on PFS1 (p =.15), while BMI ≥ 30 was associated with worse OS (p =.003). In subjects who progressed to first line (N = 575), analyzing data across PFS1 quartiles and strata of disease burden, BMI predicted lower PFS1 in patients within the I PFS1 quartile and with the lowest disease burden (p =.001). Univariate analysis showed a detrimental effect of BMI ≥ 30 on OS for women within the I PFS1 quartile (p =.03). Results were confirmed in multivariate analysis. According to PFS1 quartiles a higher percentage of patients with high BMI and low disease burden progressed within 6 months of therapy. The effect of BMI on prognosis was also confirmed in multivariate analysis of OS for overall population. In our cohort, a BMI ≥ 30 correlated with worse OS in patients with HER2+ mBC who received pertuzumab and/or T-DM1 but had no impact on PFS to first line. BMI predicted worse I PFS1 quartile.

Published
2020

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

Author

Bon, G., Pizzuti, L., Laquintana, V., Loria, R., Porru, M., Marchio, C., Krasniqi, E., Barba, M., Maugeri-Sacca, M., Gamucci, T., Berardi, R., Livi, L., Ficorella, C., Natoli, C., Cortesi, E., Generali, D., La Verde, N., Cassano, Alessandra, Bria, Emilio, Moscetti, L., Michelotti, A., Adamo, V., Zamagni, C., Tonini, G., Barchiesi, G., Mazzotta, M., Marinelli, D., Tomao, S., Marchetti, P., Valerio, M. R., Mirabelli, R., Russo, A., Fabbri, M. A., D'Ostilio, N., Veltri, E., Corsi, D., Garrone, O., Paris, I., Sarobba, G., Giotta, F., Garufi, C., Cazzaniga, M., Del Medico, P., Roselli, M., Sanguineti, G., Sperduti, I., Sapino, A., De Maria Marchiano, Ruggero, Leonetti, C., Di Leo, A., Ciliberto, G., Falcioni, R., Vici, P., Cassano A. (ORCID:0000-0002-3311-7163), Bria E. (ORCID:0000-0002-2333-704X), De Maria R. (ORCID:0000-0003-2255-0583), Bon, G., Pizzuti, L., Laquintana, V., Loria, R., Porru, M., Marchio, C., Krasniqi, E., Barba, M., Maugeri-Sacca, M., Gamucci, T., Berardi, R., Livi, L., Ficorella, C., Natoli, C., Cortesi, E., Generali, D., La Verde, N., Cassano, Alessandra, Bria, Emilio, Moscetti, L., Michelotti, A., Adamo, V., Zamagni, C., Tonini, G., Barchiesi, G., Mazzotta, M., Marinelli, D., Tomao, S., Marchetti, P., Valerio, M. R., Mirabelli, R., Russo, A., Fabbri, M. A., D'Ostilio, N., Veltri, E., Corsi, D., Garrone, O., Paris, I., Sarobba, G., Giotta, F., Garufi, C., Cazzaniga, M., Del Medico, P., Roselli, M., Sanguineti, G., Sperduti, I., Sapino, A., De Maria Marchiano, Ruggero, Leonetti, C., Di Leo, A., Ciliberto, G., Falcioni, R., Vici, P., Cassano A. (ORCID:0000-0002-3311-7163), Bria E. (ORCID:0000-0002-2333-704X), and De Maria R. (ORCID:0000-0003-2255-0583)

Abstract

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 f

Published
2020

17. Efficacy of immunotherapy in lung cancer with co-occurring mutations in NOTCH and homologous repair genes

Author

Mazzotta, M., Filetti, M., Occhipinti, M., Marinelli, D., Scalera, S., Terrenato, I., Sperati, F., Pallocca, M., Rizzo, F., Gelibter, A., Botticelli, A., Scafetta, G., Di Napoli, A., Krasniqi, E., Pizzuti, L., Barba, M., Carpano, S., Vici, P., Fanciulli, M., De Nicola, F., Ciuffreda, L., Goeman, F., De Maria Marchiano, Ruggero, Vecchione, A., Giusti, R., Ciliberto, G., Marchetti, P., Maugeri-Sacca, M., De Maria R. (ORCID:0000-0003-2255-0583), Mazzotta, M., Filetti, M., Occhipinti, M., Marinelli, D., Scalera, S., Terrenato, I., Sperati, F., Pallocca, M., Rizzo, F., Gelibter, A., Botticelli, A., Scafetta, G., Di Napoli, A., Krasniqi, E., Pizzuti, L., Barba, M., Carpano, S., Vici, P., Fanciulli, M., De Nicola, F., Ciuffreda, L., Goeman, F., De Maria Marchiano, Ruggero, Vecchione, A., Giusti, R., Ciliberto, G., Marchetti, P., Maugeri-Sacca, M., and De Maria R. (ORCID:0000-0003-2255-0583)

Abstract

Background Immune checkpoint inhibitors (ICIs) provide significant survival benefits in non-small cell lung cancer (NSCLC). Nevertheless, while some patients obtain a prolonged benefit, a non-negligible fraction of patients experiences an ultrarapid disease progression. Identifying specific molecular backgrounds predicting opposite outcomes is instrumental to optimize the use of these agents in clinical practice. Methods We carried out an observational study with prospective design envisioning targeted next-generation sequencing (NGS) with an approved assay in 55 patients with metastatic NSCLC (Rome cohort), of whom 35 were treated with ICIs. Data from three clinically comparable datasets were collected and combined into a metadataset containing 779 patients. The datasets were related to the Memorial Sloan Kettering Cancer Center (MSKCC) cohort (tissue-based NGS) and the randomized phase II and III POPLAR and OAK trials (blood-based NGS). Results In patients treated with ICIs in the Rome cohort, co-occurring mutations in NOTCH1-3 and homologous repair (HR) genes were associated with durable clinical benefit. Using the MSKCC/POPLAR/OAK metadaset, we confirmed the relationship between the NOTCH mut/HR mut signature and longer progression-free survival (PFS) in ICI-treated patients (multivariate Cox: HR 0.51, 95% CI 0.34 to 0.76, p=0.001). The NOTCH mut/HR mut genomic predictor was also associated with longer survival (log-rank p=0.008), despite patients whose tumors carried the NOTCH mut/HR mut signature had higher metastatic burden as compared with their negative counterpart. Finally, we observed that this genomic predictor was also associated with longer survival in patients with other tumor types treated with ICIs (n=1311, log-rank p=0.002). Conclusions Co-occurring mutations in the NOTCH and HR pathways are associated with increased efficacy of immunotherapy in advanced NSCLC. This genomic predictor deserves further investigation to fully assess its potential in i

Published
2020

18. Impact of BMI on HER2+ metastatic breast cancer patients treated with pertuzumab and/or trastuzumab emtansine. Real-world evidence

Author

Krasniqi, E., Pizzuti, L., Barchiesi, G., Sergi, D., Carpano, S., Botti, C., Kayal, R., Sanguineti, G., Marchetti, P., Botticelli, A., Marinelli, D., Gamucci, T., Natoli, C., Grassadonia, A., Tinari, N., Tomao, S., Tonini, Gerolamo, Santini, D., Michelotti, A., Mentuccia, L., Vaccaro, Ascanio Giuseppe, Magnolfi, E., Gelibter, A., Magri, V., Cortesi, E., D'Onofrio, L., Cassano, A., Cazzaniga, M., Moscetti, L., Fabbri, A., Scinto, A. F., Corsi, Domenico Cristiano, Carbognin, L., Bria, Emilio, La Verde, N., Garufi, C., Di Stefano, P., Mirabelli, R., Veltri, E., Paris, Ida, Giotta, F., Lorusso, V., Landucci, E., Ficorella, C., Roselli, M., Adamo, V., Ricciardi, Walter, Russo, A., Valerio, M. R., Berardi, R., Pistelli, M., Cannita, K., Zamagni, C., Garrone, O., Baldini, E., Livi, L., Meattini, I., Del Medico, P., Generali, Daniele, De Maria Marchiano, Ruggero, Risi, E., Ciliberto, G., Villa, Angela Ida, Sperduti, I., Mazzotta, M., Barba, M., Giordano, Alessandro, Vici, P., Tonini G., Vaccaro A., Corsi D., Bria E. (ORCID:0000-0002-2333-704X), Paris I., Ricciardi G. (ORCID:0000-0002-5655-688X), Generali D. (ORCID:0000-0003-2480-3855), De Maria R. (ORCID:0000-0003-2255-0583), Villa A. (ORCID:0000-0003-0679-334X), Giordano A. (ORCID:0000-0002-6978-0880), Krasniqi, E., Pizzuti, L., Barchiesi, G., Sergi, D., Carpano, S., Botti, C., Kayal, R., Sanguineti, G., Marchetti, P., Botticelli, A., Marinelli, D., Gamucci, T., Natoli, C., Grassadonia, A., Tinari, N., Tomao, S., Tonini, Gerolamo, Santini, D., Michelotti, A., Mentuccia, L., Vaccaro, Ascanio Giuseppe, Magnolfi, E., Gelibter, A., Magri, V., Cortesi, E., D'Onofrio, L., Cassano, A., Cazzaniga, M., Moscetti, L., Fabbri, A., Scinto, A. F., Corsi, Domenico Cristiano, Carbognin, L., Bria, Emilio, La Verde, N., Garufi, C., Di Stefano, P., Mirabelli, R., Veltri, E., Paris, Ida, Giotta, F., Lorusso, V., Landucci, E., Ficorella, C., Roselli, M., Adamo, V., Ricciardi, Walter, Russo, A., Valerio, M. R., Berardi, R., Pistelli, M., Cannita, K., Zamagni, C., Garrone, O., Baldini, E., Livi, L., Meattini, I., Del Medico, P., Generali, Daniele, De Maria Marchiano, Ruggero, Risi, E., Ciliberto, G., Villa, Angela Ida, Sperduti, I., Mazzotta, M., Barba, M., Giordano, Alessandro, Vici, P., Tonini G., Vaccaro A., Corsi D., Bria E. (ORCID:0000-0002-2333-704X), Paris I., Ricciardi G. (ORCID:0000-0002-5655-688X), Generali D. (ORCID:0000-0003-2480-3855), De Maria R. (ORCID:0000-0003-2255-0583), Villa A. (ORCID:0000-0003-0679-334X), and Giordano A. (ORCID:0000-0002-6978-0880)

Abstract

Body mass index (BMI) is a main indicator of obesity and its association with breast cancer is well established. However, little is known in the metastatic setting, especially in HER2-positive patients. We assessed the influence of BMI on clinical outcomes of patients treated with pertuzumab and/or trastuzumab emtansine (T-DM1) for HER2+ metastatic breast cancer (mBC). BMI was addressed as a categorical variable, being classified on the basis of the following ranges, that is, 18.5–24.9, 25–29.9, and 30.0–34.9, namely, normal weight, overweight, and Class I obesity. The outcomes chosen were progression-free survival to first-line chemotherapy (PFS1) and overall survival (OS). Overall (N = 709), no impact of BMI was observed on PFS1 (p =.15), while BMI ≥ 30 was associated with worse OS (p =.003). In subjects who progressed to first line (N = 575), analyzing data across PFS1 quartiles and strata of disease burden, BMI predicted lower PFS1 in patients within the I PFS1 quartile and with the lowest disease burden (p =.001). Univariate analysis showed a detrimental effect of BMI ≥ 30 on OS for women within the I PFS1 quartile (p =.03). Results were confirmed in multivariate analysis. According to PFS1 quartiles a higher percentage of patients with high BMI and low disease burden progressed within 6 months of therapy. The effect of BMI on prognosis was also confirmed in multivariate analysis of OS for overall population. In our cohort, a BMI ≥ 30 correlated with worse OS in patients with HER2+ mBC who received pertuzumab and/or T-DM1 but had no impact on PFS to first line. BMI predicted worse I PFS1 quartile.

