Multiomic analysis of HER2-enriched and AR-positive breast carcinoma with apocrine differentiation and an oligometastatic course: a case report.

Breast carcinoma is the most prevalent cancer among women globally. It has variable clinical courses depending on the stage and clinical-biological features. This case report describes a 56-year-old female with invasive breast cancer without estrogen or progesterone receptor expression, with apocrine differentiation, and with no germline variants in the BRCA1 and BRCA2 genes. Throughout the clinical course, the patient exhibited discordant results for HER2 in immunohistochemistry and in situ hybridization. During the second relapse, the disease displayed apocrine microscopic features. The tumor underwent analysis for the androgen receptor, GCDFP-15, RNA-seq, and whole-genome sequencing (WGS) to identify the breast cancer subtype and to characterize the cancer genome. Our bioinformatic analysis revealed 20,323 somatic SNV/Indels, including five mutations in cancer-related genes that are believed to be responsible for the tumor's development. Two of these mutations were found in the PIK3CA and TP53 genes. Furthermore, the tumor tissue exhibited large copy number alterations to the chromosomes, which could impact gene expression through complex mechanisms and contribute to the tumor phenotype. Clustering algorithms applied on RNA-sequencing data categorized this cancer as a HER2+ subtype. The second-line capecitabine chemotherapy treatment is ongoing, and the patient is responding well. Bioinformatic results support the current treatment decision and open the way to further treatments.

Different quality of treatment in retroperitoneal sarcomas (RPS) according to hospital-case volume and surgeon-case volume: a retrospective regional analysis in Italy.

BACKGROUND: Retroperitoneal sarcomas (RPS) should be surgically managed in specialized sarcoma centers. However, it is not clearly demonstrated if clinical outcome is more influenced by Center Case Volume (CCV) or by Surgeon Case Volume (SCV). The aim of this study is to retrospectively explore the relationship between CCV and SCV and the quality of surgery in a wide region of Northern Italy. METHODS: We retrospectively collected data about patients M0 surgically treated for RPSs in 22 different hospitals from 2006 to 2011, dividing them in two hospital groups according to sarcoma clinical activity volume (HCV, high case volume or LCV, low case volume hospitals). The HCV group (> 100 sarcomas observed per year) included a Comprehensive Cancer Center (HVCCC) with a high sarcoma SCV (> 20 cases/year), and a Tertiary Academic Hospital (HVTCA) with multiple surgeon teams and a low sarcoma SCV (≤ 5 cases/year for each involved surgeon). All other hospitals were included in the LCV group (< 100 sarcomas observed per year). RESULTS: Data regarding 138 patients were collected. Patients coming from LCV hospitals (66) were excluded from the analysis as prognostic data were frequently not available. Among the 72 remaining cases of HCV hospitals 60% of cases had R0/R1 margins, with a more favorable distribution of R0/R1 versus R2 in HVCCC compared to HVTCA. CONCLUSIONS: In HCV hospitals, sarcoma SCV may significantly influence RPS treatment quality. In low-volume centers surgical reports can often miss important prognostic issues and surgical quality is generally poor.

Discovery of methylated circulating DNA biomarkers for comprehensive non-invasive monitoring of treatment response in metastatic colorectal cancer.

OBJECTIVE: Mutations in cell-free circulating DNA (cfDNA) have been studied for tracking disease relapse in colorectal cancer (CRC). This approach requires personalised assay design due to the lack of universally mutated genes. In contrast, early methylation alterations are restricted to defined genomic loci allowing comprehensive assay design for population studies. Our objective was to identify cancer-specific methylated biomarkers which could be measured longitudinally in cfDNA (liquid biopsy) to monitor therapeutic outcome in patients with metastatic CRC (mCRC). DESIGN: Genome-wide methylation microarrays of CRC cell lines (n=149) identified five cancer-specific methylated loci (EYA4, GRIA4, ITGA4, MAP3K14-AS1, MSC). Digital PCR assays were employed to measure methylation of these genes in tumour tissue DNA (n=82) and cfDNA from patients with mCRC (n=182). Plasma longitudinal assessment was performed in a patient subset treated with chemotherapy or targeted therapy. RESULTS: Methylation in at least one marker was detected in all tumour tissue samples and in 156 mCRC patient cfDNA samples (85.7%). Plasma marker prevalence was 71.4% for EYA4, 68.5% for GRIA4, 69.7% for ITGA4, 69.1% for MAP3K14-AS1% and 65.1% for MSC. Dynamics of methylation markers was not affected by treatment type and correlated with objective tumour response and progression-free survival. CONCLUSION: This five-gene methylation panel can be used to circumvent the absence of patient-specific mutations for monitoring tumour burden dynamics in liquid biopsy under different therapeutic regimens. This method might be proposed for assessing pharmacodynamics in clinical trials or when conventional imaging has limitations.

Long-term survival after multidisciplinary management of a metastatic sarcomatoid porocarcinoma with repeated exeresis, radiotherapy, chemotherapy and cetuximab: case report and review of literature.

