Atypical pattern of response in rectal cancer after neoadjuvant pembrolizumab treatment: a case report, literature review, and proposed management model.

Background: Immunotherapy is the first-line treatment in patients with advanced microsatellite instability-high (MSI-H) or deficient mismatch repair (dMMR) colorectal cancer (CRC). Although immune checkpoint inhibitors (ICIs) for locally advanced rectal cancer (LARC) are not yet a standard, the results are very encouraging and raise the question of whether patients with clinical complete response (cCR) could receive nonoperative management (NOM). However, different patterns of response have challenged management strategies. Case Description: A 34-year-old woman diagnosed with dMMR LARC started treatment with capecitabine 2,000 mg/m2 on day 1 to 14 and oxaliplatin 130 mg/m2 on day 1 and every 21 days. Magnetic resonance imaging (MRI), performed three cycles later, showed local progression of the primary rectal lesion, which at that time had new peritoneal reflex involvement. A new hepatic lesion in segment V was observed. Due to disease progression, she was administered pembrolizumab 200 mg every 21 days. After three cycles, a discordant radiological response was observed on a new MRI scan that showed a complete response of the liver lesion and magnetic resonance tumor regression grade (mrTRG) 1 in the rectum. However, new involvement of the mesentery and enlargement of the regional lymph nodes (LNs) were also evident. A new colonoscopic biopsy was performed, showing no cancerous cells. She underwent surgery on the rectum and liver lesion. Pathology showed a complete response of the rectal wall and liver lesion, but 1 of 22 LNs was positive for adenocarcinoma (ypT0 N1 M0). The patient continued on pembrolizumab, and 14 months after surgery, she had not relapsed. Conclusions: Neoadjuvant immunotherapy for rectal cancer requires new recommendations for the assessment of clinical response. Pseudoprogression should be ruled out as an atypical response before deciding on surgical treatment. We propose an algorithm to address pseudoprogression in this setting.

Precision medicine in the real-world setting. Clinical activity of talazoparib in a woman with hormone receptor-positive HER2-negative metastatic breast cancer with pathogenic mutation in somatic BRCA2.

Background: Next-generation sequencing (NGS) has proven to be a key implementation to understanding biological pathways involved in cancer. In daily practice, the identification of somatic and germline mutations has allowed physicians to gather relevant information to make therapeutic decisions and benefit patients. Importantly, somatic mutations provide targeted opportunities for treatment and reveal resistance mechanisms to understand patients' tumour evolution. Scanty data in clinical trials and in a real-world setting is available regarding the utility of poly(ADP-ribose) polymerase inhibitors in pathogenic or likely-pathogenic somatic breast cancer gene 1/2 (BRCA1/2) mutations and/or germline or somatic Homologous Recombination-Related Gene mutations in advanced breast cancer (ABC). Case report: Here we report a real-life case of a 47-year-old postmenopausal woman with hormone receptor-positive (HR-positive) Epidermal growth factor receptor 2 (HER2)-negative metastatic BC that had poor response to classic therapeutic strategies for HR+/HER2- ABC. At this point, the possibility of using NGS to guide the treatment was decided in a Molecular Tumour Board (MTB), and the patient had a major response to talazoparib targeting a non-germline BRCA2 mutation. Conclusion: Undoubtedly, more information regarding the cost effectiveness of NGS is needed to develop adequate reimbursement policies for this technology. It should be highlighted that the generalisation of MTBs and the implementation of molecular screening programmes are greatly needed in our region to gain more knowledge of somatic mutations implicated in the Hispanic and Latin-American population with BC diagnosis. Recently presented results of randomised studies may support the evaluation of somatic mutations with NGS to find targeted therapies for ABC patients.

Implementation of a virtual multicenter gastrointestinal tumor board to reduce cancer disparities in Argentina.

Given the increasing complexity of cancer care, multidisciplinary tumor boards have become essential in daily clinical oncology practice. The Project Extension for Community Healthcare Outcomes (ECHO) initiative developed an innovative telementoring model using a "hub and spoke" design consisting of a team of experts (hub) that offers a full service to multiple participants (the spokes) during regularly scheduled sessions discussing patients' clinical cases. The Alexander Fleming Cancer Institute in Buenos Aires was the first hub in Latin America to implement Project ECHO for gastrointestinal tumors. In our 3-year experience, 80 patients from 37 centers were evaluated within Project ECHO and a range of three to five cases were discussed in each meeting. From our perspective, the impact of this novel approach was a remarkable strategy to reduce care disparities by equalizing access to high-quality medical knowledge in a multidisciplinary environment for medical discussions. Additionally, it was shown to have a cost-effective impact directly on the patients and the local health system, since relevant costs were saved after unnecessary treatments, studies and travel expenses were avoided.