Published
2020

19. 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

Author

Pizzuti, L., Krasniqi, E., Barchiesi, G., Della Giulia, M., Izzo, F., Sanguineti, G., Marchetti, P., Mazzotta, M., Giusti, R., Botticelli, A., Gamucci, T., Natoli, C., Grassadonia, A., Tinari, N., Iezzi, L., Tomao, S., Tomao, F., Tonini, G., Santini, D., Astone, Antonio, Michelotti, A., De Angelis, C., Mentuccia, L., Vaccaro, A., Magnolfi, E., Gelibter, A., Magri, V., Cortesi, E., D'Onofrio, L., Cassano, A., Rossi, E., Cazzaniga, M., Moscetti, L., Omarini, C., Piacentini, F., Fabbri, M. A., Scinto, A. F., Corsi, D., Carbognin, L., Bria, Emilio, La Verde, N., Samaritani, R., Garufi, C., Barni, S., Mirabelli, R., Sarmiento, R., Veltri, E. M., D'Auria, G., Paris, I., Giotta, F., Lorusso, V., Cardillo, F., Landucci, E., Mauri, M., Ficorella, C., Roselli, M., Adamo, V., Ricciardi, G. R. R., Russo, A., Berardi, R., Pistelli, M., Fiorio, E., Cannita, K., Sini, V., D'Ostilio, N., Foglietta, J., Greco, F., Zamagni, C., Garrone, O., Di Cocco, B., Baldini, E., Livi, L., Desideri, I., Meattini, I., Sarobba, G., Del Medico, P., De Tursi, M., Generali, D., De Maria Marchiano, Ruggero, Risi, E., Ciliberto, G., Sperduti, I., Villa, A., Barba, M., Di Leo, A., Vici, P., Astone A. (ORCID:0000-0001-9572-309X), Bria E. (ORCID:0000-0002-2333-704X), De Maria R. (ORCID:0000-0003-2255-0583), Pizzuti, L., Krasniqi, E., Barchiesi, G., Della Giulia, M., Izzo, F., Sanguineti, G., Marchetti, P., Mazzotta, M., Giusti, R., Botticelli, A., Gamucci, T., Natoli, C., Grassadonia, A., Tinari, N., Iezzi, L., Tomao, S., Tomao, F., Tonini, G., Santini, D., Astone, Antonio, Michelotti, A., De Angelis, C., Mentuccia, L., Vaccaro, A., Magnolfi, E., Gelibter, A., Magri, V., Cortesi, E., D'Onofrio, L., Cassano, A., Rossi, E., Cazzaniga, M., Moscetti, L., Omarini, C., Piacentini, F., Fabbri, M. A., Scinto, A. F., Corsi, D., Carbognin, L., Bria, Emilio, La Verde, N., Samaritani, R., Garufi, C., Barni, S., Mirabelli, R., Sarmiento, R., Veltri, E. M., D'Auria, G., Paris, I., Giotta, F., Lorusso, V., Cardillo, F., Landucci, E., Mauri, M., Ficorella, C., Roselli, M., Adamo, V., Ricciardi, G. R. R., Russo, A., Berardi, R., Pistelli, M., Fiorio, E., Cannita, K., Sini, V., D'Ostilio, N., Foglietta, J., Greco, F., Zamagni, C., Garrone, O., Di Cocco, B., Baldini, E., Livi, L., Desideri, I., Meattini, I., Sarobba, G., Del Medico, P., De Tursi, M., Generali, D., De Maria Marchiano, Ruggero, Risi, E., Ciliberto, G., Sperduti, I., Villa, A., Barba, M., Di Leo, A., Vici, P., Astone A. (ORCID:0000-0001-9572-309X), Bria E. (ORCID:0000-0002-2333-704X), and De Maria R. (ORCID:0000-0003-2255-0583)

Abstract

We analyzed data from 738 HER2-positive metastatic breast cancer (mbc) patients treated with pertuzumab-based regimens and/or T-DM1 at 45 Italian centers. Outcomes were explored in relation to tumor subtype assessed by immunohistochemistry (IHC). The median progression-free survival at first-line (mPFS1) was 12 months. Pertuzumab as first-line conferred longer mPFS1 compared to other first-line treatments (16 vs. 9 months, p = 0.0001), regardless of IHC subtype. Median PFS in second-line (mPFS2) was 7 months, with no difference by IHC subtype, but it was more favorable with T-DM1 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-negative 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-DM1 in second-line after pertuzumab were significantly lower compared to pertuzumab-naïve 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-related outcomes of HER2-positive 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 pathways in HER2-positive (mbc) patients.

Published
2020

20. Mutations in the KEAP1-NFE2L2 Pathway Define a Molecular Subset of Rapidly Progressing Lung Adenocarcinoma

Author

Goeman, F., De Nicola, F., Scalera, S., Sperati, F., Gallo, E., Ciuffreda, L., Pallocca, M., Pizzuti, L., Krasniqi, E., Barchiesi, G., Vici, P., Barba, M., Buglioni, S., Casini, B., Visca, P., Pescarmona, E., Mazzotta, M., De Maria, R., Fanciulli, M., Ciliberto, G., Maugeri-Sacca, M., De Maria R. (ORCID:0000-0003-2255-0583), Goeman, F., De Nicola, F., Scalera, S., Sperati, F., Gallo, E., Ciuffreda, L., Pallocca, M., Pizzuti, L., Krasniqi, E., Barchiesi, G., Vici, P., Barba, M., Buglioni, S., Casini, B., Visca, P., Pescarmona, E., Mazzotta, M., De Maria, R., Fanciulli, M., Ciliberto, G., Maugeri-Sacca, M., and De Maria R. (ORCID:0000-0003-2255-0583)

Abstract

Introduction: Molecular characterization studies revealed recurrent kelch like ECH associated protein 1 gene (KEAP1)/nuclear factor, erythroid 2 like 2 gene (NFE2L2) alterations in NSCLC. These genes encode two interacting proteins (a stress response pathway [SRP]) that mediate a cytoprotective response to oxidative stress and xenobiotics. Nevertheless, whether KEAP1/NFE2L2 mutations have an impact on clinical outcomes is unclear. Methods: We performed amplicon-based next-generation sequencing to characterize the SRP in patients with metastatic NSCLC (Regina Elena National Cancer Institute cohort [n = 88]) treated with first-line chemotherapy. Mutations in the DNA damage response (tumor protein p53 gene [TP53], ATM serine/threonine kinase gene [ATM], and ATR serine/threonine kinase gene [ATR]) were concomitantly analyzed. In lung adenocarcinoma (LAC), we also determined the expression of phosphorylated ataxia telangiectasia mutated kinase and ataxia telangiectasia and Rad3-related protein. Two independent cohorts (the Memorial Sloan Kettering Cancer Center cohort and The Cancer Genome Atlas cohort) with data from approximately 1400 patients with advanced LAC were used to assess the reproducibility of the results. Results: In the Regina Elena National Cancer Institute cohort, patients whose tumors carried mutations in the KEAP1/NFE2L2 pathway had significantly shorter progression-free survival and overall survival than their wild-type counterparts did (log-rank p = 0.006 and p = 0.018, respectively). This association was driven by LAC in which KEAP1/NFE2L2 mutations were overrepresented in fast progressors and associated with an increased risk of disease progression and death. LACs carrying KEAP1/NFE2L2 mutations were characterized by elevated expression of phosphorylated ataxia telangiectasia mutated (pATM) kinase and ataxia telangiectasia and Rad3-related (pATR) protein in association with a pattern of mutual exclusivity with TP53 alterations. The relationship betw

Published
2019

22. Cisplatin plus capecitabine (CisCape) and concurrent pelvic radiotheapy for the neoadjuvant treatment of rectal cancer (RC)

Author

Formica V, Martano L, Nardecchia A, Benassi M, Blanco GD, Giudice E, Mannisi E, Sileri P, Franceschilli L, Rossi P, Portarena I, Pellicori S, Krasniqi E, Adamo R, Riondino S, Santoni R, Roselli M, Formica, V, Martano, L, Nardecchia, A, Benassi, M, Blanco, Gd, Giudice, E, Mannisi, E, Sileri, P, Franceschilli, L, Rossi, P, Portarena, I, Pellicori, S, Krasniqi, E, Adamo, R, Riondino, S, Santoni, R, and Roselli, M

Published
2015

23. Same Goal, Different Paths, Different Class: Women’s Feminist Political Engagements in Kosovo from the Mid-1970s until the Mid-1990s

Author

Krasniqi Elife

Subjects
feminism, kosovo, class, resistance, History (General) and history of Europe, Political science
Abstract

The year 1989, when Serbia revoked Kosovo’s autonomy, was a break that changed also the course of women’s political engagements. Women had always to negotiate and strategise with different layers of power and against different forms of oppression—state and patriarchal oppression and cultural racism as well as class oppression. The author highlights the convergences and divergences of women’s political activism in the political dynamics of late socialism and then in the 1990s in Kosovo. She looks at gender, class and national dimensions of women’s political engagements with a focus on women who were part of the underground resistance movement commonly known as Ilegalja in the 1970s and 1980s as well as women intellectuals who held high state positions and were considered a part of the elite. After 1989, many engaged in the peacaful resistance movement of the 1990s.

Published
2021
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24. Cisplatin plus capecitabine (CisCape) and concurrent pelvic radiotheapy for the neoadjuvant treatment of rectal cancer (RC)

Author

Formica, V., primary, Martano, L., additional, Nardecchia, A., additional, Benassi, M., additional, Del Vecchio Blanco, G., additional, Giudice, E., additional, Mannisi, E., additional, Sileri, P., additional, Franceschilli, L., additional, Rossi, P., additional, Portarena, I., additional, Pellicori, S., additional, Krasniqi, E., additional, Adamo, R., additional, Riondino, S., additional, Santoni, R., additional, and Roselli, M., additional

Published
2015
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25. A quantitative approach for conservation of endangered and endemic plants from Kosovo, SE Europe

Author

Berisha Naim, Krasniqi Elez, and Millaku Fadil

Subjects
iucn, kosovo, plant conservation, threatened plants, Ecology, QH540-549.5
Abstract

Basic patterns of most priority biodiversity areas of Kosovo that shall be considered for conservation studies are offered here. On this work, all plant taxa that are included in the Kosovarian Red list are analysed and their analogy is interpreted to conservation priority hotspots. Kosovo represents an important centre for Balkan biodiversity; therefore a quantitative evaluation of the importance of different priority areas for conserving plant diversity of Kosovo is very much needed. This study provides a detailed quantitative approach concerning the identification of priority areas for biodiversity conservation, using threatened and endangered plant taxa in well-known grid squares system. Used grid squares (20 × 20 km) were classified into four different groups in terms of their conservation importance. Valuation factors taken into account are IUCN based risk category, endemism as well as ecological and distributional attributes. The results indicated that there are four grid squares – D4 (0.4300), G7 (0.3910), G8 (0.2750) and E4 (0.2860), that have remarkable conservation importance. These grid squares are all located along mostly high-elevation areas of two National Parks in Kosovo. These national scale data should prove to be very appropriate and easy to follow evidence for environmental decision-making bodies as well as be used for further research.

Published
2020
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26. Pattern and Factors Associated with Medicine Usage in Middle-aged Adults: a Population Based Cross-Sectional Study

Author

Krasniqi Ermira, Koni Mynyr, Berisha Idriz, and Boshnjaku Arben

Subjects
physical activity, education, adherence, compliance, Medicine
Abstract

Aim: The present study analyzes the adherence phenomenon and possible correlations between active individuals and their educational status on the prevalence of medicine use in the population of a young and developing country such as Kosova.

Published
2018
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27. Driver profiles based on values and traffic safety climate and their relationships with driver behaviors

Author

Kaçan B., Fındık G., Üzümcüoğlu Y., Azık D., Solmazer G., Ersan Ö., Özkan T., Lajunen T., Öz B., Pashkevich A., Pashkevich M., Danelli-Mylona V., Georgogianni D., Berisha Krasniqi E., Krasniqi M., Makris E., Shubenkova K., Xheladini G., Kaçan B., Fındık G., Üzümcüoğlu Y., Azık D., Solmazer G., Ersan Ö., Özkan T., Lajunen T., Öz B., Pashkevich A., Pashkevich M., Danelli-Mylona V., Georgogianni D., Berisha Krasniqi E., Krasniqi M., Makris E., Shubenkova K., and Xheladini G.