Eccrine porocarcinoma is a rare and aggressive skin neoplasm; only two cases of sarcomatoid differentiation have been reported. Whereas surgery is effective as first line treatment, optimal management of recurrent or metastatic porocarcinoma is not defined and needs multidisciplinary approach. Here we described the first reported case of metastatic sarcomatoid porocarcinoma. Our patient experienced multiple recurrences, mainly loco-regional, and was treated with a multidisciplinary treatment, involving surgery, radiotherapy, chemotherapy and target therapy, leading to a more than 4 years survival, from the first recurrence. We conclude that multidisciplinary approach in metastatic porocarcinoma must involve surgeon, radiotherapist and medical oncologist. The combination of local and systemic treatments can delay recurrence and prolong survival also in very aggressive cases.

Acquired RAS or EGFR mutations and duration of response to EGFR blockade in colorectal cancer.

Blockade of the epidermal growth factor receptor (EGFR) with the monoclonal antibodies cetuximab or panitumumab is effective in a subset of colorectal cancers (CRCs), but the emergence of resistance limits the efficacy of these therapeutic agents. At relapse, the majority of patients develop RAS mutations, while a subset acquires EGFR extracellular domain (ECD) mutations. Here we find that patients who experience greater and longer responses to EGFR blockade preferentially develop EGFR ECD mutations, while RAS mutations emerge more frequently in patients with smaller tumour shrinkage and shorter progression-free survival. In circulating cell-free tumour DNA of patients treated with anti-EGFR antibodies, RAS mutations emerge earlier than EGFR ECD variants. Subclonal RAS but not EGFR ECD mutations are present in CRC samples obtained before exposure to EGFR blockade. These data indicate that clonal evolution of drug-resistant cells is associated with the clinical outcome of CRC patients treated with anti-EGFR antibodies.

Current therapeutic strategies for advanced pancreatic cancer: A review for clinicians.

Pancreatic cancer (PC) would become the second leading cause of cancer death in the near future, despite representing only 3% of new cancer diagnosis. Survival improvement will come from a better knowledge of risk factors, earlier diagnosis, better integration of locoregional and systemic therapies, as well as the development of more efficacious drugs rising from a deeper understanding of disease biology. For patients with unresectable, non-metastatic disease, combined strategies encompassing primary chemotherapy and radiation seems to be promising. In fit patients, new polychemotherapy regimens can lead to better outcomes in terms of slight but significant survival improvement associated with a positive impact on quality of life. The upfront use of these regimes can also increase the rate of radical resections in borderline resectable and locally advanced PC. Second line treatments showed to positively affect both overall survival and quality of life in fit patients affected by metastatic disease. At present, oxaliplatin-based regimens are the most extensively studied. Nonetheless, other promising drugs are currently under evaluation. Presently, in addition to surgery and conventional radiation therapy, new locoregional treatment techniques are emerging as alternative options in the multimodal approach to patients or diseases not suitable for radical surgery. As of today, in contrast with other types of cancer, targeted therapies failed to show relevant activity either alone or in combination with chemotherapy and, thus, current clinical practice does not include them. Up to now, despite the fact of extremely promising results in different tumors, also immunotherapy is not in the actual therapeutic armamentarium for PC. In the present paper, we provide a comprehensive review of the current state of the art of clinical practice and research in PC aiming to offer a guide for clinicians on the most relevant topics in the management of this disease.

Jaw osteonecrosis associated with aflibercept, irinotecan and fluorouracil: attention to oral district.

INTRODUCTION: The antiangiogenic monoclonal antibody aflibercept in association with fluorouracil and irinotecan improves the survival of patients with metastatic colorectal cancer (mCRC) treated previously with oxaliplatin-based therapy. Multiple reports raised the hypothesis that the concomitant use of antiresorptive drugs and antiangiogenic drugs may increase the risk of osteonecrosis of the jaw (ONJ). Some reports have been published regarding cases of ONJ during treatment with bevacizumab for mCRC. CASE DESCRIPTION: Here we describe the first reported case of ONJ occurring in a 64-year-old woman with untreated periodontitis and episodic previous pyorrhea occurring during treatment with aflibercept plus FOLFIRI during the expanded-access program. CONCLUSIONS: This case report warrants further investigation into the potential association between the use of anti-VEGF agents and ONJ. Given the serious nature of ONJ, we recommend that particular attention be paid to the oral district prior to treating patients and during treatment with chemotherapy and targeted agents, especially anti-VEGF agents. Such measures could also be useful in reducing the incidence of stomatitis.

Clonal evolution and resistance to EGFR blockade in the blood of colorectal cancer patients.