PALB2 germline mutations in a multi-gene panel testing cohort of 1905 breast-ovarian cancer patients in Argentina.

PURPOSE: PALB2 variants have been scarcely described in Argentinian and Latin-American reports. In this study, we describe molecular and clinical characteristics of PALB2 mutations found in multi-gene panels (MP) from breast-ovarian cancer (BOC) families in different institutions from Argentina. METHODS: We retrospectively identified PALB2 pathogenic (PV) and likely pathogenic (LPV) variants from a cohort of 1905 MP results, provided by one local lab (Heritas) and SITHER (Hereditary Tumor Information System) public database. All patients met hereditary BOC clinical criteria for testing, according to current guidelines. RESULTS: The frequency of PALB2 mutations is 2.78% (53/1905). Forty-eight (90.5%) are PV and five (9.5%) are LPV. Most of the 18 different mutations (89%) are nonsense and frameshift types and 2 variants are novel. One high-rate recurrent PV (Y551*) is present in 43% (23/53) of the unrelated index cases. From the 53 affected carriers, 94% have BC diagnosis with 14% of bilateral cases. BC phenotype is mainly invasive ductal (78%) with 62% of hormone-receptor positive and 22% of triple negative tumors. Self-reported ethnic background of the cohort is West European (66%) and native Latin-American (20%) which is representative of Buenos Aires and other big urban areas of the country. CONCLUSION: This is the first report describing molecular and clinical characteristics of PALB2 carriers in Argentina. Frequency of PALB2 PV in Argentinian HBOC families is higher than in other reported populations. Y551* is a recurrent mutation that seems to be responsible for almost 50% of PALB2 cases.

Cyclin-Dependent Kinase 4/6 Inhibitor Outcomes in Patients With Advanced Breast Cancer Carrying Germline Pathogenic Variants in DNA Repair-Related Genes.

PURPOSE: In recent years, unprecedented benefits have been observed with the development of cyclin-dependent kinase (CDK) 4 and 6 inhibitors for the treatment of hormone receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer. However, there is scarce evidence of their value in specific populations, such as patients carrying germline pathogenic variants in DNA repair-related genes. PATIENTS AND METHODS: We retrospectively studied the efficacy of CDK 4/6 inhibitors plus endocrine therapy in patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer. Three cohorts were compared, including patients harboring germline pathogenic variants in DNA repair-related genes (gBRCA1/2-ATM-CHEK2 mutated), those tested without these mutations (wild type [WT]), and the nontested subgroup. Relevant prognostic factors including age, metastatic site (visceral v nonvisceral), Eastern Cooperative Oncology Group, and prior treatment with CDK 4/6 inhibitors were stratified by univariate and multivariate Cox regression models. RESULTS: Among the total population (n = 217), 15 (6.9%) patients carried gBRCA1/2 (n = 10)-ATM (n = 4)-CHEK2 (n = 1) pathogenic variants, 45 (20.7%) were WT, and 157 (72.4%) were nontested. Gene pathogenic variant carriers were younger (P < .001). Most patients (164, 75.6%) had not received prior endocrine therapy in the advanced setting. Median progression-free survival was shorter in patients with evaluated germline pathogenic variants (10.2 months [95% CI, 5.7 to 14.7]), compared with WT and nontested patients (15.6 months [95% CI, 7.8 to 23.4], and (17.6 months [95% CI, 12.9 to 22.2]; P = .002). Consistently, a worse median overall survival was observed in the subgroup with germline pathogenic variants than in the WT group (P = .006). Multivariable analysis showed that mutation status was an independent prognostic factor of progression-free survival (P = .020) and overall survival (P = .012). CONCLUSION: In this retrospective real-world study, gBRCA1/2-ATM-CHEK2 pathogenic variants were independently associated with poor outcomes in patients with advanced breast cancer treated with CDK4/6 inhibitors.

