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Phase I and pharmacokinetic study of lonafarnib, SCH 66336, using a 2-week on, 2-week off schedule in patients with advanced solid tumors
(Springer Verlag, 2011) Castaneda, Carlos; Meadows, Kellen L; Truax, Roxanne; Michael A; Morse; Kaufmann, Scott H; Petros, William P; Yali Zhu, Paul; Statkevich; Cutler, David L; Hurwitz, Herbert I
Purpose: This phase I study was performed to determine the safety profile, maximum tolerated dose (MTD) and biological activity of lonafarnib (SCH 66336). Single-dose and multi-dose pharmacokinetics were conducted. Methods: Twenty-one patients with advanced solid tumors were enrolled. Each patient received single-dose administration on day 1, cycle 1 then switched to a twice daily (BID) dosing regimen on days 2-14 of a 28-day cycle; subsequent cycles continued BID dosing on days 1-14. Dose-limiting toxicity (DLT) was assessed during the cycle one; toxicity evaluation was closely monitored throughout the treatment. Radiographic scans were completed to assess tumor response. Blood and urine pharmacokinetics were evaluated on days 1 and 14 in cycle 1. SCH 66336- induced farnesylation inhibition was assessed via conversion of prelamin A to lamin in buccal mucosa. Results: DLT and most common adverse events were diarrhea, fatigue, nausea and anorexia. No grade 3 or 4 hematological toxicities were observed. Nineteen of 21 patients were evaluable for response; short-term stable disease was observed in 5 patients. SCH 66336 systemic exposure increased with dose; however, drug accumulation was higher than projected. Renal excretion of parent drug was negligible. Farnesyl transferase inhibition was detected at the 200 and 300 mg BID doses. Conclusion: The MTD and recommended phase II dose is 200 mg BID on days 1-14 of a 28-day dosing regimen. The plasma concentration profile suggests the pharmacokinetics of SCH 66336 is dose and time dependent. Farnesyl transferase target inhibition was observed at doses of lonafarnib recommended for further study.
Implication of miRNA in the diagnosis and treatment of breast cancer
(Taylor and Francis Ltd., 2011) Castañeda, CA; Agullo-Ortuño, MT; Fresno Vara, JA; Cortes-Funes, H; Gomez, HL; Ciruelos, E
Breast cancer (BC) comprises a group of different diseases characterized by changes in tissue structure and gene expression. Recent advances in molecular biology have shed new light on the participation of genes and their products in the biology of BC. MicroRNAs (miRNAs) are small noncoding endogenous RNA molecules that appear to modulate the expression of more than a third of human genes, and their implications in cancer have grasped the attention of the scientific community. Recently, several studies have described the association between miRNA expression profiles and pathological and clinical BC features. Moreover, these molecules represent a new type of molecular marker that can identify prognosis and guide the management of BC patients. With the increasing understanding of miRNA networks and their impact in the biology of BC, as well as the development of viable strategies to modulate specific miRNAs, we could improve the treatment of this disease.
Relationship between tumor-associated immune infiltrate and p16 staining over clinicopathological features in acral lentiginous melanoma
(Springer-Verlag Italia Srl, 2013) Castaneda, Carlos; Castillo, Miluska; Torres-Cabala, C; Bernabe, LA; Casavilca, S; Villegas, V; Sanchez, J; de la Cruz, M; Dunstan, J; Cotrina, JM; Gomez, HL; Chavez, C; Landa-Baella, MP; Tello, K; Felix, BF; Abugattas, J
Purpose: This study aims to evaluate the association between composition of tumor-infiltrating lymphocytes (TIL) and expression of p16 in acral lentiginous melanoma (ALM), and their impact on prognosis.