Abstract

© 2019 Elsevier Ltd Drivers have an important place in the traffic system when the human factor is taken into consideration. Drivers from different cultures are exposed to different values, norms, and traffic systems, and these differences may form various driver behaviors. Thus, traffic climate and individual values can impact driver behaviors. In this study, the relationships between Schwartz's individual values and traffic climate dimensions were examined. Clusters were then created from the traffic climate dimensions and individual values, and the differences in driver behavior within these clusters were investigated. In order to examine similarities and differences between countries, the results from 5 countries (Estonia, Greece, Kosovo, Russia, and Turkey)are presented. Correlational analyses indicated that, while internal requirements and self-transcendence are positively related in all countries, external affective demands and conservation are positively related in Estonia, Kosovo, Russia, and Turkey. Additionally, external affective demands and self-transcendence are positively related in Greece, Kosovo, Russia, and Turkey. A three-cluster structure fitted the data well in all of the five countries. Within-country differences were observed in clusters of Russian and Turkish data in terms of driver behaviors. The detailed results are presented and discussed in relation to the literature.

28. The relationship between self and other in aggressive driving and driver behaviors across countries

Author

Ersan Ö., Üzümcüoğlu Y., Azık D., Fındık G., Kaçan B., Solmazer G., Özkan T., Lajunen T., Öz B., Pashkevich A., Pashkevich M., Danelli-Mylona V., Georgogianni D., Krasniqi E., Krasniqi M., Makris E., Shubenkova K., Xheladini G., Ersan Ö., Üzümcüoğlu Y., Azık D., Fındık G., Kaçan B., Solmazer G., Özkan T., Lajunen T., Öz B., Pashkevich A., Pashkevich M., Danelli-Mylona V., Georgogianni D., Krasniqi E., Krasniqi M., Makris E., Shubenkova K., and Xheladini G.

Abstract

© 2019 Elsevier Ltd The main aim of the present study was to investigate the moderating role of aggressive driving of others on the relationship between self-reported aggressive driving behaviors committed by driver himself/herself and drivers’ aberrant and positive driver behaviors (i.e. errors, violations, and positive driver behaviors) among drivers from Estonia, Greece, Kosovo, Russia, and Turkey as the total sample in order to understand the grand pattern. The other aim was to examine the same moderating role of aggressive driving for each country separately. It was hypothesized that the combination of self-reported of aggressive driving behaviors committed by the driver himself/herself and perceiving aggressive acts of other drivers against them associates with more errors and violations for each country and the total sample. On the other hand, this combination was expected to associate with less positive driver behaviors. Surveys were completed by 743 participants from five countries (i.e., Estonia, Greece, Kosovo, Russia, and Turkey). The Driver Anger Indicators Scale (DAIS) and the short version of the Driver Behavior Questionnaire (DBQ) with items of Positive Driver Behavior Scale were used as measurement tools. Moderation analyses were conducted for the total sample and each country separately. The results of the moderation analyses indicated that there was a moderating role of perceiving other drivers as engaging in aggressive behaviors on the relationship between aggressive behaviors of the driver himself/herself and their errors or violations in the total sample and every country except for Russia. However, the significant interaction between aggressive behaviors committed by the driver himself/herself and other drivers' aggressive acts in traffic was related to more positive driver behaviors for Kosovar drivers and less positive driver behaviors for Russian drivers and the total sample. It could be discussed that the way of understanding aggressive be

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

Author

Pietro Del Medico, Rossana Berardi, Enzo Veltri, Maria Rosaria Valerio, Alessandra Cassano, Daniele Marinelli, Vito Lorusso, Patrizia Vici, Nicola D’Ostilio, Silverio Tomao, Enrico Cortesi, Nicola Tinari, Emilio Bria, Domenico Sergi, Luca Moscetti, Giuseppe Sanguineti, Teresa Gamucci, Claudio Zamagni, Maddalena Barba, Clara Natoli, Theodora Daralioti, Giancarlo Paoletti, Antonino Grassadonia, Marina Elena Cazzaniga, Icro Meattini, Ornella Garrone, Andrea Michelotti, Giuseppina Sarobba, Nicla La Verde, Laura Pizzuti, Letizia Perracchio, Vincenzo Adamo, Giuseppe Tonini, A. Vaccaro, Francesco Giotta, Corrado Ficorella, Maria Agnese Fabbri, Antonio Russo, Paolo Marchetti, Gennaro Ciliberto, Mirco Pistelli, Rosanna Mirabelli, Marco Mazzotta, Daniele Generali, Marcello Maugeri-Saccà, Mario Roselli, Angelo Di Leo, Anna Di Benedetto, Isabella Sperduti, Ida Paris, Eriseld Krasniqi, Carlo Garufi, Lorenzo Livi, Ruggero De Maria, Andrea Botticelli, Domenico Corsi, 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, Mirabelli, R, Fabbri, M, 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, Laura, Barba, Maddalena, Mazzotta, Marco, Krasniqi, Eriseld, Maugeri-Saccà, Marcello, Gamucci, Teresa, Berardi, Rossana, Livi, Lorenzo, Ficorella, Corrado, Natoli, Clara, Cortesi, Enrico, Generali, Daniele, La Verde, Nicla, Cassano, Alessandra, Bria, Emilio, Moscetti, Luca, Michelotti, Andrea, Adamo, Vincenzo, Zamagni, Claudio, Tonini, Giuseppe, Sergi, Domenico, Marinelli, Daniele, Paoletti, Giancarlo, Tomao, Silverio, Botticelli, Andrea, Marchetti, Paolo, Tinari, Nicola, Grassadonia, Antonino, Valerio, Maria Rosaria, Mirabelli, Rosanna, Fabbri, Maria Agnese, D’Ostilio, Nicola, Veltri, Enzo, Corsi, Domenico, Garrone, Ornella, Paris, Ida, Sarobba, Giuseppina, Meattini, Icro, Pistelli, Mirco, Giotta, Francesco, Lorusso, Vito, Garufi, Carlo, Russo, Antonio, Cazzaniga, Marina, Del Medico, Pietro, Roselli, Mario, Vaccaro, Angela, Perracchio, Letizia, di Benedetto, Anna, Daralioti, Theodora, Sperduti, Isabella, De Maria, Ruggero, Di Leo, Angelo, Sanguineti, Giuseppe, Ciliberto, Gennaro, Vici, Patrizia, 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., and Vici P.

Subjects
0301 basic medicine, Oncology, Cancer therapy, Receptor, ErbB-2, medicine.medical_treatment, Ado-Trastuzumab Emtansine, progesterone receptor, Settore MED/06, 0302 clinical medicine, human epidermal growth factor receptor 2 (HER2), Antineoplastic Combined Chemotherapy Protocols, estrogen, Neoplasm Metastasis, skin and connective tissue diseases, Multidisciplinary, Brain Neoplasms, Middle Aged, Prognosis, Metastatic breast cancer, Neoplasm Metastasi, 030220 oncology & carcinogenesis, Medicine, Female, Pertuzumab, metastatic breast cancer, Receptors, Progesterone, Breast Neoplasm, HER2 positivity, medicine.drug, Human, Adult, medicine.medical_specialty, medicine.drug_class, Science, trastuzumab-emtansine, Breast Neoplasms, cancer, Article, Disease-Free Survival, Brain Neoplasm, 03 medical and health sciences, Breast cancer, breast cancer, Settore MED/04 - PATOLOGIA GENERALE, pertuzumab, Internal medicine, Progesterone receptor, medicine, Humans, neoplasms, Aged, Chemotherapy, Antineoplastic Combined Chemotherapy Protocol, business.industry, Cancer, medicine.disease, HER2-positive, oncology, radiotherapy, chemotherapy, HER2, Radiation therapy, 030104 developmental biology, Estrogen, business, prognostic relevance
Abstract

Breast cancer (BC) heterogeneity is composite in nature, with a wide variety of factors concurring to define several pathological entities, which differ by clinical presentation, pathologic features, therapy administered, and inherent outcomes1. Additional sources of breast cancer heterogeneity may raise during the disease course. In BC patients whose disease was initially diagnosed in the early stage and subsequently progressed with metastatic involvement of one single or multiple site/s, the molecular characteristics of metastatic lesions do not necessary mimic those of the disease initially diagnosed. A well-depicted molecular landscape is crucial for subtype definition, prognostic evaluation and appropriate therapeutic decisions. Accordingly, current guidelines suggest repeating the immunohistochemical (IHC) assessment in patients with metastatic spread and at least one secondary lesion amenable to biopsy2. Discordance in human epidermal growth factor receptor 2 (HER2) status between the tumor and metastatic lesions is widely acknowledged, and not yet completely unraveled in their biologic meaning and prognostic relevance3–11. The overexpression of HER2 or amplification of the related gene is extensively recognized as a feature associated with more aggressive biological behavior12,13. However, the extent to which changes in HER2 status may affect patients’ prognosis is still a matter of debate14. We herein propose an observational study of HER2-positive metastatic breast cancer (mBC) patients treated with the anti-HER2 targeted agents pertuzumab and/or trastuzumab emtansine (T-DM1). Our research question is whether relevant differences exist in long-term outcomes of patients with concordant HER2 status between the primary tumor and its secondary lesion/s compared to patients whose disease revealed HER2-positivity gain at the IHC assessment of metastatic lesions. In our historical cohorts, we also sought to identify factors associated with HER2-positivity gain at the IHC reassessment, for which an impact on prognosis may be foreseen.

Published
2021

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

Author

Nicla La Verde, Domenico Corsi, Patrizia Vici, Angelo Di Leo, Enzo Veltri, Lorenzo Livi, Marina Elena Cazzaniga, Laura Pizzuti, Pietro Del Medico, Caterina Marchiò, Maria Rosaria Valerio, Ornella Garrone, Giuseppina Sarobba, Rossella Loria, Gennaro Ciliberto, Eriseld Krasniqi, Marcello Maugeri-Saccà, Anna Sapino, Paolo Marchetti, Rossana Berardi, Rita Falcioni, Silverio Tomao, Clara Natoli, Vincenzo Adamo, Valentina Laquintana, Maddalena Barba, Claudio Zamagni, Maria Agnese Fabbri, Carlo Garufi, Giulia Bon, Giuseppe Sanguineti, Giacomo Barchiesi, Enrico Cortesi, Rosanna Mirabelli, Francesco Giotta, Nicola D’Ostilio, Giuseppe Tonini, Emilio Bria, Daniele Marinelli, Manuela Porru, Luca Moscetti, Marco Mazzotta, Ida Paris, Andrea Michelotti, Mario Roselli, Alessandra Cassano, Teresa Gamucci, Antonio Russo, Isabella Sperduti, Corrado Ficorella, Daniele Generali, Ruggero De Maria, Carlo Leonetti, Bon G., Pizzuti L., Laquintana V., Loria R., Porru M., Marchio C., Krasniqi E., Barba M., 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., Barchiesi G., Mazzotta M., Marinelli D., Tomao S., Marchetti P., Valerio M.R., Mirabelli R., Russo A., Fabbri M.A., D'Ostilio N., Veltri E., Corsi D., Garrone O., Paris I., Sarobba G., Giotta F., Garufi C., Cazzaniga M., Del Medico P., Roselli M., Sanguineti G., Sperduti I., Sapino A., De Maria R., Leonetti C., Di Leo A., Ciliberto G., Falcioni R., Vici P., Bon, Giulia, Pizzuti, Laura, Laquintana, Valentina, Loria, Rossella, Porru, Manuela, Marchiò, Caterina, Krasniqi, Eriseld, Barba, Maddalena, Maugeri-Saccà, Marcello, Gamucci, Teresa, Berardi, Rossana, Livi, Lorenzo, Ficorella, Corrado, Natoli, Clara, Cortesi, Enrico, Generali, Daniele, La Verde, Nicla, Cassano, Alessandra, Bria, Emilio, Moscetti, Luca, Michelotti, Andrea, Adamo, Vincenzo, Zamagni, Claudio, Tonini, Giuseppe, Barchiesi, Giacomo, Mazzotta, Marco, Marinelli, Daniele, Tomao, Silverio, Marchetti, Paolo, Valerio, Maria Rosaria, Mirabelli, Rosanna, Russo, Antonio, Fabbri, Maria Agnese, D’Ostilio, Nicola, Veltri, Enzo, Corsi, Domenico, Garrone, Ornella, Paris, Ida, Sarobba, Giuseppina, Giotta, Francesco, Garufi, Carlo, Cazzaniga, Marina, Del Medico, Pietro, Roselli, Mario, Sanguineti, Giuseppe, Sperduti, Isabella, Sapino, Anna, De Maria, Ruggero, Leonetti, Carlo, Di Leo, Angelo, Ciliberto, Gennaro, Falcioni, Rita, Vici, Patrizia, Bon, G, Pizzuti, L, Laquintana, V, Loria, R, Porru, M, Marchio, C, Krasniqi, E, Barba, M, 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, Barchiesi, G, Mazzotta, M, Marinelli, D, Tomao, S, Marchetti, P, Valerio, M, Mirabelli, R, Russo, A, Fabbri, M, D'Ostilio, N, Veltri, E, Corsi, D, Garrone, O, Paris, I, Sarobba, G, Giotta, F, Garufi, C, Cazzaniga, M, Del Medico, P, Roselli, M, Sanguineti, G, Sperduti, I, Sapino, A, De Maria, R, Leonetti, C, Di Leo, A, Ciliberto, G, Falcioni, R, and Vici, P