¿Cuál es el impacto emocional de los resultados de estudios genéticos en pacientes oncológicos con sospecha de síndrome hereditario para cáncer? / What is the emotional impact of the genetic test results on oncologic patients with suspected hereditary cancer syndrome?

Objetivos: valorar el impacto emocional de recibir los resultados del estudio genético (EG) en pacientes con antecedente oncológico personal y sospecha de síndrome hereditario, aplicando el Cuestionario Multidimensional del Impacto de la evaluación de riesgo de cáncer (MICRA). Método: 219 pacientes con diagnóstico oncológico que concurrieron a la consulta de Asesoramiento Genético Oncológico en el Instituto Alexander Fleming entre 2014 y 2019, fueron evaluados aplicando el MICRA. Resultados: Edad promedio 49,84 (42,21; 62,02), 82,2% con diagnóstico de cáncer de mama. En un 16% se halló una variante patogénica (VP). La media de los puntajes obtenidos por cada subescala fue: 5,26 (DS=4,48, rango 0-22) para Malestar Emocional (ME); 12,31 (DS 7,42 rango 0-37) para Incertidumbre (I); 16,36 (DS 4.30 rango 2-20) para Experiencias Positivas (EP) y de 34,37 (DS 10,24 rango 8-62) para la puntuación global, lo que muestra un bajo nivel de ME e I y la presencia de EP entre los pacientes. Se hallaron diferencias significativas según tipo de resultado: los portadores de VP, mostraron una modesta elevación del nivel de ME y menor puntuación en EP, respecto de aquellos que tuvieron resultados no informativos o inciertos. Sin diferencias significativas según edad, pacientes con o sin hijos, o tiempo entre la realización del estudio y la aplicación del cuestionario. Conclusiones: Recibir resultados de estudio genético no produciría un impacto psicológico adverso. Las puntuaciones altas de esta escala podrían ser usadas para identificar a pacientes con malestar emocional y ofrecerles un seguimiento psicooncológico específico (AU)

Objective: The aim of our study is to assess the emotional impact of genetic test results disclosure to patients with a personal cancer history and suspected hereditary syndrome, applying the Multidimensional Impact of Cancer Risk Assessment (MICRA) Questionnaire. Methods: two hundred nineteen patients affected with cancer, referred to the Cancer Genetic Counseling department at the Alexander Fleming Institute, between 2014 and 2019, were evaluated using the MICRA questionnaire. Results: Average age 49.84 (42,21; 62,02), 82.2% presented breast cancer. In 16% a pathogenic variant (PV) was found. The mean of the scores obtained for each subscale in the questionnaire was 5.26 (0-22, SD 4.48) for Distress (D); 12.31 (0-37, DS 7.42) for Uncertainty (U); 16.36 (2-20 SD 4.30) for Positive Experiences (PE) and 34.37 (8-62 SD 10.24) for the global score, which shows a low level of D and U and the presence of PE among the patients. Significant differences were found according to the type of result: We found modestly increased distress in PV carriers compared to patients who received uninformative or negative test results. No significant differences according to age, patients with or without children, or time between the completion of the genetic test and the application of the questionnaire. Conclusion: Genetic test disclosure does not seem to produce an adverse psychological impact. High scores on this scale could be used to identify patients with emotional distress and offer them specific psycho-oncological follow-up (AU)

A snapshot of current genetic testing practice in Lynch syndrome: The results of a representative survey of 33 Latin American existing centres/registries.

We aimed to assess the current genetics practice to manage patients with Lynch syndrome (LS) across Latin America. A Latin American LS survey was sent out to 52 centres/registries, comprising a total of 12 countries from the region. Overall, 33 centres completed the survey, of which the oldest LS registry was established in 1992 in Sao Paulo (Brazil), and the youngest this year in San Jose (Costa Rica). In total, 87% (26/30) of the participating centres/registries belonging to the nine countries are performing genetic testing. Overall, 1352 suspected families were sequenced. Pathogenic variants were identified in 34% of the families, with slightly differing distribution of variants between females and males. Path_MLH1 variants were identified in 39% of females and 50% of males (p = 0.023), while path_MSH2 were identified in 37% of females and males, followed by path_PMS2 in 11% of females and 8% of males, path_MSH6 in 13% of females and 3% of males (p < 0.001) and path_EPCAM in 0.3% of females and 2% of males. In Latin America, 9 of 12 (75%) participating countries had implemented healthcare for LS. LS screening is inconsistently applied within Latin America healthcare systems because of structural differences in the healthcare systems between the countries.