Efficacy and safety of ixabepilone plus capecitabine in elderly patients with anthracycline- and taxane-pretreated metastatic breast cancer
(Elsevier Ltd., 2013) Vahdat, LT; Vrdoljak, E; Gómez, H; Li, RK; Bosserman, L; Sparano, JA; Baselga, J; Mukhopadhyay, P; Valero, V
Objectives: Data on chemotherapy regimens in elderly patients with metastatic breast cancer (MBC) are limited. The aim of this retrospective pooled analysis was to determine efficacy and safety of ixabepilone plus capecitabine versus capecitabine alone in patients with MBC aged ≥ 65 years. Materials and methods: A total of 1973 patients with MBC previously treated with or resistant to anthracyclines and taxanes were randomized in two open-label, multinational, phase 3 studies (study 046 and study 048). Patients received ixabepilone (40 mg/m(2) as a 3-hour intravenous infusion every 3 weeks) plus oral capecitabine (1000 mg/m(2) administered twice each day), or capecitabine alone (1250 mg/m(2) twice each day). Results: In total, 251 randomized patients were aged ≥ 65 years (ixabepilone plus capecitabine, n=116; capecitabine monotherapy, n=135). Efficacy results were consistent in patients aged <65 and ≥ 65 years with respect to the observed improvement in progression-free survival and objective response rate with ixabepilone plus capecitabine compared with capecitabine alone. No significant differences in overall survival between arms were observed for either subgroup. In the ixabepilone plus capecitabine arm, grade 3/4 hematologic adverse events (AEs) were similar in both subgroups except leukopenia and febrile neutropenia, which had a higher incidence in patients aged ≥ 65 years. The majority of grade 3/4 nonhematologic AEs were similar in the two subgroups, including fatigue, peripheral sensory neuropathy, and hand-foot syndrome. Conclusion: The combination of ixabepilone plus capecitabine maintains its efficacy in elderly patients with anthracycline and taxane pretreated MBC, with a similar safety profile to patients aged < 65 years.
Association between mammographic features and response to neoadjuvant chemotherapy in locally advanced breast carcinoma
(Elsevier Ltd., 2014) Castaneda, Carlos; Flores, Raymundo; Katerin, Rojas; Claudio, Flores; Miluska, Castillo; Esperanza, Milla
Purpose: Mammography is the cornerstone of breast cancer (BC) evaluation. This report investigates whether breast density (BD) and mammographic features of the tumor can provide information on both BC susceptibility to chemotherapy and other clinicopathologic features of locally advanced BC (LA BC). Materials and methods: We evaluated mammography films and clinicopathological information of patients with LA BC who received neoadjuvant chemotherapy (NAC) followed by tumor resection at the Instituto Nacional de Enfermedades Neoplásicas (INEN) from 2000 to 2011. Results: We selected 494 LA BC cases. Most cases were at clinical tumor stage 4 (48.5%), node stage 1 (58.8%) and had high histologic grade (53.3%). BI-RADS 1, 2, 3, and 4 BD were found in 16.9%, 22%, 35.7% and 25.1% of patients, respectively. High BD has been associated with younger age (p < 0.001), obesity (p = 0.017) and no skin infiltration (T3 vs T4) (p = 0.018). An association between dusty microcalcifications and HER2 group, as well as between casting microcalcifications and TN BC group (p = 0.05) was found. NAC included anthracyclines and taxanes in 422 (85.5%) cases. Miller–Payne pathologic responses 4 and 5 (pCR) in the primary lesion and absence of axillary lymph nodes involvement were found in 15.3% of cases and were associated with younger age (p < 0.001) and HG-3 lesions (p < 0.001), but not with mammographic images. Conclusion: Mammographic features are associated with specific clinicopathological features of pre-NAC BC lesions but do not predict pCR. The implications and biological reasons for these findings require further study.
Twelve serum proteins progressively increase with disease stage in squamous cell cervical cancer patients
(BMJ Publishing Group, 2014) Zhi W; Ferris D; Sharma A; Purohit S; Santos C; He M; Ghamande S; She JX
Objective This study aimed to reliably identify serum protein profile alterations that may be useful for elucidation of the disease mechanism and/or finding new targets for treatment and intervention. Materials and Methods A total of 1057 women at 4 different squamous cell cervical cancer stages (noninvasive, invasive International Federation of Gynecology and Obstetrics stages I, II, and III) were included in this cross-sectional study. Forty-seven serum proteins were profiled using multiplex Luminex immunoassays. Results Serum concentration of serum amyloid A (SAA), C-reactive protein (CRP), soluble tumor necrosis factor receptor I and II (sTNFRI and sTNFRII), soluble interleukin 2 receptor α (sIL2Rα), CXCL1, CXCL9, hepatocyte growth factor, squamous cell carcinoma antigen (SCCA), insulin-like growth factor binding protein 2, CA125, and carcinoembryonic antigen (CEA) were elevated significantly as disease progressed in cervical cancer patients. Serum levels are significantly different at early stage (I) for SAA, CRP, sIL2Rα, sTNFRII, SCCA, and CEA (P values ranged from 0.02 for CEA to 0.0001 for CRP and SCCA) and at late stages (II and III) for all 12 proteins (P values ranged from 8.78E-5 for CA125 to 3.49E-47 for SAA), as compared to the noninvasive stage. The areas under the curves of these proteins for disease state separation also improved with the advancement of the disease. The correlations between serum concentrations of these proteins also show different patterns at different clinical stages. These proteins are involved in multiple mechanisms including inflammation and immunity, angiogenesis, growth promotion, and metastasis. Conclusions A number of serum proteins are significantly different between patients at different stages of cervical cancer.