Subjects
0301 basic medicine, Oncology, Cancer Research, Receptor, ErbB-2, Apoptosis, Ado-Trastuzumab Emtansine, Settore MED/06, chemistry.chemical_compound, 0302 clinical medicine, Trastuzumab, Antineoplastic Combined Chemotherapy Protocols, Tumor Cells, Cultured, skin and connective tissue diseases, Aged, 80 and over, Middle Aged, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Prognosis, Gene Expression Regulation, Neoplastic, Survival Rate, 030220 oncology & carcinogenesis, Female, Pertuzumab, medicine.drug, T-DM1 efficacy, musculoskeletal diseases, Adult, medicine.medical_specialty, HER2+ breast cancer, Trastuzumab/pertuzumab blockade, Breast Neoplasms, Antibodies, Monoclonal, Humanized, lcsh:RC254-282, 03 medical and health sciences, Settore MED/04 - PATOLOGIA GENERALE, Internal medicine, medicine, Biomarkers, Tumor, Humans, neoplasms, Aged, Cell Proliferation, Retrospective Studies, Taxane, business.industry, Research, Cancer, medicine.disease, Blockade, Log-rank test, 030104 developmental biology, chemistry, Trastuzumab emtansine, Cancer cell, business
Abstract

BackgroundHER2-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.MethodsThe 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.ResultsWe 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).ConclusionsOur 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.

Published
2020

31. PANHER study: a 20-year treatment outcome analysis from a multicentre observational study of HER2-positive advanced breast cancer patients from the real-world setting

Author

Angela Maione, Nicola Tinari, Paola Pinnarò, Enzo Maria Ruggeri, Isabella Sperduti, Olivia Bacciu, Emanuela Risi, Icro Meattini, Federica Tomao, Luca Marchetti, Nicola D’Ostilio, Patrizia Vici, Lorenza Landi, Giuseppina Sarobba, Lucia Mentuccia, Elisabetta Landucci, Emilio Bria, A.F. Scinto, Gennaro Ciliberto, Laura Pizzuti, Elena Fiorio, Andrea Michelotti, Ida Paris, Simonetta Stani, Antonio Russo, Clara Natoli, Rosa Saltarelli, Alessandra Cassano, Paolo Marchetti, Maria Agnese Fabbri, Daniele Marinelli, Ferdinando Riccardi, Mauro Minelli, Corrado Ficorella, Anna Ceribelli, Maria Rosaria Valerio, Maddalena Barba, Jennifer Foglietta, Maria Mauri, Teresa Gamucci, Luca Moscetti, Beatrice Taurelli Salimbeni, Fabio Pelle, Daniele Santini, Andrea Botticelli, Vito Lorusso, Mirco Pistelli, Giacomo Barchiesi, Francesco Giotta, Eriseld Krasniqi, Antonino Grassadonia, Simone Scagnoli, Valentina Sini, Katia Cannita, Flavia Cavicchi, Michele De Tursi, Mimma Raffaele, Marco Mazzotta, Sonia Cappelli, Paola Scavina, Francesca Sofia Di Lisa, Giuliana D’Auria, Armando Orlandi, Marcello Maugeri-Saccà, Federico Cappuzzo, Claudio Botti, Nello Salesi, Lorenzo Livi, Beatrice Fratini, Giulia Bon, Silverio Tomao, Giuseppe Sanguineti, Enzo Veltri, Domenico Corsi, Enrico Cortesi, Rossana Berardi, Laura Iezzi, Rosalinda Rossi, Giuseppe Tonini, Elisabetta Maria Capomolla, Pizzuti L., Krasniqi E., Sperduti I., Barba M., Gamucci T., Mauri M., Veltri E.M., Meattini I., Berardi R., Di Lisa F.S., Natoli C., Pistelli M., Iezzi L., Risi E., D'Ostilio N., Tomao S., Ficorella C., Cannita K., Riccardi F., Cassano A., Bria E., Fabbri M.A., Mazzotta M., Barchiesi G., Botticelli A., D'Auria G., Ceribelli A., Michelotti A., Russo A., Salimbeni B.T., Sarobba G., Giotta F., Paris I., Saltarelli R., Marinelli D., Corsi D., Capomolla E.M., Sini V., Moscetti L., Mentuccia L., Tonini G., Raffaele M., Marchetti L., Minelli M., Ruggeri E.M., Scavina P., Bacciu O., Salesi N., Livi L., Tinari N., Grassadonia A., Fedele Scinto A., Rossi R., Valerio M.R., Landucci E., Stani S., Fratini B., Maugeri-Sacca M., De Tursi M., Maione A., Santini D., Orlandi A., Lorusso V., Cortesi E., Sanguineti G., Pinnaro P., Cappuzzo F., Landi L., Botti C., Tomao F., Cappelli S., Bon G., Pelle F., Cavicchi F., Fiorio E., Foglietta J., Scagnoli S., Marchetti P., Ciliberto G., and Vici P.

Subjects
Oncology, medicine.medical_specialty, Advanced breast, T-DM1, Treatment outcome, Lapatinib, Breast cancer, pertuzumab, Internal medicine, Medicine, lapatinib, RC254-282, advanced breast cancer, business.industry, Human epidermal growth factor, HER2-positive, sequence, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Cancer, medicine.disease, Observational study, Pertuzumab, business, medicine.drug
Abstract

Background: The evolution of therapeutic landscape of human epidermal growth factor receptor-2 (HER2)-positive breast cancer (BC) has led to an unprecedented outcome improvement, even if the optimal sequence strategy is still debated. To address this issue and to provide a picture of the advancement of anti-HER2 treatments, we performed a large, multicenter, retrospective study of HER2-positive BC patients. Methods: The observational PANHER study included 1,328 HER2-positive advanced BC patients treated with HER2 blocking agents since June 2000 throughout July 2020. Endpoints of efficacy were progression-free survival (PFS) and overall survival (OS). Results: Patients who received a first-line pertuzumab-based regimen showed better PFS ( p < 0.0001) and OS ( p = 0.004) than those receiving other treatments. Median PFS and mOS from second-line starting were 8 and 28 months, without significant differences among various regimens. Pertuzumab-pretreated patients showed a mPFS and a mOS from second-line starting not significantly affected by type of second line, that is, T-DM1 or lapatinib/capecitabine ( p = 0.80 and p = 0.45, respectively). Conversely, pertuzumab-naïve patients receiving second-line T-DM1 showed a significantly higher mPFS compared with that of patients treated with lapatinib/capecitabine ( p = 0.004). Median OS from metastatic disease diagnosis was higher in patients treated with trastuzumab-based first line followed by second-line T-DM1 in comparison to pertuzumab-based first-line and second-line T-DM1 ( p = 0.003), although these data might be partially influenced by more favorable prognostic characteristics of patients in the pre-pertuzumab era. No significant differences emerged when comparing patients treated with ‘old’ or ‘new’ drugs ( p = 0.43), even though differences in the length of the follow-up between the two cohorts should be taken into account. Conclusion: Our results confirmed a relevant impact of first-line pertuzumab-based treatment and showed lower efficacy of second-line T-DM1 in trastuzumab/pertuzumab pretreated, as compared with pertuzumab-naïve patients. Our findings may help delineate a more appropriate therapeutic strategy in HER2-positive metastatic BC. Prospective randomized trials addressing this topic are awaited.

Published
2021

32. Prognostic Relevance of Neutrophil to Lymphocyte Ratio (NLR) in Luminal Breast Cancer: A Retrospective Analysis in the Neoadjuvant Setting

Author

Marco Mazzotta, Nicola Tinari, Eriseld Krasniqi, Laura Iezzi, A. Amodio, Clara Natoli, Laura Pizzuti, Giuseppe Cicero, Maddalena Barba, Vincenzo Graziano, Patrizia Vici, Antonino Grassadonia, Daniele Marinelli, Grassadonia A., Graziano V., Iezzi L., Vici P., Barba M., Pizzuti L., Cicero G., Krasniqi E., Mazzotta M., Marinelli D., Amodio A., Natoli C., Tinari N., Graziano, Vincenzo [0000-0001-7656-824X], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, Oncology, Adult, medicine.medical_specialty, Multivariate analysis, Neutrophils, QH301-705.5, medicine.medical_treatment, Breast Neoplasms, Article, Disease-Free Survival, predictive/prognostic biomarkers, 03 medical and health sciences, 0302 clinical medicine, Text mining, Breast cancer, luminal breast cancer, Internal medicine, Medicine, Humans, Lymphocytes, Neutrophil to lymphocyte ratio, Biology (General), Neoadjuvant therapy, Aged, Retrospective Studies, Chemotherapy, business.industry, Proportional hazards model, allergology, fungi, Luminal breast cancer, Neoadjuvant chemotherapy, Neutrophil to lymphocyte ratio (NLR), Predictive/prognostic biomarkers, Female, Ki-67 Antigen, Middle Aged, Multivariate Analysis, Prognosis, Treatment Outcome, Neoadjuvant Therapy, Histology, General Medicine, medicine.disease, neutrophil to lymphocyte ratio (NLR), 030104 developmental biology, 030220 oncology & carcinogenesis, Population study, business, neoadjuvant chemotherapy
Abstract

The neutrophil to lymphocyte ratio (NLR) is a promising predictive and prognostic factor in breast cancer. We investigated its ability to predict disease-free survival (DFS) and overall survival (OS) in patients with luminal A- or luminal B-HER2-negative breast cancer who received neoadjuvant chemotherapy (NACT). Pre-treatment complete blood cell counts from 168 consecutive patients with luminal breast cancer were evaluated to assess NLR. The study population was stratified into NLRlow or NLRhigh according to a cut-off value established by receiving operator curve (ROC) analysis. Data on additional pre- and post-treatment clinical-pathological characteristics were also collected. Kaplan–Meier curves, log-rank tests, and Cox proportional hazards models were used for statistical analyses. Patients with pre-treatment NLRlow showed a significantly shorter DFS (HR: 6.97, 95% CI: 1.65–10.55, p = 0.002) and OS (HR: 7.79, 95% CI: 1.25–15.07, p = 0.021) compared to those with NLRhigh. Non-ductal histology, luminal B subtype, and post-treatment Ki67 ≥ 14% were also associated with worse DFS (p = 0.016, p = 0.002, and p = 0.001, respectively). In a multivariate analysis, luminal B subtype, post-treatment Ki67 ≥ 14%, and NLRlow remained independent prognostic factors for DFS, while only post-treatment Ki67 ≥ 14% and NLRlow affected OS. The present study provides evidence that pre-treatment NLRlow helps identify women at higher risk of recurrence and death among patients affected by luminal breast cancer treated with NACT.

