Alessandro Leal

Direct detection of early-stage cancers using circulating tumor DNA

Noninvasive liquid biopsy analysis of circulating tumor DNA permits direct detection of early-stage cancers. Finding smaller needles in haystacks The detection and analysis of cell-free DNA in patients’ blood are becoming increasingly accepted in oncology. However, this approach has generally been applied for the monitoring of patients with existing tumors. It has not been useful for early diagnosis of cancer because of insufficient sensitivity to detect really small tumors that only shed minute quantities of DNA into the blood, as well as difficulties with identifying cancer-associated genetic changes without knowing what mutations are present in the primary tumor. A method developed by Phallen et al., called targeted error correction sequencing, addresses both of these limitations and demonstrates the feasibility of detecting circulating cell-free DNA from many early tumors, suggesting its potential use for cancer screening. Early detection and intervention are likely to be the most effective means for reducing morbidity and mortality of human cancer. However, development of methods for noninvasive detection of early-stage tumors has remained a challenge. We have developed an approach called targeted error correction sequencing (TEC-Seq) that allows ultrasensitive direct evaluation of sequence changes in circulating cell-free DNA using massively parallel sequencing. We have used this approach to examine 58 cancer-related genes encompassing 81 kb. Analysis of plasma from 44 healthy individuals identified genomic changes related to clonal hematopoiesis in 16% of asymptomatic individuals but no alterations in driver genes related to solid cancers. Evaluation of 200 patients with colorectal, breast, lung, or ovarian cancer detected somatic mutations in the plasma of 71, 59, 59, and 68%, respectively, of patients with stage I or II disease. Analyses of mutations in the circulation revealed high concordance with alterations in the tumors of these patients. In patients with resectable colorectal cancers, higher amounts of preoperative circulating tumor DNA were associated with disease recurrence and decreased overall survival. These analyses provide a broadly applicable approach for noninvasive detection of early-stage tumors that may be useful for screening and management of patients with cancer.

Angioimmunoblastic T-Cell Lymphoma: Clinical Aspects and Recent Advances in Biology and Therapy

Angioimmunoblastic T-cell lymphoma (AITL) comprehends 20% of the peripheral T-cell lymphomas (PTCL). Although rare, its clinical features may overlap with many other inflammatory, infectious or neoplastic disorders. Therefore, that patients are often diagnosed with advanced stage disease, which contributes for the disease´s dismal prognosis. The clinical presentation of AITL is frequently an assemblage of symptoms including generalized and painful lymphadenopathy, multiple cutaneous alterations, hypergammaglobulinemia, fever, loss of weight and significant autoimmune phenomena. Recent advances in AITL biology have implicated a cell with T-follicular helper phenotype as the origin of the disorder. This rare type of T lymphocyte has a peculiar capacity of interact with microenviroment, which results in an important production of cytokines, explaining the clinical findings of this type of lymphoma. In addition to its pathologic features, AITL can be distinguished from other T-cell lymphomas based on gene expression arrangement, suggesting that AITL has a unique biology. Moreover, somatic mutations in the epigenetic regulators DNMT3A, TET2, IDH2, and, especially, in the multifunctional RHOA GTPase gene, have emerged as very consistent genetic abnormalities in AITL. Considering its low incidence, the development of clinical trials in AITL is a challenging matter. Furthermore, the majority of data available originates from studies that contain other subtypes of PTCL, making prognosis analysis and treatment decision a tough work. In this review, we discuss the biological and clinical aspects of AITL and the alternatives for frontline treatment and the management of relapsed disease.

Metronomic chemotherapy (MC) in the neoadjuvant setting: Results of two parallel feasibility trials in patients (pts) with HER2 positive (HER2+) and negative (HER2-) locally advanced breast cancer (LABC) (Traq-Me and TAME).

197 Background: In a previous randomized trial (SWOG 0012), MC seemed to improve pCR rates compared to standard anthracycline/taxane neoadjuvant chemotherapy (NC). We aimed to evaluate the feasibility of MC with a taxane→anthracycline schedule, which has also been shown potentially superior to the reverse sequence [J Clin Oncol 28:15s, 2010 (suppl; abstr 548)]. We also aimed to establish the feasibility of MC in combination with trastuzumab. METHODS The original accrual goal was 25 HER2+ pts and 40 HER2- pts. HER2- pts received MC consisting of paclitaxel (100mg/m2) x8 weeks followed by doxorubicin (24mg/m2) x9 weeks combined with oral cyclophosphamide (100mg/day), without G-CSF. HER2+ pts also received trastuzumab (4 mg/kg followed by 2mg/kg) concurrently with the entire CT. OBJECTIVES Primary: To evaluate the feasibility of these schedules (defined as a febrile neutropenia [FN] rate no higher than 10%). Secondary: cardiac safety and general tolerability; efficacy as measured by objective clinical, radiological and pathologic complete response (pCR). RESULTS Almost all pts were staged as III (TraQme 8/9 88% and MeTo 4/11 36%). The HER2+ cohort was prematurely closed after 2 (22%) pts developed G3 pneumonitis (during the metromonic phase). Both responded to medical treatment and recovered. One pt had G2 hand-foot skin reaction (HFS) and another had G2 mucositis. The HER2- cohort was also prematurely closed with only 11 pts because of high rates of mucocutaneous toxicity (G3 HFS in 36%, G3 rash in 9%) and also due to the recent SWOG0221 negative results. There were 2 (18%) cases of FN and 3 (27%) of G4 neutropenia in this cohort, but no cases of pneumonitis. 1/11(9%) HER2- and 5/9HER2+(55%) pts had a pCR. VEGF pathway-related biomarkers were collected and will be presented at a later date. CONCLUSIONS The proposed MC schedules proved too toxic to be considered for further clinical development. In addition, MC resulted in unexpectedly high rates of severe pulmonary toxicity when given in combination with trastuzumab. HER2+ but not HER2- pts had an impressively high pCR rate.

Standard cisplatin and etoposide (PE)-based chemotherapy in young adult patients with pineal germinomas.

e12547 Background: Pineal germ cell tumors are very rare, accounting for less than 1% of all intracranial tumors. The peak incidence occurs in the second decade of life. The mainstay of therapy is radiation, especially for germinomas that are very radiosensitive. Leptomeningeal dissemination and histology seem to confer a higher risk for recurrence after radiation. These tumors are also very sensitive to chemotherapy. Attempts to decrease the dose and field of radiation or even to avoid radiotherapy at all have been published. However, the experience with the adult population is very limited. We review retrospectively our experience in adult patients with PGCT that received cisplatin and etoposide-based (PE) chemotherapy in two Brazilian instituition in the last five years. Methods: Consecutive review of patient charts of the last five years of two Brazilian instituitions (Instituto do Cancer de Sao Paulo and Hospital A. C. Camargo). Results: In the last 5 years we identified 6 young adult patients bearin...