Prognostic factors for patients with newly diagnosed brain metastasis from breast cancer
(Future Medicine Ltd., 2015) Castaneda, Carlos; Flores, R; Castillo, Miluska; Rojas, KY; Castillo, M; Dolores-Cerna, K; Flores, C; Belmar-Lopez, C; Milla, E; Gomez, HL
Aim: This retrospective study determined features associated with brain metastasis (BM) in women with breast cancer. Patients & methods: A total of 215 initially early breast cancer cases were included. We reviewed files and CT scan images of BM. Results: Median age was 47 years and most of our cases were stage III (58.6%), grade III (62.8%), ER negative (62.3%) and nonluminal (59.1%). Median survival after BM was 4 months. Nonluminal, extracranial disease, time to CNS shorter than 15 months, >three brain lesions and poor breast-graded prognostic assessment and recursive partitioning analysis scores were associated with shorter survival. Adding extracranial disease to breast-graded prognostic assessment score also predicted survival after BM. Radiation response was assessed in 57 patients and response tended to be associated with nonluminal phenotype but not with survival. Conclusion: Factors associated with both initial tumor and clinical features at BM time are associated with shorter survival in our Latinas population.
Combined Label-Free Quantitative Proteomics and microRNA Expression Analysis of Breast Cancer Unravel Molecular Differences with Clinical Implications
(American Association for Cancer Research Inc., 2015) Gámez-Pozo, A; ABerges-Soria, J; Arevalillo, JM; Nanni, P; López-Vacas, R; Navarro, H; Grossmann, J; Castaneda, CA; Main, P; Díaz-Almirón, M; Espinosa, E; Ciruelos, E; Fresno Vara, Á
Better knowledge of the biology of breast cancer has allowed the use of new targeted therapies, leading to improved outcome. High-throughput technologies allow deepening into the molecular architecture of breast cancer, integrating different levels of information, which is important if it helps in making clinical decisions. microRNA (miRNA) and protein expression profiles were obtained from 71 estrogen receptor-positive (ER(+)) and 25 triple-negative breast cancer (TNBC) samples. RNA and proteins obtained from formalin-fixed, paraffin-embedded tumors were analyzed by RT-qPCR and LC/MS-MS, respectively. We applied probabilistic graphical models representing complex biologic systems as networks, confirming that ER(+) and TNBC subtypes are distinct biologic entities. The integration of miRNA and protein expression data unravels molecular processes that can be related to differences in the genesis and clinical evolution of these types of breast cancer. Our results confirm that TNBC has a unique metabolic profile that may be exploited for therapeutic intervention.
Prospective Validation of a 21-Gene Expression Assay in Breast Cancer
(Massachussetts Medical Society, 2015) Sparano, JA; Gray, RJ; Makower, DF; Pritchard, KI; Albain, KS; Hayes, DF; Geyer, CE Jr; Dees, EC; Perez, EA; Olson, JA Jr; Zujewski, J; Lively, T; Badve, SS; Saphner, TJ; Wagner, LI; Whelan, TJ; Ellis, MJ; Paik, S; Wood, WC; Ravdin, P; Keane, MM; Gomez, HL; Reddy, PS; Goggins, TF; Mayer, IA; Brufsky, AM; Toppmeyer, DL; Kaklamani, VG; Atkins, JN; Berenberg, JL; Sledge, GW
Prior studies with the use of a prospective–retrospective design including archival tumor samples have shown that gene-expression assays provide clinically useful prognostic information. However, a prospectively conducted study in a uniformly treated population provides the highest level of evidence supporting the clinical validity and usefulness of a biomarker.