Published
2021

33. Impact of BMI on HER2+ metastatic breast cancer patients treated with pertuzumab and/or trastuzumab emtansine. Real-world evidence

Author

Aangela Vaccaro, Antonio Giordano, Marina Elena Cazzaniga, Antonio Russo, Maddalena Barba, Emilio Bria, Corrado Ficorella, Claudio Botti, Nicla La Verde, Clara Natoli, Valentina Magri, Loretta D'Onofrio, Carlo Garufi, Ruggero De Maria, Maria Rosaria Valerio, Gennaro Ciliberto, Mario Roselli, A. Fabbri, Emanuela Magnolfi, Giuseppina Rosaria Rita Ricciardi, Patrizia Vici, Alessandra Cassano, Emanuela Risi, Isabella Sperduti, Daniele Generali, Daniele Marinelli, Vito Lorusso, Teresa Gamucci, Lorenzo Livi, Giuseppe Tonini, Antonino Grassadonia, Editta Baldini, Marco Mazzotta, Luca Moscetti, Silverio Tomao, Claudio Zamagni, Silvia Carpano, Ornella Garrone, Icro Meattini, Giuseppe Sanguineti, Eriseld Krasniqi, Lucia Mentuccia, Katia Cannita, Daniele Santini, Rossana Mirabelli, Enzo Veltri, Domenico Sergi, Aandrea Michelotti, Alice Villa, Nicola Tinari, Vincenzo Adamo, A. Botticelli, Ramy Kayal, Mirco Pistelli, Domenico Corsi, Pietro Del Medico, Rossana Berardi, Enrico Cortesi, Giacomo Barchiesi, Alain Gelibter, Ida Paris, Elisa Landucci, Pia Di Stefano, Laura Pizzuti, Paolo Marchetti, Luisa Carbognin, Francesco Giotta, A.F. Scinto, Krasniqi, E, Pizzuti, L, Barchiesi, G, Sergi, D, Carpano, S, Botti, C, Kayal, R, Sanguineti, G, Marchetti, P, Botticelli, A, Marinelli, D, Gamucci, T, Natoli, C, Grassadonia, A, Tinari, N, Tomao, S, Tonini, G, Santini, D, Michelotti, A, Mentuccia, L, Vaccaro, A, Magnolfi, E, Gelibter, A, Magri, V, Cortesi, E, D'Onofrio, L, Cassano, A, Cazzaniga, M, Moscetti, L, Fabbri, A, Scinto, A, Corsi, D, Carbognin, L, Bria, E, La Verde, N, Garufi, C, Di Stefano, P, Mirabelli, R, Veltri, E, Paris, I, Giotta, F, Lorusso, V, Landucci, E, Ficorella, C, Roselli, M, Adamo, V, Ricciardi, G, Russo, A, Valerio, M, Berardi, R, Pistelli, M, Cannita, K, Zamagni, C, Garrone, O, Baldini, E, Livi, L, Meattini, I, Del Medico, P, Generali, D, De Maria, R, Risi, E, Ciliberto, G, Villa, A, Sperduti, I, Mazzotta, M, Barba, M, Giordano, A, Vici, P, Eriseld K., Laura P., Giacomo B., Domenico S., Silvia C., Claudio B., Ramy K., Giuseppe S., Paolo M., Andrea B., Daniele M., Teresa G., Clara N., Antonino G., Nicola T., Silverio T., Giuseppe T., Daniele S., Aandrea M., Lucia M., Aangela V., Emanuela M., Alain G., Valentina M., Enrico C., Loretta D., Alessandra C., Marina C., Luca M., Agnese F., Angelo Fedele S., Domenico C., Luisa C., Emilio B., Nicla L.V., Carlo G., Pia D.S., Rossana M., Enzo V., Ida P., Francesco G., Vito L., Elisa L., Corrado F., Mario R., Vincenzo A., Giuseppina R., Antonio R., Maria Rosaria V., Rossana B., Mirco P., Katia C., Claudio Z., Ornella G., Editta B., Lorenzo L., Icro M., Pietro D.M., Daniele G., Ruggero D.M., Emanuela R., Gennaro C., Alice V., Isabella S., Marco M., Maddalena B., Antonio G., and Patrizia V.

Subjects
0301 basic medicine, Oncology, Physiology, Receptor, ErbB-2, Clinical Biochemistry, Ado-Trastuzumab Emtansine, Settore MED/06, body mass index, HER2-positive metastatic breast cancer, pertuzumab, trastuzumab emtansine, chemistry.chemical_compound, 0302 clinical medicine, Antineoplastic Agents, Immunological, Aged, 80 and over, education.field_of_study, Univariate analysis, Middle Aged, Metastatic breast cancer, Progression-Free Survival, Quartile, 030220 oncology & carcinogenesis, Disease Progression, Female, Pertuzumab, medicine.drug, Adult, medicine.medical_specialty, Population, Breast Neoplasms, Antibodies, Monoclonal, Humanized, 03 medical and health sciences, Breast cancer, Settore MED/04 - PATOLOGIA GENERALE, Internal medicine, medicine, Humans, Obesity, education, Aged, business.industry, nutritional and metabolic diseases, Cell Biology, Overweight, medicine.disease, 030104 developmental biology, chemistry, Trastuzumab emtansine, MED/06 - ONCOLOGIA MEDICA, business, Body mass index
Abstract

Body mass index (BMI) is a main indicator of obesity and its association with breast cancer is well established. However, little is known in the metastatic setting, especially in HER2-positive patients. We assessed the influence of BMI on clinical outcomes of patients treated with pertuzumab and/or trastuzumab emtansine (T-DM1) for HER2+ metastatic breast cancer (mBC). BMI was addressed as a categorical variable, being classified on the basis of the following ranges, that is, 18.5-24.9, 25-29.9, and 30.0-34.9, namely, normal weight, overweight, and Class I obesity. The outcomes chosen were progression-free survival to first-line chemotherapy (PFS1) and overall survival (OS). Overall (N = 709), no impact of BMI was observed on PFS1 (p = .15), while BMI ≥ 30 was associated with worse OS (p = .003). In subjects who progressed to first line (N = 575), analyzing data across PFS1 quartiles and strata of disease burden, BMI predicted lower PFS1 in patients within the I PFS1 quartile and with the lowest disease burden (p = .001). Univariate analysis showed a detrimental effect of BMI ≥ 30 on OS for women within the I PFS1 quartile (p = .03). Results were confirmed in multivariate analysis. According to PFS1 quartiles a higher percentage of patients with high BMI and low disease burden progressed within 6 months of therapy. The effect of BMI on prognosis was also confirmed in multivariate analysis of OS for overall population. In our cohort, a BMI ≥ 30 correlated with worse OS in patients with HER2+ mBC who received pertuzumab and/or T-DM1 but had no impact on PFS to first line. BMI predicted worse I PFS1 quartile.

Published
2020

34. 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

Author

Isacco Desideri, G. Tonini, Emanuela Magnolfi, L. Pizzuti, Jennifer Foglietta, Marina Elena Cazzaniga, Adamo, Patrizia Vici, Enrico Cortesi, Emanuela Risi, G. D'Auria, Loretta D'Onofrio, Mario Roselli, Isabella Sperduti, N. Tinari, Nicola D’Ostilio, A. Vaccaro, Icro Meattini, Federica Tomao, Giacomo Barchiesi, B Di Cocco, F Cardillo, Enzo Veltri, Claudia Omarini, Mirco Pistelli, Clara Natoli, Carlo Garufi, E. Landucci, M. Mauri, Rosanna Mirabelli, Federico Piacentini, Domenico Corsi, A.F. Scinto, Alice Villa, Alain Gelibter, C. De Angelis, Marco Mazzotta, Gennaro Ciliberto, Claudio Zamagni, Giuseppe Sanguineti, Fiorentino Izzo, Elizabeth H. Baldini, Rossana Berardi, Grr Ricciardi, Maddalena Barba, Ornella Garrone, Ida Paris, Luisa Carbognin, A. Botticelli, Giuseppina Sarobba, Silverio Tomao, Antonio Astone, Lucia Mentuccia, P Del Medico, Lorusso, Daniele Santini, M. Della Giulia, Riccardo Samaritani, Francesco Giotta, Alessandra Cassano, Laura Iezzi, Maria Agnese Fabbri, R De Maria, Eriseld Krasniqi, Raffaele Giusti, Sini, Lorenzo Livi, Ernesto Rossi, Andrea Michelotti, Emilio Bria, A Di Leo, Luca Moscetti, Corrado Ficorella, Antonino Grassadonia, Roberta Sarmiento, Katia Cannita, Filippo Greco, Sandro Barni, Elena Fiorio, Teresa Gamucci, Magri, Antonio Russo, M. De Tursi, N. La Verde, Daniele Generali, Paolo Marchetti, Pizzuti, L, Krasniqi, E, Barchiesi, G, Della Giulia, M, Izzo, F, Sanguineti, G, Marchetti, P, Mazzotta, M, Giusti, R, Botticelli, A, Gamucci, T, Natoli, C, Grassadonia, A, Tinari, N, Iezzi, L, Tomao, S, Tomao, F, Tonini, G, Santini, D, Astone, A, Michelotti, A, De Angelis, C, Mentuccia, L, Vaccaro, A, Magnolfi, E, Gelibter, A, Magri, V, Cortesi, E, D'Onofrio, L, Cassano, A, Rossi, E, Cazzaniga, M, Moscetti, L, Omarini, C, Piacentini, F, Fabbri, M, Scinto, A, Corsi, D, Carbognin, L, Bria, E, La Verde, N, Samaritani, R, Garufi, C, Barni, S, Mirabelli, R, Sarmiento, R, Veltri, E, D'Auria, G, Paris, I, Giotta, F, Lorusso, V, Cardillo, F, Landucci, E, Mauri, M, Ficorella, C, Roselli, M, Adamo, V, Ricciardi, G, Russo, A, Berardi, R, Pistelli, M, Fiorio, E, Cannita, K, Sini, V, D'Ostilio, N, Foglietta, J, Greco, F, Zamagni, C, Garrone, O, Di Cocco, B, Baldini, E, Livi, L, Desideri, I, Meattini, I, Sarobba, G, Del Medico, P, De Tursi, M, Generali, D, De Maria, R, Risi, E, Ciliberto, G, Sperduti, I, Villa, A, Barba, M, Di Leo, A, and Vici, P

Subjects
Oncology, Cancer Research, Multivariate analysis, Settore MED/06 - Oncologia Medica, Receptor, ErbB-2, T-DM1, Estrogen receptor, 0302 clinical medicine, ErbB-2, Trastuzumab, Receptors, Antineoplastic Combined Chemotherapy Protocols, 80 and over, Molecular Targeted Therapy, Neoplasm Metastasis, Cancer Therapy and Prevention, Progesterone, Aged, 80 and over, advanced breast cancer, Tumor, real world, Middle Aged, Prognosis, Metastatic breast cancer, Immunohistochemistry, Gene Expression Regulation, Neoplastic, trastuzumab, Receptors, Estrogen, 030220 oncology & carcinogenesis, Female, HER2 positive, pertuzumab, Adult, Aged, Biomarkers, Tumor, Breast Neoplasms, Humans, Neoplasm Staging, Receptors, Progesterone, Pertuzumab, medicine.drug, Receptor, medicine.medical_specialty, T‐DM1, chemotherapy, 03 medical and health sciences, Breast cancer, Settore MED/04 - PATOLOGIA GENERALE, Internal medicine, medicine, Neoplastic, business.industry, medicine.disease, Estrogen, Settore CHIM/08 - Chimica Farmaceutica, Gene Expression Regulation, MED/06 - ONCOLOGIA MEDICA, business, Biomarkers, Hormone
Abstract

We analyzed data from 738 HER2‐positive metastatic breast cancer (mbc) patients treated with pertuzumab‐based regimens and/or T‐DM1 at 45 Italian centers. Outcomes were explored in relation to tumor subtype assessed by immunohistochemistry (IHC). The median progression‐free survival at first‐line (mPFS1) was 12 months. Pertuzumab as first‐line conferred longer mPFS1 compared to other first‐line treatments (16 vs. 9 months, p = 0.0001), regardless of IHC subtype. Median PFS in second‐line (mPFS2) was 7 months, with no difference by IHC subtype, but it was more favorable with T‐DM1 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‐negative 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‐DM1 in second‐line after pertuzumab were significantly lower compared to pertuzumab‐naïve 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‐related outcomes of HER2‐positive 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 pathways in HER2‐positive (mbc) patients., What's new? About half of breast cancers positive for human epidermal growth factor (HER2) also express hormone receptors but the impact of hormone receptor status on the success of HER2‐directed treatments is not fully explored. Here the authors retrospectively assessed tumor behavior and treatment outcomes in 738 women with HER2+ metastatic breast cancer treated with new generation anti‐HER2 agents. Distinct hormone receptor expression patterns significantly affected the progression free and overall survival, justifying further studies to define optimal treatment regimens and the interplay between hormone receptor and HER2 signaling.