Phenotypic and Functional Dysregulated Blood NK Cells in Colorectal Cancer Patients Can Be Activated by Cetuximab Plus IL-2 or IL-15.

The clinical outcome of colorectal cancer (CRC) is associated with the immune response; thus, these tumors could be responsive to different immune therapy approaches. Natural killer (NK) cells are key antitumor primary effectors that can eliminate CRC cells without prior immunization. We previously determined that NK cells from the local tumor environment of CRC tumors display a profoundly altered phenotype compared with circulating NK cells from healthy donors (HD). In this study, we evaluated peripheral blood NK cells from untreated patients and their possible role in metastasis progression. We observed profound deregulation in receptor expression even in early stages of disease compared with HD. CRC-NK cells displayed underexpression of CD16, NKG2D, DNAM-1, CD161, NKp46, and NKp30 activating receptors, while inhibitory receptors CD85j and NKG2A were overexpressed. This inhibited phenotype affected cytotoxic functionality against CRC cells and interferon-γ production. We also determined that NKp30 and NKp46 are the key receptors involved in detriment of CRC-NK cells' antitumor activity. Moreover, NKp46 expression correlated with relapse-free survival of CRC patients with a maximum follow-up of 71 months. CRC-NK cells also exhibited altered antibody-dependent cellular cytotoxicity function responding poorly to cetuximab. IL-2 and IL-15 in combination with cetuximab stimulated NK cell, improving cytotoxicity. These results show potential strategies to enhance CRC-NK cell activity.

Altered phenotype in peripheral blood and tumor-associated NK cells from colorectal cancer patients.

Despite NK cells being originally identified because of their ability to kill tumor cells in vitro, only limited information is available on NK cells infiltration of malignant tumors, especially in humans. NK cells infiltrating human colorectal carcinomas (CRCs) were analyzed to identify their potential protective role in an antitumor immune response. The expression and function of relevant molecules were analyzed from different sources, comparing tumor-associated NK cells (TANKs) with autologous peripheral blood NK cells (PB-NKs) from CRC patients-the latter in comparison with PB-NKs from normal donors. TANKs displayed a profound alteration of their phenotype with a drastic reduction of NK cell receptor expression. Co-culture experiments showed that CRC cells produce modulation in NK phenotype and functionality. Moreover, PB-NKs from CRC patients also exhibited an altered phenotype and profound defects in the ability to activate degranulation and IFN-γ production. For the first time, TANK and PB-NK cells from CRC patients have been characterized. It is shown that they are not capable of producing relevant cytokines and degranulate. Taken together, our results suggest that NK cells from CRC patients present alterations of phenotype and function therefore supporting the progression of cancer.

Metallothionein expression in colorectal cancer: relevance of different isoforms for tumor progression and patient survival.

Metallothioneins are a family of small, cysteine-rich proteins with many functions. Immunohistochemical evaluation of all metallothionein 1 + 2 isoforms in colorectal tumors has demonstrated an important down-regulation compared with normal tissue, although its prognostic significance is unclear. Moreover, the contribution of individual isoforms to overall metallothionein down-regulation is not known. To address these important issues, we analyzed the messenger RNA expression levels of all functional metallothionein 1 + 2 isoforms by quantitative reverse transcription polymerase chain reaction in 22 pairs of normal and tumor-microdissected epithelia and correlated these to the overall immunohistochemical protein expression. Our results showed that 5 isoforms (MT1G, 1E, 1F, 1H, and 1M) were lost during the transition from normal mucosa to tumor, whereas MT1X and MT2A were less down-regulated, and their expression was correlated with overall protein positivity. Second, we showed that MT1G hypermethylation occurred in cell lines and in 29% of tumor samples, whereas histone deacetylase inhibitors are able to induce most isoforms. Furthermore, we analyzed by immunohistochemistry 107 normal mucosae, 25 adenomas, 81 carcinomas, and 19 lymph node metastases to evaluate metallothionein expression during different stages of cancer development and to assess its relationship to patient survival. A lower immunohistochemical expression was associated with poorer survival, although it was not an independent predictor. Overall, this study identifies for the first time the relevant metallothionein isoforms for colorectal cancer progression, supports the concept that their loss is associated with worse prognosis, and suggests 2 mechanisms for epigenetic repression of metallothionein expression in colorectal tumors.