Final 5-Year Study Results of DASISION: The Dasatinib Versus Imatinib Study in Treatment-Naïve Chronic Myeloid Leukemia Patients Trial
(American Society of Clinical Oncology, 2016) Cortes, JE; Saglio, G; Kantarjian, HM; Baccarani, M; Mayer, J; Boqué, C; Shah, NP; Chuah, C; Casanova, L; Bradley-Garelik, B; Manos, G; Hochhaus, A
Purpose: We report the 5-year analysis from the phase III Dasatinib Versus Imatinib Study in Treatment-Naïve Chronic Myeloid Leukemia Patients (DASISION) trial, evaluating long-term efficacy and safety outcomes of patients with chronic myeloid leukemia (CML) in chronic phase (CP) treated with dasatinib or imatinib. Patients and methods: Patients with newly diagnosed CML-CP were randomly assigned to receive dasatinib 100 mg once daily (n = 259) or imatinib 400 mg once daily (n = 260). Results: At the time of study closure, 61% and 63% of dasatinib- and imatinib-treated patients remained on initial therapy, respectively. Cumulative rates of major molecular response and molecular responses with a 4.0- or 4.5-log reduction in BCR-ABL1 transcripts from baseline by 5 years remained statistically significantly higher for dasatinib compared with imatinib. Rates for progression-free and overall survival at 5 years remained high and similar across treatment arms. In patients who achieved BCR-ABL1 ≤ 10% at 3 months (dasatinib, 84%; imatinib, 64%), improvements in progression-free and overall survival and lower rates of transformation to accelerated/blast phase were reported compared with patients with BCR-ABL1 greater than 10% at 3 months. Transformation to accelerated/blast phase occurred in 5% and 7% of patients in the dasatinib and imatinib arms, respectively. Fifteen dasatinib-treated and 19 imatinib-treated patients had BCR-ABL1 mutations identified at discontinuation. There were no new or unexpected adverse events identified in either treatment arm, and pleural effusion was the only drug-related, nonhematologic adverse event reported more frequently with dasatinib (28% v 0.8% with imatinib). First occurrences of pleural effusion were reported with dasatinib, with the highest incidence in year 1. Arterial ischemic events were uncommon in both treatment arms. Conclusion: These final results from the DASISION trial continue to support dasatinib 100 mg once daily as a safe and effective first-line therapy for the long-term treatment of CML-CP.
Hepatocellular carcinoma surgery outcomes in the developing world: A 20-year retrospective cohort study at the National Cancer Institute of Peru
(Elsevier BV, 2016) Ruiz, E; Rojas Rojas, T; Berrospi, F; Chávez, I; Luque, C; Cano, L; Doimi, F; Pineau, P; Deharo, E; Bertani, S
In the developing world, most patients with hepatocellular carcinoma present with advanced-stage disease, considered to be incurable based on current therapeutic algorithms. Here, we demonstrate that curative liver resection is achievable in a portion of Peruvian patients not addressed by these treatment algorithms. We conducted a retrospective cohort study of 253 hepatocellular carcinoma patients that underwent a curative hepatectomy between 1991 and 2011 at the National Cancer Institute of Peru. The median age of the cohort was 36 years, and merely 15.4% of the patients displayed cirrhosis. The average tumor size was over 14 cm in diameter, resulting in 76.3% of major hepatectomies performed. The 5- and 10-year survival probability estimates were 37.5% and 26.2%, respectively. Age (>44 vs. ≤44 years old; P = 0.005), tumor size (>10 cm vs. ≤10 cm in diameter; P = 0.009), cirrhosis (P < 0.001), satellite lesions (P < 0.001), macroscopic vascular invasion (P < 0.001), allogeneic blood transfusion (P = 0.011), and spontaneous rupture of the tumor (P = 0.006) were independent predictive factors for prognosis. Hepatocellular carcinomas in Peru are characterized by a distinct clinical presentation with notable features compared with those typically described throughout relevant literature. Despite a large number of advanced-stage hepatocellular carcinomas, the outcomes of liver resection observed in the present study were in good standing with the results previously described in other series. It thus appears that staging systems and associated therapeutic algorithms designed for use in the developed world remain inadequate in certain populations, especially in the context of Peruvian patients. Our findings suggest that clinicians in the developing world should reconsider management guidelines pertaining to hepatocellular carcinoma. Indeed, we hypothesize that, in developing countries, a strict adherence to these therapeutic algorithms might create a selection bias resulting in the dismissal of patients who could eventually be treated. Keywords: Cancer; Health sciences; Pathobiology of cancer; Treatment of cancer.