Published
2020

35. Rosaceae (Cydonia to Prunus, excl. Sorbus)

Author

Kurtto, Arto, Sennikov, Alexander N., Lampinen, Raino, Zając, Adam, Zając, Maria, Uotila, P., Kurtto, A., Sennikov, A., Ahti, T., Czopyk, V.I., Edmondson, J., Greuter, W., Montserrat, P., Niklfeld, H., Stevanović, V., Suominen, J., Shuka, L., Dubovik, D.V., Dzhus, M.A., Skuratovich, A.N., Tretyakov, D.I., Van, W., Brujić, J., Milanović, D., Stupar, V., Preston, C.D., Ames, S.L., Vladimirov, V., Zieliński, J., Ozimec, S., Zázvorka, J., Lepší, M., Lepší, P., Kukk, T., Lampinen, R., Lazare, J.-J., Jeanmonod, D., Jordan, D., Matevski, V., Kostadinovski, M., May, R., Buttler, K.P., Caspari, S., Kasperek, G., Constantinidis, T., Strid, A., Király, G., Barina, Z., Németh, C., Somlyay, L., Einarsson, E., Cuccuini, P., Argenti, C., Arrigoni, P.V., Baldini, M.R., Bartolucci, F., Bernardo, L., Bertolli, A., Bouvet, D., Brentan, M., Conti, F., Cornara, L., Domina, G., Fascetti, S., Festi, F., Gubellini, L., Guglielmone, L., Gudžinskas, Z., Helminger, T., Mârza, M., Ufimov, R.A., Caković, D., Abramov, †N.V., Baranova, O.G., Borisova, E.A., Chkalov, A.V., Demakhina, T.V., Glazkova, E.A., Grigorjevskaya, A.J., Gubareva, I.YU., Kalashnikova, O.V., Khapugin, A.A., Knjazev, M.S., Iberite, M., Marcucci, R., Krylov, A.V., La, A., Marsili, S., Holverda, W.J., Pedersen, O., Kulikov, P.V., Lastrucci, L., Medagli, P., Weeda, E.J., Majorov, S.R., Lattanzi, E., Olmo, M., Løfall, B.P., Peccenini, S., Pistarino, A., Poldini, L., Prosser, F., Raffaelli, M., Raimondo, F.M., Rinaldi, G., Ruocco, G., Santangelo, A., Siniscalco, C., Tognon, G., Vidali, M., Muldashev, A.A., Notov, A.A., Orlova, L.V., Ovesnov, S.A., Plaksina, T.I., Popchenko, M.I., Rakov, N.S., Reshetnikova, N.M., Saksonov, S.V., Sennikov, A.N., Oklejewicz, K., Danielewicz, W., Maliński, T., Stadnicka-futoma, A., Wolanin, M., Hinneri, S., Hyvärinen, M., Lahti, T., Rikkinen, J., Ulvinen, T., Väre, H., Wilhalm, T., Zappa, E., Almeida, R., Seregin, A.P., Alves, P.J., Vasjukov, V.M., Coutinho, A.X.P., Zhukova, O.V., Crespí, A.L., De, J.D., Honrado, J.P., Krasniqi, E., Gavrilova, Ģ., Šulcs, V., Dihoru, G., Dihoru, A., Drăgulescu, C., Oltu, E., Popescu, G., Sârbu, I., Mininzon, I.L., Niketić, M., Tomović, G., Vukojičić, S., Goliašová, K., Šipošová, H., Bernátová, D., Marhold, K., Vreš, B., Delgado, L., Devesa, J.A., De, M., Fraga, M.I., Rico, E., Ruiz, E., Ericsson, S., Ljungstrand, E., Gygax, A., Özhatay, N., Fedoronchuk, N.M., Kagalo, A.A., Sytschak, N.M., and Yena, A.V.

Published
2013

36. Breast and cervical cancer in transgender men: literature review and a case report.

Author

Di Lisa FS, Villa A, Filomeno L, Arcuri T, Chiofalo B, Sanguineti G, Pizzuti L, Krasniqi E, Barba M, Sergi D, Lombardo F, Romanelli F, Botti C, Zoccali G, Ciliberto G, and Vici P

Abstract

Transgender individuals exhibit a higher prevalence of cancer-related risk factors, such as substance abuse and sexually transmitted infections. These factors, coupled with suboptimal adherence to cancer screening recommendations, may lead to a higher incidence of cancers, such as breast and cervical cancer, and contribute to delayed diagnoses in transgender patients. Herein, we report a unique case of a transgender man with a history of alcohol and drug abuse, undergoing gender-affirming exogenous testosterone therapy, who developed synchronous locally advanced breast cancer and human papilloma virus (HPV)-related cervical cancer. He underwent concurrent chemoradiation for cervical cancer and surgery followed by endocrine therapy for breast cancer. The treatments were suboptimals due to patient's comorbidities, among them liver cirrhosis leading to an early death. Additionally, we have conducted a review of existing literature, including case reports, clinical studies, and review articles investigating the role of potential risk factors specifically related to breast and cervical tumors in transgender men. Gender-affirming testosterone therapy is common among transgender men to induce gender affirmation, but its link to breast cancer risk remains ambiguous, with studies being limited and sometimes contradictory. Conversely, HPV is a well-established cause of up to 99% of cervical cancers. Despite persistent risk for cervical cancer in transgender men who retain their cervix, several studies indicate notable disparities in screening adherence, due to personal and structural barriers. Moreover, alcohol and drug use disorders, commonly encountered in transgender population, may negatively influence the adherence to screening programs. Current cancer screening guidelines for this population are somewhat unclear, and specific programs based on more robust data are urgently required along with further tailored studies., Competing Interests: FSDL: Novartis, Gentili, Pfizer, Daiichi-Sankyo and Ipsen, outside the submitted manuscript. LF: Gilead, Daiichi-Sankyo, Gentili and Eisai, outside the submitted manuscript. LP: Pfizer and Novartis, outside the submitted manuscript. DS: MSD, outside the submitted work. PV: Pfizer, Novartis, Eisai, Daiichi Sankyo, Ipsen and Eli Lilly, outside the submitted work. AV, TA, BC, GS, EK, MB, FL, FR, CB, and GC declare no competing interests., (© The Author(s), 2024.)

Published
2024
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38. DNA Damage Response in Early Breast Cancer: A Phase III Cohort in the Phobos Study.

Author

Krasniqi E, Ercolani C, Di Benedetto A, Di Lisa FS, Filomeno L, Arcuri T, Botti C, Pelle F, Cavicchi F, Cappelli S, Barba M, Pizzuti L, Maugeri-Saccà M, Moscetti L, Grassadonia A, Tinari N, Sanguineti G, Takanen S, Fragnito D, Terrenato I, Buglioni S, Perracchio L, Latorre A, De Maria R, Pallocca M, Ciliberto G, Giotta F, and Vici P

Abstract

We assessed the impact of DNA damage response and repair (DDR) biomarker expressions in 222 node-positive early breast cancer (BC) patients from a previous Phase III GOIM 9902 trial of adjuvant taxanes. At a median follow-up of 64 months, the original study showed no disease-free survival (DFS) or overall survival (OS) differences with the addition of docetaxel (D) to epirubicine-cyclophosphamide (EC). Immunohistochemistry was employed to assess the expression of DDR phosphoproteins (pATM, pATR, pCHK1, γH2AX, pRPA32, and pWEE1) in tumor tissue, and their association with clinical outcomes was evaluated through the Cox elastic net model. Over an extended follow-up of 234 months, we confirmed no significant differences in DFS or OS between patients treated with EC and those receiving D → EC. A DDR risk score, inversely driven by ATM and ATR expression, emerged as an independent prognostic factor for both DFS (HR = 0.41, p < 0.0001) and OS (HR = 0.61, p = 0.046). Further validation in a public adjuvant BC cohort was possible only for ATM, confirming its protective role. Overall, our findings confirm the potential role of the DDR pathway in BC prognostication and in shaping treatment strategies advocating for an integrated approach, combining molecular markers with clinical-pathological factors.

Published
2024
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39. HER2 mutation as an emerging target in advanced breast cancer.

Author

Bon G, Di Lisa FS, Filomeno L, Arcuri T, Krasniqi E, Pizzuti L, Barba M, Messina B, Schiavoni G, Sanguineti G, Botti C, Cappelli S, Pelle F, Cavicchi F, Puccica I, Costantini M, Perracchio L, Maugeri-Saccà M, Ciliberto G, and Vici P

Subjects
Humans, Female, Molecular Targeted Therapy methods, Prognosis, Clinical Trials as Topic, Antineoplastic Agents therapeutic use, Antineoplastic Agents pharmacology, Breast Neoplasms genetics, Breast Neoplasms drug therapy, Breast Neoplasms pathology, Receptor, ErbB-2 genetics, Mutation, Drug Resistance, Neoplasm genetics
Abstract

HER2 activating mutations have emerged as oncogenic drivers and therapeutic targets in a variety of human tumors. In breast cancer, these deregulations occur at low frequency, and are mostly detected in HER2-nonamplified, metastatic disease. Preclinical evidence has clarified the role of hotspot mutations in HER2 constitutive activation, defining them as an alternative mechanism to HER2 gene amplification. Furthermore, recent clinical studies have indicated the emergence of newly acquired HER2 deregulations in significant proportions of breast cancer patients who experience disease progression following both endocrine and HER2-targeted therapies. As the involvement of HER2 mutation in therapy resistance may profoundly impact patient outcomes on successive therapies, several clinical trials are currently investigating the efficacy of various HER2-targeted drugs in HER2-mutant breast cancer. In this review, we firstly summarize the structural organization of the HER2 oncogene and its historical impact on breast cancer prognosis and therapeutic advancement. Then, we provide an overview of the frequencies and functional relevance of clinically recurrent HER2 mutations in breast cancer with a special focus on their role in therapeutic resistance. Finally, we provide a collection of the clinical trials that are currently exploring novel therapeutic approaches for this patient subset and discuss the related perspectives and challenges., (© 2024 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Published
2024
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40. TRF2 as novel marker of tumor response to taxane-based therapy: from mechanistic insight to clinical implication.

Author

Iachettini S, Terrenato I, Porru M, Di Vito S, Rizzo A, D'Angelo C, Petti E, Dinami R, Maresca C, Di Benedetto A, Palange A, Mulè A, Santoro A, Palazzo A, Fuso P, Stoppacciaro A, Vici P, Filomeno L, Di Lisa FS, Arcuri T, Krasniqi E, Fabi A, Biroccio A, and Zizza P

Subjects
Humans, Animals, Mice, Retrospective Studies, Taxoids pharmacology, Taxoids therapeutic use, Bridged-Ring Compounds pharmacology, Bridged-Ring Compounds therapeutic use, Cell Line, Tumor, Triple Negative Breast Neoplasms drug therapy, Triple Negative Breast Neoplasms genetics, Triple Negative Breast Neoplasms pathology
Abstract

Background: Breast Cancer (BC) can be classified, due to its heterogeneity, into multiple subtypes that differ for prognosis and clinical management. Notably, triple negative breast cancer (TNBC) - the most aggressive BC form - is refractory to endocrine and most of the target therapies. In this view, taxane-based therapy still represents the elective strategy for the treatment of this tumor. However, due variability in patients' response, management of TNBC still represents an unmet medical need. Telomeric Binding Factor 2 (TRF2), a key regulator of telomere integrity that is over-expressed in several tumors, including TNBC, has been recently found to plays a role in regulating autophagy, a degradative process that is involved in drug detoxification. Based on these considerations, we pointed, here, at investigating if TRF2, regulating autophagy, can affect tumor sensitivity to therapy., Methods: Human TNBC cell lines, over-expressing or not TRF2, were subjected to treatment with different taxanes and drug efficacy was tested in terms of autophagic response and cell proliferation. Autophagy was evaluated first biochemically, by measuring the levels of LC3, and then by immunofluorescence analysis of LC3-puncta positive cells. Concerning the proliferation, cells were subjected to colony formation assays associated with western blot and FACS analyses. The obtained results were then confirmed also in mouse models. Finally, the clinical relevance of our findings was established by retrospective analysis on a cohort of TNBC patients subjected to taxane-based neoadjuvant chemotherapy., Results: This study demonstrated that TRF2, inhibiting autophagy, is able to increase the sensitivity of TNBC cells to taxanes. The data, first obtained in in vitro models, were then recapitulated in preclinical mouse models and in a cohort of TNBC patients, definitively demonstrating that TRF2 over-expression enhances the efficacy of taxane-based neoadjuvant therapy in reducing tumor growth and its recurrence upon surgical intervention., Conclusions: Based on our finding it is possible to conclude that TRF2, already known for its role in promoting tumor formation and progression, might represents an Achilles' heel for cancer. In this view, TRF2 might be exploited as a putative biomarker to predict the response of TNBC patients to taxane-based neoadjuvant chemotherapy., (© 2024. The Author(s).)