Colorectal cancers (CRCs) evolve by a reiterative process of genetic diversification and clonal evolution. The molecular profile of CRC is routinely assessed in surgical or bioptic samples. Genotyping of CRC tissue has inherent limitations; a tissue sample represents a single snapshot in time, and it is subjected to spatial selection bias owing to tumor heterogeneity. Repeated tissue samples are difficult to obtain and cannot be used for dynamic monitoring of disease progression and response to therapy. We exploited circulating tumor DNA (ctDNA) to genotype colorectal tumors and track clonal evolution during treatment with the epidermal growth factor receptor (EGFR)-specific antibodies cetuximab or panitumumab. We identified alterations in ctDNA of patients with primary or acquired resistance to EGFR blockade in the following genes: KRAS, NRAS, MET, ERBB2, FLT3, EGFR and MAP2K1. Mutated KRAS clones, which emerge in blood during EGFR blockade, decline upon withdrawal of EGFR-specific antibodies, indicating that clonal evolution continues beyond clinical progression. Pharmacogenomic analysis of CRC cells that had acquired resistance to cetuximab reveals that upon antibody withdrawal KRAS clones decay, whereas the population regains drug sensitivity. ctDNA profiles of individuals who benefit from multiple challenges with anti-EGFR antibodies exhibit pulsatile levels of mutant KRAS. These results indicate that the CRC genome adapts dynamically to intermittent drug schedules and provide a molecular explanation for the efficacy of rechallenge therapies based on EGFR blockade.

Role of multidimensional assessment of frailty in predicting short-term outcomes in hospitalized cancer patients: results of a prospective cohort study.

AIMS AND BACKGROUND: The study analyzed the value of physical and psychosocial frailty assessment in predicting the need for supportive care and the risk of short-term failures after discharge in hospitalized cancer patients. METHODS AND STUDY DESIGN: Frailty was assessed in 350 consecutive patients using a multidimensional tool. Patients were followed for 4 months after discharge to record the occurrence of chemotherapy interruption, urgent hospital readmission or death. The association between patient characteristics and the outcomes were analyzed with either logistic or Cox multivariable models. RESULTS: About 40% of patients were classified as frail, with a higher prevalence of clinical frailty (alone or together with psychosocial frailty). Psychosocial frailty was positively associated with the need for supportive care at discharge (adjusted OR, 3.46; 95% CI, 1.55-7.76) but did not predict a worse prognosis when other important clinical factors were considered. However, the need for supportive care at discharge, in addition to advanced disease and reduced performance status, was a strong predictor of short-term hospital readmission or death (HR 7.50; 95% CI, 3.12-18.02). CONCLUSIONS: A more comprehensive assessment of frailty in cancer patients can aid in the timely identification of the need for supportive care after hospital discharge and improves the prediction of the short-term risk of hospital readmission or death.

Pilot clinical trial on the efficacy of prophylactic use of vitamin K1-based cream (Vigorskin) to prevent cetuximab-induced skin rash in patients with metastatic colorectal cancer.

BACKGROUND: Cetuximab is an effective option for the treatment of metastatic colorectal cancer in the first and subsequent lines of treatment; among its side effects, acneiform skin rash is one of the major causes of treatment delay, reduction, or interruption, with a negative effect on quality of life. No effective strategy to prevent skin rash induced by epidermal growth factor receptor inhibitors is available; however, encouraging results have come from vitamin K1, phytomenadione, applied as a topical formulation. Available studies have been conducted in heterogeneous populations and are mainly focused on the use of vitamin K1-based cream for the treatment, rather than the prophylaxis, of acneiform rash. PATIENTS AND METHODS: Forty-one consecutive patients from a single center all affected by metastatic colorectal cancer and receiving cetuximab, alone or combined with chemotherapy, applied vitamin K1-based cream to prevent the occurrence of acneiform skin rash. The cream was applied twice a day on the face and trunk from the first day of administration of cetuximab. RESULTS: The application of the cream was well tolerated. No grade 4 rash was reported. The proportion of grade 3 skin rash in the first 8 weeks of treatment in this population was 15%, at the lower limit of values reported in the literature, and the proportion of patients with grade 2 rash was reduced (22.5%). CONCLUSION: This experience confirms available data in a homogeneous population, suggesting a possible benefit of topical vitamin K1 as prophylaxis for cetuximab-induced skin rash in patients with metastatic colorectal cancer.

Complete response of metastatic cutaneous squamous cell carcinoma to cetuximab plus paclitaxel.

BACKGROUND AND METHODS: Cetuximab therapy results strongly active in advanced cutaneous squamous cell carcinoma (cSCC). A patient affected by a rapidly progressing, already irradiated and cisplatin-refractory cSCC, with lung, pleura and thoracic lymph nodes metastasis, was treated with weekly cetuximab and paclitaxel. RESULTS: Treatment was well tolerated and a partial response was obtained after four months of cetuximab plus paclitaxel therapy. Then we continued maintenance cetuximab for another seven months with tumor shrinkage until complete response, maintained after six months. CONCLUSIONS: Cetuximab was safely associated with paclitaxel, obtaining a rapid tumor response in cisplatin-refractory metastatic cSCC. Single-agent cetuximab maintenance sustained tumor shrinkage until complete response.