Low-Dose Oral Cyclophosphamide and Methotrexate Maintenance for Hormone Receptor-Negative Early Breast Cancer: International Breast Cancer Study Group Trial 22-00
(American Society of Clinical Oncology, 2017) Colleoni, M; Gray, KP; Gelber,S; Láng, I; Thürlimann, B; Gianni, L; Abdi, EA; Gomez, HL; inderholm, BK; Puglis,i F; Tondini, C; Kralidis, E; Eniu, A; Cagossi, K; Rauch, D; Chirgwin, J; Gelber, RD; Regan, MM; Coates, AS; Price, KN; Viale, G; Goldhirsch, A
Purpose: To evaluate the benefit of low-dose cyclophosphamide and methotrexate (CM) maintenance, which previously demonstrated antitumor activity and few adverse effects in advanced breast cancer, in early breast cancer. Patients and methods: International Breast Cancer Study Group (IBCSG) Trial 22-00, a randomized phase III clinical trial, enrolled 1,086 women (1,081 intent-to-treat) from November 2000 to December 2012. Women with estrogen receptor- and progesterone receptor-negative (< 10% positive cells by immunohistochemistry) early breast cancer any nodal and human epidermal growth factor receptor 2 status, were randomly assigned anytime between primary surgery and 56 days after the first day of last course of adjuvant chemotherapy to CM maintenance (cyclophosphamide 50 mg/day orally continuously and methotrexate 2.5 mg twice/day orally on days 1 and 2 of every week for 1 year) or to no CM. The primary end point was disease-free survival (DFS), which included invasive recurrences, second (breast and nonbreast) malignancies, and deaths. Results: After a median of 6.9 years of follow-up, DFS was not significantly better for patients assigned to CM maintenance compared with patients assigned to no CM, both overall (hazard ratio [HR], 0.84; 95% CI, 0.66 to 1.06;P = .14) and in triple-negative (TN) disease (n = 814; HR, 0.80; 95% CI, 0.60 to 1.06). Patients with TN, node-positive disease had a nonstatistically significant reduced HR (n = 340; HR, 0.72; 95% CI, 0.49 to 1.05). Seventy-one (13%) of 542 patients assigned to CM maintenance did not start CM. Of 473 patients who received at least one CM maintenance dose (including two patients assigned to no CM), 64 (14%) experienced a grade 3 or 4 treatment-related adverse event; elevated serum transaminases was the most frequently reported (7%), followed by leukopenia (2%). Conclusion: CM maintenance did not produce a significant reduction in DFS events in hormone receptor-negative early breast cancer. The trend toward benefit observed in the TN, node-positive subgroup supports additional exploration of this strategy in the TN, higher-risk population.