Published
2024
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42. DARPP-32 and t-DARPP in the development of resistance to anti-HER2 agents. Pre-clinical evidence from the STEP study.

Author

Bon G, Krasniqi E, Porru M, D'Ambrosio L, Scalera S, Maugeri-Saccà M, Di Lisa FS, Filomeno L, Arcuri T, Botticelli A, Santini D, Fabbri MA, D'Auria G, Pulito C, Blandino G, Marchiò C, Barba M, Ciliberto G, Vici P, and Pizzuti L

Subjects
Mice, Animals, Humans, Female, Trastuzumab therapeutic use, Retrospective Studies, Prospective Studies, Dopamine and cAMP-Regulated Phosphoprotein 32, Biomarkers, Receptor, ErbB-2 genetics, Receptor, ErbB-2 metabolism, Antineoplastic Combined Chemotherapy Protocols, Breast Neoplasms drug therapy, Breast Neoplasms genetics, Breast Neoplasms metabolism
Abstract

The therapeutic scenario of Human Epidermal Growth Factor Receptor 2 positive advanced breast cancer (ABC) has been recently enriched by a number of innovative agents, which are reshaping treatment sequence. While randomized trials have documented an advantage in terms of efficacy, for the newly available agents we lack effectiveness and tolerability evidence from the real-world setting. Similarly, the identification of predictive biomarkers might improve clinical decision. We herein describe the outline of a prospective/retrospective study which aims to explore the optimal sequence of treatment in HER2+, pertuzumab pre-treated ABC patients treated in II line with anti-HER2 agents in clinical practice. As part of the pre-clinical tasks envisioned by the STEP study, in vitro cell models of resistance were exploited to investigate molecular features associated with reduced efficacy of HER2 targeting agents at the transcript level. The aggressive behavior of resistant cell populations was measured by growth assessment in mouse models. This approach led to the identification of DARPP-32 and t-DARPP proteins as possible predictive biomarkers of efficacy of anti-HER2 agents. Biomarkers validation and the clinical goals will be reached through patients' inclusion into two independent cohorts, i.e., the prospective and retrospective cohorts, whose setup is currently ongoing., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: FSDL: Ipsen and Novartis, outside the submitted work. AB: Pfizer, Roche, Lilly, Novartis, Msd, Seagen, Gilead and Daiichi Sankyo, outside the submitted work. DS: Amgen, Astellas, Astrazeneca, Bayer, BMS, Eisai, Ipsen, Janssen, Merck, MSD, Novartis, Pfizer, outside the submitted work. GDA: Novartis, Amgen, Eli Lilly, outside the submitted work. CM: Bayer, Roche, AstraZeneca and Daiichi-Sankyo, outside the submitted work. P.V.: Pfizer, Novartis, Eisai, Daiichi Sankyo and Eli Lilly, outside of the manuscript under consideration L.P.: Novartis and Pfizer, outside of the manuscript under consideration. No potential conflicts of interest were disclosed for other authors, (Copyright © 2023. Published by Elsevier Inc.)

Published
2023
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43. The Molecular Tumor Board of the Regina Elena National Cancer Institute: from accrual to treatment in real-world.

Author

Giacomini P, Valenti F, Allegretti M, Pallocca M, De Nicola F, Ciuffreda L, Fanciulli M, Scalera S, Buglioni S, Melucci E, Casini B, Carosi M, Pescarmona E, Giordani E, Sperati F, Jannitti N, Betti M, Maugeri-Saccà M, Cecere FL, Villani V, Pace A, Appetecchia M, Vici P, Savarese A, Krasniqi E, Ferraresi V, Russillo M, Fabi A, Landi L, Minuti G, Cappuzzo F, Zeuli M, and Ciliberto G

Subjects
United States, Humans, National Cancer Institute (U.S.), Retrospective Studies, Mutation, DNA, Neoplasm genetics, High-Throughput Nucleotide Sequencing methods, Biomarkers, Tumor genetics, Neoplasms genetics
Abstract

Background: Molecular Tumor Boards (MTB) operating in real-world have generated limited consensus on good practices for accrual, actionable alteration mapping, and outcome metrics. These topics are addressed herein in 124 MTB patients, all real-world accrued at progression, and lacking approved therapy options., Methods: Actionable genomic alterations identified by tumor DNA (tDNA) and circulating tumor DNA (ctDNA) profiling were mapped by customized OncoKB criteria to reflect diagnostic/therapeutic indications as approved in Europe. Alterations were considered non-SoC when mapped at either OncoKB level 3, regardless of tDNA/ctDNA origin, or at OncoKB levels 1/2, provided they were undetectable in matched tDNA, and had not been exploited in previous therapy lines., Results: Altogether, actionable alterations were detected in 54/124 (43.5%) MTB patients, but only in 39 cases (31%) were these alterations (25 from tDNA, 14 from ctDNA) actionable/unexploited, e.g. they had not resulted in the assignment of pre-MTB treatments. Interestingly, actionable and actionable/unexploited alterations both decreased (37.5% and 22.7% respectively) in a subset of 88 MTB patients profiled by tDNA-only, but increased considerably (77.7% and 66.7%) in 18 distinct patients undergoing combined tDNA/ctDNA testing, approaching the potential treatment opportunities (76.9%) in 147 treatment-naïve patients undergoing routine tDNA profiling for the first time. Non-SoC therapy was MTB-recommended to all 39 patients with actionable/unexploited alterations, but only 22 (56%) accessed the applicable drug, mainly due to clinical deterioration, lengthy drug-gathering procedures, and geographical distance from recruiting clinical trials. Partial response and stable disease were recorded in 8 and 7 of 19 evaluable patients, respectively. The time to progression (TTP) ratio (MTB-recommended treatment vs last pre-MTB treatment) exceeded the conventional Von Hoff 1.3 cut-off in 9/19 cases, high absolute TTP and Von Hoff values coinciding in 3 cases. Retrospectively, 8 patients receiving post-MTB treatment(s) as per physician's choice were noted to have a much longer overall survival from MTB accrual than 11 patients who had received no further treatment (35.09 vs 6.67 months, p = 0.006)., Conclusions: MTB-recommended/non-SoC treatments are effective, including those assigned by ctDNA-only alterations. However, real-world MTBs may inadvertently recruit patients electively susceptible to diverse and/or multiple treatments., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Published
2023
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44. Adjuvant capecitabine in triple negative breast cancer patients with residual disease after neoadjuvant treatment: real-world evidence from CaRe , a multicentric, observational study.

Author

Di Lisa FS, Krasniqi E, Pizzuti L, Barba M, Cannita K, De Giorgi U, Borella F, Foglietta J, Cariello A, Ferro A, Picardo E, Mitidieri M, Sini V, Stani S, Tonini G, Santini D, La Verde N, Gambaro AR, Grassadonia A, Tinari N, Garrone O, Sarobba G, Livi L, Meattini I, D'Auria G, Vergati M, Gamucci T, Pistelli M, Berardi R, Risi E, Giotta F, Lorusso V, Rinaldi L, Artale S, Cazzaniga ME, Zustovich F, Cappuzzo F, Landi L, Torrisi R, Scagnoli S, Botticelli A, Michelotti A, Fratini B, Saltarelli R, Paris I, Muratore M, Cassano A, Gianni L, Gaspari V, Veltri EM, Zoratto F, Fiorio E, Fabbri MA, Mazzotta M, Ruggeri EM, Pedersini R, Valerio MR, Filomeno L, Minelli M, Scavina P, Raffaele M, Astone A, De Vita R, Pozzi M, Riccardi F, Greco F, Moscetti L, Giordano M, Maugeri-Saccà M, Zennaro A, Botti C, Pelle F, Cappelli S, Cavicchi F, Vizza E, Sanguineti G, Tomao F, Cortesi E, Marchetti P, Tomao S, Speranza I, Sperduti I, Ciliberto G, and Vici P

Abstract

Background: In triple negative breast cancer patients treated with neoadjuvant chemotherapy, residual disease at surgery is the most relevant unfavorable prognostic factor. Current guidelines consider the use of adjuvant capecitabine, based on the results of the randomized CREATE-X study, carried out in Asian patients and including a small subset of triple negative tumors. Thus far, evidence on Caucasian patients is limited, and no real-world data are available., Methods: We carried out a multicenter, observational study, involving 44 oncologic centres. Triple negative breast cancer patients with residual disease, treated with adjuvant capecitabine from January 2017 through June 2021, were recruited. We primarily focused on treatment tolerability, with toxicity being reported as potential cause of treatment discontinuation. Secondarily, we assessed effectiveness in the overall study population and in a subset having a minimum follow-up of 2 years., Results: Overall, 270 patients were retrospectively identified. The 50.4% of the patients had residual node positive disease, 7.8% and 81.9% had large or G3 residual tumor, respectively, and 80.4% a Ki-67 >20%. Toxicity-related treatment discontinuation was observed only in 10.4% of the patients. In the whole population, at a median follow-up of 15 months, 2-year disease-free survival was 62%, 2 and 3-year overall survival 84.0% and 76.2%, respectively. In 129 patients with a median follow-up of 25 months, 2-year disease-free survival was 43.4%, 2 and 3-year overall survival 78.0% and 70.8%, respectively. Six or more cycles of capecitabine were associated with more favourable outcomes compared with less than six cycles., Conclusion: The CaRe study shows an unexpectedly good tolerance of adjuvant capecitabine in a real-world setting, although effectiveness appears to be lower than that observed in the CREATE-X study. Methodological differences between the two studies impose significant limits to comparability concerning effectiveness, and strongly invite further research., Competing Interests: LP received speaker fees from Novartis, outside the submitted work. UDG: Pfizer, BMS, MSD, PharmaMAR, AStellas, Bayer, Ipsen, Novartis; Invited speaker Roche, BMS, SAnofi, AstraZeneca; received research grants from AstraZeneca, SAnofi, Roche, outside the submitted work. AF received honoraria as a speaker from Eli Lilly, Novartis, Pierre-Fabre, outside the submitted work. GT: advisory boards from Novartis, Pfizer, Eisai, Roche, and Eli Lilly, outside the submitted work. DS: advisory boards from Novartis, Pfizer, Eisai, Roche, and Eli Lilly, outside the submitted work. NLV: Roche, MSD, Eisai, Novartis, AstraZeneca, GSK, Pfizer, Gentili, Daiichi Sankyo, Dephaforum, outside the submitted work. OG: Eisai, MSD, Gilead, Seagen, Novartis, Eli Lilly, outside the submitted work. IM: advisory boards from Eli Lilly, Novartis, Gentili, Roche, Pfizer, Ipsen, and Pierre-Fabre, outside the submitted work. GD’A: Novartis, Amgen, Eli Lilly outside the submitted work. TG received travel grants from Eisai, Roche, Pfizer, and Novartis; speaker fees/advisory boards from Roche, Pfizer, Novartis, Gentili, and Eli Lilly, outside the submitted work. MPi Consultant/advisory boards from Gilead, Eli Lilly, Pfizer, Novartis, Gentili, MSD, outside the submitted work. RB received research grant/advisory boards from AstraZeneca, Boehringer Ingelheim, Novartis, MSD, Otsuka, Eli Lilly, Roche, Amgen, GSK, Eisai, outside the submitted work. FGi: advisory boards from Gilead, Daiichi Sankyo, Seagen, outside the submitted work. MEC consultant/advisory role for Pierre-Fabre, Roche, Novartis, Eli Lilly, Celgene, outside the submitted work. RT: AstraZeneca, Eisai, Pfizer, Eli Lilly, MSD, Exact Science, outside the submitted work. AB: MSD, BMS, Pfizer, Novartis, Roche outside the submitted work. AM received travel grants from Eisai, Celgene, and Novartis Ipsen; personal fees/advisory boards from Eisai, Novartis, AstraZeneca, Teva, Pfizer, and Celgene, outside the submitted work. IP received personal fees/advisory boards from Roche, Pfizer, Novartis, Italfarmaco, Gentili, and Pierre-Fabre. LG received congress travel accomodation from Roche, Daiichi Sankyo, AstraZeneca, Pfizer, Novartis; advisory role for Astra Zeneca outside the submitted work. MMin: Novartis, MSD, Eli Lilly, outside the submitted work. LM received personal fees/advisory board from Roche, Novartis, Eisai, and Pfizer, outside the submitted work. EC: Astellas, Roche, BMS, Jansen, MSD, Sirtex, Merck, Bayer, Servier, Novartis, outside the submitted work. PM has/had a consultant/advisory role for BMS, Roche, Genentech, MSD, Novartis, Amgen, Merck Serono, Pierre-Fabre and Incyte, outside the submitted work. PV received speaker fees/advisory boards from Roche, Pfizer, Novartis and Eli Lilly, outside the submitted work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Di Lisa, Krasniqi, Pizzuti, Barba, Cannita, De Giorgi, Borella, Foglietta, Cariello, Ferro, Picardo, Mitidieri, Sini, Stani, Tonini, Santini, La Verde, Gambaro, Grassadonia, Tinari, Garrone, Sarobba, Livi, Meattini, D’Auria, Vergati, Gamucci, Pistelli, Berardi, Risi, Giotta, Lorusso, Rinaldi, Artale, Cazzaniga, Zustovich, Cappuzzo, Landi, Torrisi, Scagnoli, Botticelli, Michelotti, Fratini, Saltarelli, Paris, Muratore, Cassano, Gianni, Gaspari, Veltri, Zoratto, Fiorio, Fabbri, Mazzotta, Ruggeri, Pedersini, Valerio, Filomeno, Minelli, Scavina, Raffaele, Astone, De Vita, Pozzi, Riccardi, Greco, Moscetti, Giordano, Maugeri-Saccà, Zennaro, Botti, Pelle, Cappelli, Cavicchi, Vizza, Sanguineti, Tomao, Cortesi, Marchetti, Tomao, Speranza, Sperduti, Ciliberto and Vici.)