Concurrent and sequential initiation of ovarian function suppression with chemotherapy in premenopausal women with endocrine-responsive early breast cancer: an exploratory analysis of TEXT and SOFT
(Elsevier Ltd., 2017) Regan, MM; Walley, BA; Francis, PA; Fleming, GF; Láng, I; Gómez, HL; Colleoni, M; Tondini, C; Pinotti, G; Salim, M; Spazzapan, S; Parmar, V; Ruhstaller, T; Abdi, EA; Gelber, RD; Coates, AS; Goldhirsch, A; Pagani, O
Background: Recent breast cancer treatment guidelines recommend that higher-risk premenopausal patients should receive ovarian function suppression (OFS) as part of adjuvant endocrine therapy. If chemotherapy is also given, it is uncertain whether to select concurrent or sequential OFS initiation. Design and methods: We analyzed 1872 patients enrolled in the randomized phase III TEXT and SOFT trials who received adjuvant chemotherapy for hormone receptor-positive, HER2-negative breast cancer and upon randomization to an OFS-containing adjuvant endocrine therapy, initiated gonadotropin-releasing-hormone-agonist triptorelin. Breast cancer-free interval (BCFI) was compared between patients who received OFS concurrently with chemotherapy in TEXT (n = 1242) versus sequentially post-chemotherapy in SOFT (n = 630). Because timing of trial enrollment relative to adjuvant chemotherapy differed, we implemented landmark analysis re-defining BCFI beginning 1 year after final dose of chemotherapy (median, 15.5 and 8.1 months from enrollment to landmark in TEXT and SOFT, respectively). As a non-randomized treatment comparison, we implemented comparative-effectiveness propensity score methodology with weighted Cox modeling. Results: Distributions of several clinico-pathologic characteristics differed between groups. Patients who were premenopausal post-chemotherapy in SOFT were younger on average. The median duration of adjuvant chemotherapy was 18 weeks in both groups. There were 231 (12%) BC events after post-landmark median follow-up of about 5 years. Concurrent use of triptorelin with chemotherapy was not associated with a significant difference in post-landmark BCFI compared with sequential triptorelin post-chemotherapy, either in the overall population (HR = 1.11, 95% CI 0.72-1.72; P = 0.72; 4-year BCFI 89% in both groups), or in the subgroup of 692 women <40 years at diagnosis (HR = 1.13, 95% CI 0.69-1.84) who are less likely to develop chemotherapy-induced amenorrhea. Conclusion: Based on comparative-effectiveness modeling of TEXT and SOFT after about 5 years median follow-up, with limited statistical power especially for the subgroup <40 years, neither detrimental nor beneficial effect of concurrent administration of OFS with chemotherapy on the efficacy of adjuvant therapy that includes chemotherapy was detected.
Glioblastoma of pineal region: report of four cases and literature review
(Future Medicine Ltd., 2017) Orrego Puelles, Enrique; Casavilca Sambrano, Sandro; Garcia-Corrochano, Pamela; Rojas-Meza, S; Castillo, Miluska; Castaneda, Carlos A
We report four cases of glioblastoma in the pineal region. The patients presented a severe headache and vomiting. Brain imaging showed a heterogeneously enhanced tumor in the pineal region with obstructive hydrocephalus. Case 3 developed a subependymal dissemination. The patient went to ventricular-peritoneal shunt and subtotal or total resection and radiotherapy with/without chemotherapy. Cases 1 and 2 received radiation and died 8 and 11 later months. Cases 3 and 4 completed radiotherapy and chemotherapy, and survived 28 and 31 months after the initial diagnosis. Glioblastoma in the pineal region carry a poor prognosis and require neurooncology teams.
Treatment Efficacy, Adherence, and Quality of Life Among Women Younger Than 35 Years in the International Breast Cancer Study Group TEXT and SOFT Adjuvant Endocrine Therapy Trials
(American Society of Clinical Oncology, 2017) Saha, P; Regan, MM; Pagani, O; Francis, PA; Walley, BA; Ribi, K; Bernhard, J; Luo, W; Gómez, HL; Burstein, HJ; Parmar, V; Torres, R; Stewart, J; Bellet, M; Perelló, A; Dane, F; Moreira, A; Vorobiof, D; Nottage, M; Price, KN; Coates, AS; Goldhirsch, A; Gelber, RD; Colleoni, M; Fleming, GF; SOFT TEXT Investigators; International Breast Cancer Study Group
Purpose To describe benefits and toxicities of adjuvant endocrine therapies in women younger than 35 years with breast cancer (n = 582) enrolled in the Suppression of Ovarian Function Trial (SOFT) and Tamoxifen and Exemestane Trial (TEXT). Methods In SOFT, women still premenopausal after surgery with or without chemotherapy were randomly assigned to tamoxifen alone, tamoxifen plus ovarian function suppression (OFS), or exemestane plus OFS. In TEXT, all received OFS with or without concomitant chemotherapy and were randomly assigned to exemestane plus OFS or tamoxifen plus OFS. We summarize treatment efficacy, quality of life, and adherence of the cohort of women younger than 35 years in SOFT and TEXT, alongside data from the cohort of older premenopausal women. Results For 240 human epidermal growth factor receptor 2-negative patients younger than 35 years enrolled in SOFT after receiving chemotherapy, the 5-year breast cancer-free interval (BCFI) was 67.1% (95% CI, 54.6% to 76.9%) with tamoxifen alone, 75.9% with tamoxifen plus OFS (95% CI, 64.0% to 84.4%), and 83.2% with exemestane plus OFS (95% CI, 72.7% to 90.0%). For 145 human epidermal growth factor receptor 2-negative patients younger than 35 years in TEXT, 5-year BCFI was 79.2% (95% CI, 66.2% to 87.7%) with tamoxifen plus OFS and 81.6% (95% CI, 69.8% to 89.2%) with exemestane plus OFS. The most prominent quality of life symptom for patients younger than 35 years receiving OFS was vasomotor symptoms, with the greatest worsening from baseline at 6 months (on the order of 30 to 40 points), but loss of sexual interest and difficulties in becoming aroused were also clinically meaningful (≥ 8-point change). The level of symptom burden was similar in older premenopausal women. A total of 19.8% of women younger than 35 years stopped all protocol-assigned endocrine therapy early. Conclusion In women younger than 35 years with hormone receptor-positive breast cancer, adjuvant OFS combined with tamoxifen or exemestane produces large improvements in BCFI compared with tamoxifen alone. Menopausal symptoms are significant but are not worse than those seen in older premenopausal women.