Published
2023
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45. Biomarkers of Response and Resistance to CDK4/6 Inhibitors in Breast Cancer: Hints from Liquid Biopsy and microRNA Exploration.

Author

Krasniqi E, Goeman F, Pulito C, Palcau AC, Ciuffreda L, Di Lisa FS, Filomeno L, Barba M, Pizzuti L, Cappuzzo F, Sanguineti G, Maugeri-Saccà M, Ciliberto G, Fanciulli M, Blandino G, and Vici P

Subjects
Female, Humans, Cyclin-Dependent Kinase 4 antagonists & inhibitors, Cyclin-Dependent Kinase 6 antagonists & inhibitors, Liquid Biopsy, Molecular Targeted Therapy, Purines pharmacology, Breast Neoplasms drug therapy, Breast Neoplasms genetics, Breast Neoplasms metabolism, MicroRNAs genetics, MicroRNAs therapeutic use, Protein Kinase Inhibitors pharmacology, Protein Kinase Inhibitors therapeutic use
Abstract

New evidence on the impact of dysregulation of the CDK4/6 pathway on breast cancer (BC) cell proliferation has led to the development of selective CDK4/6 inhibitors, which have radically changed the management of advanced BC. Despite the improved outcomes obtained by CDK4/6 inhibitors, approximately 10% of tumors show primary resistance, whereas acquired resistance appears to be an almost ubiquitous occurrence, leading to treatment failure. The identification of differentially expressed genes or genomic mutational signatures able to predict sensitivity or resistance to CDK4/6 inhibitors is critical for medical decision making and for avoiding or counteracting primary or acquired resistance against CDK4/6 inhibitors. In this review, we summarize the main mechanisms of resistance to CDK4/6 inhibitors, focusing on those associated with potentially relevant biomarkers that could predict patients' response/resistance to treatment. Recent advances in biomarker identification are discussed, including the potential use of liquid biopsy for BC management and the role of multiple microRNAs as molecular predictors of cancer cell sensitivity and resistance to CDK4/6 inhibitors.

Published
2022
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46. The Management Perspective in Digital Health Literature: Systematic Review.

Author

Angerer A, Stahl J, Krasniqi E, and Banning S

Subjects
Humans, Delivery of Health Care, Technology, Knowledge, Publications, Telemedicine
Abstract

Background: New digital health technologies are considered one solution to challenges in the health sector, which include rising numbers of chronic diseases and increased health spending. As digitalization in health care is still in its infancy, there are many unanswered questions about the impact of digital health on management., Objective: This paper assesses the current state of knowledge in the field of digital health from a management perspective. It highlights research gaps within this field to determine future research opportunities., Methods: A systematic review of digital health literature was conducted using 3 databases. The chosen articles (N=38) were classified according to a taxonomy developed for the purpose, and research gaps were identified based on the topic areas discussed., Results: The literature review revealed a slight prevalence of practical (n=21, 55%) over theoretical (n=17, 45%) approaches. Most of the papers (n=23, 61%) deal with information technology (IT) and are, therefore, focused more on technology and less on management. The research question in most of the papers (n=31, 82%) deals with the creation of concepts, and very few (n=4, 11%) evaluate or even question existing solutions. Most consider the main reason for digitalization to be the optimization of operational processes (n=26, 68%), and 42% (n=16) deal with new business models. The topic area discussed most frequently was found to be eHealth (n=30, 79%). By contrast, the field of tech health with topics such as sensors receives the least attention (n=3, 8%), despite its significant potential for health care processes and strategy., Conclusions: Three main research propositions were identified. First, research into digital health innovation should not focus solely on the technology aspects but also on its implications for strategic and operational management. Second, the research community should target other domains besides eHealth. Third, we observed a lack of quantitative research on the real impact of digital health on organizations and their management. More quantitative evidence is required regarding the expected outcome and impact of the implementation of digital health solutions into our health care organizations., (©Alfred Angerer, Johanna Stahl, Egzona Krasniqi, Stefan Banning. Originally published in JMIR mHealth and uHealth (https://mhealth.jmir.org), 10.11.2022.)

Published
2022
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47. The Impact of the Hippo Pathway and Cell Metabolism on Pathological Complete Response in Locally Advanced Her2+ Breast Cancer: The TRISKELE Multicenter Prospective Study.

Author

Krasniqi E, Di Lisa FS, Di Benedetto A, Barba M, Pizzuti L, Filomeno L, Ercolani C, Tinari N, Grassadonia A, Santini D, Minelli M, Montemurro F, Fabbri MA, Mazzotta M, Gamucci T, D'Auria G, Botti C, Pelle F, Cavicchi F, Cappelli S, Cappuzzo F, Sanguineti G, Tomao S, Botticelli A, Marchetti P, Maugeri-Saccà M, De Maria R, Ciliberto G, Sperati F, and Vici P

Abstract

The Hippo pathway and its two key effectors, Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ), are consistently altered in breast cancer. Pivotal regulators of cell metabolism such as the AMP-activated protein kinase (AMPK), Stearoyl-CoA-desaturase 1 (SCD1), and HMG-CoA reductase (HMGCR) are relevant modulators of TAZ/YAP activity. In this prospective study, we measured the tumor expression of TAZ, YAP, AMPK, SCD1, and HMGCR by immunohistochemistry in 65 Her2+ breast cancer patients who underwent trastuzumab-based neoadjuvant treatment. The aim of the study was to assess the impact of the immunohistochemical expression of the Hippo pathway transducers and cell metabolism regulators on pathological complete response. Low expression of cytoplasmic TAZ, both alone and in the context of a composite signature identified by machine learning including also low nuclear levels of YAP and HMGCR and high cytoplasmic levels of SCD1, was a predictor of residual disease in the univariate logistic regression. This finding was not confirmed in the multivariate model including estrogen receptor > 70% and body mass index > 20. However, our findings were concordant with overall survival data from the TCGA cohort. Our results, possibly affected by the relatively small sample size of this study population, deserve further investigation in adequately sized, ad hoc prospective studies.

Published
2022
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48. Impact of Using Population-Specific Cut-Points, Self-Reported Health, and Socio-Economic Parameters to Predict Sarcopenia: A Cross-Sectional Study in Community-Dwelling Kosovans Aged 60 Years and Older.

Author

Boshnjaku A, Bahtiri A, Feka K, Krasniqi E, Tschan H, and Wessner B

Abstract

The age-related decline of muscle strength, mass, and physical performance (sarcopenia) has been raising concerns among the scientific and healthcare communities. This decline may differ between populations, age groups, and sexes. Therefore, we aimed to explore sarcopenia together with the impact of health and socio-economic parameters in mature Kosovans. A cross-sectional study was conducted on community-dwelling adults aged ≥ 60 years (n = 240, 47.1% female) from the Prishtina region. Sarcopenia was identified using the following criteria: (i) the European Working Group in Sarcopenia for Older People (EWGSOP1), (ii) the revised EWGSOP2 algorithms, and (iii) sex-specific cut-points derived from the Kosovan population. In males, pre-sarcopenia/probable sarcopenia was detected from the EWGSOP1, EWGSOP2 and Kosovan-specific criteria at values of 3.1%, 5.5%, and 28.3%; sarcopenia was detected at 1.6%, 5.5%, and 0.0%, and severe sarcopenia was detected at 4.7%, 2.4%, and 4.7%, respectively. Pre-sarcopenia was lower in females (0.9%, 5.3%, 16.8%), with no cases of sarcopenia or severe sarcopenia detected by either algorithm. Sarcopenic males were older, had a lower weight, BMI, skeletal muscle mass, performance score, nutritional status (p < 0.001), educational level (p = 0.035), and higher malnourishment risk (p = 0.005). It is notable that high overweight and obesity levels were also detected (93.8% of females, 77.1% of males). This study highlights the importance of using population-specific cut-points when diagnosing sarcopenia, as otherwise its occurrence may be underestimated, especially in obese persons. Age, body composition, physical performance, health, and socio-economic conditions can influence the occurrence of sarcopenia., Competing Interests: The authors declare no conflict of interest.

Published
2022
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50. KEAP1-Mutant NSCLC: The Catastrophic Failure of a Cell-Protecting Hub.

Author

Scalera S, Mazzotta M, Cortile C, Krasniqi E, De Maria R, Cappuzzo F, Ciliberto G, and Maugeri-Saccà M

Subjects
Humans, Kelch-Like ECH-Associated Protein 1 genetics, Kelch-Like ECH-Associated Protein 1 metabolism, Mutation, NF-E2-Related Factor 2 genetics, NF-E2-Related Factor 2 metabolism, Tumor Microenvironment, Adenocarcinoma of Lung pathology, Carcinoma, Non-Small-Cell Lung pathology, Lung Neoplasms pathology
Abstract

Mutations in the KEAP1-NRF2 pathway are common in NSCLC, albeit with a prevalence of KEAP1 mutations in lung adenocarcinoma and an equal representation of KEAP1 and NFE2L2 (the gene encoding for NRF2) alterations in lung squamous cell carcinoma. The KEAP1-NRF2 axis is a crucial modulator of cellular homeostasis, enabling cells to tolerate oxidative and metabolic stresses, and xenobiotics. The complex cytoprotective response orchestrated by NRF2-mediated gene transcription embraces detoxification mechanisms, ferroptosis protection, and metabolic reprogramming. Given that the KEAP1-NRF2 pathway controls core cellular functions, it is not surprising that a number of clinical studies connected KEAP1 mutations to increased resistance to chemotherapy, radiotherapy, and targeted agents. More recently, an immune-cold tumor microenvironment was described as a typical feature of KEAP1-mutant lung adenocarcinoma. Consistently, a reduced efficacy of immunotherapy was reported in the KEAP1-mutant background. Nevertheless, the connection between KEAP1 and immune resistance seems more complex and dependent on coexisting genomic alterations. Given the clinical implications of deregulated KEAP1-NRF2 pathway in lung cancer, the development of pathway-directed anticancer treatments should be considered a priority in the domain of thoracic oncology., (Copyright © 2022 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Published
2022
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