Treatment of cervical intraepithelial lesions
(Wiley-Blackwell Publishing Ltd, 2017) Castle, PE; Murokora, D; Perez, C; Alvarez, M; Quek, SC; Campbell, C
Precancerous cervical lesions precede the development of invasive cervical cancer by 10–20 years, making cervical cancer preventable if these lesions are detected and effectively treated. Treatment has evolved in the last few decades and now includes ablative options that can be performed in lower-resource settings where surgical excision is not feasible or routinely available. Gas-based cryotherapy, which freezes cervical tissue to induce localized necrosis, is the most commonly used ablative treatment. However, its implementation in low-resource settings is difficult because the refrigerant gas can be difficult to procure and transport, and is expensive. New cryotherapy devices that do not require an external supply of gas appear promising. Thermal coagulation, which burns cervical tissue to induce necrosis, has become more widely available in the last few years owing to its portability and the feasibility of using battery-powered devices. These two ablative treatments successfully eradicate 75%–85% of high-grade cervical lesions and have minor adverse effects.
Anthracyclines in Early Breast Cancer: The ABC Trials-USOR 06-090, NSABP B-46-I/USOR 07132, and NSABP B-49 (NRG Oncology)
(American Society of Clinical Oncology, 2017) Blum, JL; Flynn, PJ; Yothers, G; Asmar, L; Geyer, CE Jr; Jacobs, SA; Robert, NJ; Hopkins, JO; O'Shaughnessy, JA; Dang, CT; Gómez, HL; Fehrenbacher, L; Vukelja, SJ; Lyss, AP; Paul, D; Brufsky, AM; Jeong, JH; Colangelo, LH; Swain, SM; Mamounas, EP; Jones, SE; Wolmark, N
Purpose Docetaxel and cyclophosphamide (TC) was superior to doxorubicin and cyclophosphamide (AC) in a trial in early breast cancer. However, activity of TC relative to AC regimens with a taxane (TaxAC) is unknown. Methods In a series of three adjuvant trials, women were randomly assigned to TC for six cycles (TC6) or to a standard TaxAC regimen. US Oncology Research (USOR) 06-090 compared TC6 with docetaxel, doxorubicin, and cyclophosphamide (TAC6). National Surgical Adjuvant Breast and Bowel Project (NSABP) B-46-I/USOR 07132 compared TC6, TAC6, or TC6 plus bevacizumab. NSABP B-49 compared TC6 with several standard AC and taxane combination regimens. Before any analysis of individual trials, a joint efficacy analysis of TC versus the TaxAC regimens was planned, with invasive disease-free survival (IDFS) as the primary end point. Patients who received TC6 plus bevacizumab on NSABP B-46-I/USOR 07132 were not included. A hazard ratio (HR) from a stratified Cox model that exceeded 1.18 for TC6 versus TaxAC was predefined as inferiority for TC6. The prespecified interim monitoring plan was to report for futility if the HR was > 1.18 when 334 IDFS events were observed (50% of 668 events required for definitive analysis). Results A total of 2,125 patients were randomly assigned to receive TC6 regimens and 2,117 patients were randomly assigned to receive TaxAC regimens. The median follow-up time was 3.3 years. There were 334 IDFS events, and the HR for TC6 versus TaxAC was 1.202 (95% CI, 0.97 to 1.49), which triggered early reporting for futility. The 4-year IDFS was 88.2% for TC6 and was 90.7% for TaxAC ( P = .04). Tests for treatment interaction by protocol, hormone receptor status, and nodal status were negative. Conclusion The TaxAC regimens improved IDFS in patients with high-risk human epidermal growth factor receptor 2-negative breast cancer compared with the TC6 regimen.
Nevoid basal-cell carcinoma syndrome (Gorlin Syndrome): report of two cases and review of the literature
(Instituto Nacional de Salud, 2017) Castro-Mujica, María del Cármen; Barletta-Carrillo, Claudia; Poterico, Julio A.; Acosta, María; Valer, Jaurigue,; De La Cruz Sacasqui, Jesús Miguel
Gorlin syndrome (GS) is a genetic disorder with an autosomal dominant inheritance pattern, with complete penetrance and variable expressivity. GS is caused by germline mutations in the genes PTCH1 or SUFU, which are components of the Sonic hedgehog molecular pathway. GS is characterized by the presence of multiple nevoid basal cell carcinomas, odontogenic cysts, calcification of the brain sickle, and lesions in the palms and soles. This study is the first to report cases in Peru of patients with GS who underwent genetic evaluation and counseling. We present two GS cases that meet the clinical criteria for the syndrome and review the literature.
Metronomic chemotherapy for non-metastatic triple negative breast cancer: Selection is the key
(Baishideng Publishing Group, 2017) Rabanal, Connie; Ruiz, Rossana; Neciosup, Silvia; Gomez, Henry L
Triple negative breast cancer (TNBC) accounts for 15%-20% of all breast cancer, and is still defined as what it is not. Currently, TNBC is the only type of breast cancer for which there are no approved targeted therapies and maximum tolerated dose chemotherapy with taxanes and anthracycline-containing regimens is still the standard of care in both the neoadjuvant and adjuvant settings. In the last years, metronomic chemotherapy (MC) is being explored as an alternative to improve outcomes in TNBC. In the neoadjuvant setting, purely metronomic and hybrid approaches have been developed with the objective of increasing complete pathologic response (pCR) and prolonging disease free survival. These regimens proved to be very effective achieving pCR rates between 47%-60%, but at the cost of great toxicity. In the adjuvant setting, MC is used to intensify adjuvant chemotherapy and, more promisingly, as maintenance therapy for high-risk patients, especially those with no pCR after neoadjuvant chemotherapy. Considering the dismal prognosis of TNBC, any strategy that potentially improves outcomes, specially being the oral agents broadly available and inexpensive, should be considered and certainly warrants further exploration. Finally, the benefit of MC needs to be validated in properly designed clinical trials were the selection of the population is the key.
Early-onset liver cancer in South America associates with low hepatitis B virus DNA burden
(Nature Publishing Group, 2018) Marchio, A; Cerapio, JP; Ruiz, E; Cano, L; Casavilca-Sambrano, S; Terris, B; Deharo, E; Dejean, A; Bertani, S; Pineau, P
In Peru, hepatocellular carcinoma (HCC) arises in young non-cirrhotic patients. Hepatitis B virus (HBV) is suspected to be the prominent etiological agent. We thus performed a comprehensive molecular study of HBV infection in 65 Peruvian HCC patients. Only 51% were considered as persistently infected at the onset. HBV DNA was found by PCR in the tumor and/or matched non-tumor liver tissues in more than 80% of cases (n = 53/65). HBV DNA was significantly more abundant in livers of younger patients than in those of the older ones. We consistently observed low viral DNA burden (0.1-6.5 copies for 100 cells), with viral genomes in younger patients displaying higher proportion of mutations at di-pyrimidines (TpT and CpC, P = 0.006). A drastic activation of multiple DNA repair pathways in tumors of younger patients was observed. Our observations clearly challenge the current vision that associates high HBV DNA load with earlier tumor development. We concluded that in Peru, and maybe in other populations with Americas' indigenous ancestry, HBV-associated liver tumorigenesis might differ significantly from that generally observed in the rest of the world. Procedures used to screen for HCC development in subjects at risk should be adapted to the local situation.

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