Efficacy and Safety of First-line Carboplatin-paclitaxel and Carboplatin-gemcitabine in Patients With Advanced Triple-negative Breast Cancer: A Monocentric, Retrospective Comparison.

BACKGROUND: Platinum-based chemotherapy is widely used in patients with advanced triple-negative breast cancer (TNBC). However, the most effective platinum-based combination in the first-line treatment setting remains unclear. MATERIALS AND METHODS: We evaluated the efficacy of first-line carboplatin-paclitaxel (CP) or carboplatin-gemcitabine (CG) combinations in advanced TNBC patients treated between April 2007 and April 2021. CP and CG were compared in terms of progression-free survival (PFS), overall survival (OS), and incidence of adverse events (AEs). Multivariable Cox Models were used to adjust the efficacy of CP versus CG for clinically relevant covariates. RESULTS: Of 88 consecutive advanced TNBC patients receiving first-line carboplatin-based doublets, 56 (63.6%) received CP and 32 (36.4%) CG. After adjusting for clinically relevant variables, patients receiving CG had significantly better PFS when compared to CP-treated patients (HR: 0.49 (95% CI, 0.27-0.87), P value 0.014). Of note, CG was associated with better PFS only among patients previously treated with taxanes in the (neo)adjuvant setting (HR: 0.39; 95% CI, 0.21-0.75), but not in patients not exposed to taxanes (HR: 1.20; 95% CI, 0.37-3.88). CG was also independently associated with better OS when compared to CP (HR: 0.31 (95% CI: 0.15-0.64), P value 0.002). Overall, grade 3-4 AEs were more common in patients treated with CG than in patients treated with CP (68.8% vs. 21.4%, P value .009). CONCLUSION: CG and CP are effective and well tolerated first-line platinum doublets in advanced TNBC patients. CG could be more effective than CP in patients previous exposed to taxanes despite worse toxicity profile.

Case Report: Prolonged clinical benefit with sequential trastuzumab-containing treatments in a patient with advanced extramammary Paget disease of the groin.

Extramammary Paget disease (EMPD) is a rare form of cutaneous, intraepithelial adenocarcinoma, which typically presents itself as an erythematous plaque originating from apocrine-gland rich regions, such as the vulva, the perianal region, the scrotum, the penis, or the axilla. EMPD patients typically have a good prognosis, with expected 5-year survival of 60%-92%, but it is estimated that about one-third of EMPD patients will develop lymph node or distant metastases. Treatment approaches for EMPD include locoregional therapies such as broad surgical resection, radiotherapy, or topical imiquimod, when the disease is localized, and chemotherapy and biological agents for advanced EMPD. We report the case of a 58-year-old man diagnosed with locally advanced, symptomatic HER2-overexpressing, AR-positive EMPD, who achieved long-term tumor control with a sequence of several trastuzumab-based treatments (more than 30 months with second-line carboplatin plus paclitaxel plus trastuzumab followed by trastuzumab maintenance; 9 months for third-line vinorelbine plus trastuzumab). Even if it is reported that AR expression occurs concomitantly with HER2 overexpression in more than half of the cases of EMPD, to the best of our knowledge, this is the first case report describing androgen receptor blockade therapy in combination with an anti-HER2 agent. Our patient did not benefit from androgen receptor blockade in combination with trastuzumab, thus suggesting that AR expression may simply reflect an intrinsic characteristic of the EMPD cell of origin, rather than tumor dependence upon AR signaling. Given the reported sensibility to anti-HER2 therapy, also new antibody drug conjugates targeting HER2 are worth exploring in the management of advanced EMPD.

Antitumor activity and efficacy of shorter versus longer duration of anthracycline-taxane neoadjuvant chemotherapy in stage II-III HER2-negative breast cancer: a 10-year, retrospective analysis.

BACKGROUND: Neoadjuvant anthracycline-taxane-based chemotherapy (ChT) is a standard of care treatment option for stage II-III breast cancer (BC) patients. However, the optimal duration of neoadjuvant ChT has been poorly investigated so far. MATERIAL AND METHODS: We retrospectively retrieved clinical data of patients with stage II-III human epidermal growth factor receptor 2-negative (HER2-) BC who were treated between October 2007 and January 2018 with neoadjuvant AT (doxorubicin-paclitaxel) for three cycles followed by CMF (cyclophosphamide-methotrexate-5-fluorouracil) for three cycles (cohort A) or with four AT cycles followed by four CMF cycles (cohort B). The aim of our study was to investigate the impact of neoadjuvant ChT duration (cohort A versus cohort B) on pathological complete response (pCR) rates, disease-free survival (DFS) and overall survival (OS). RESULTS: Of 209 HER2- BC patients included, 62 had triple-negative breast cancer (TNBC) and 147 had hormone receptor-positive (HR+) BC. Median age was 48 years (range 30-74 years). A total of 111 patients belonged to cohort A and 98 patients belonged to cohort B. pCR was detected in 29 (13.9%) patients, 25 (40.3%) of whom had TNBC and four (2.7%) had HR+ HER2- BC. Patients achieving pCR had significantly longer DFS and OS, with statistical significance reached only in patients with TNBC. We found no differences between cohort A and cohort B in terms of pCR rates (15.3% versus 12.2%; p = 0.55), DFS (p = 0.49) or OS (p = 0.94). The incidence of grade 3/4 adverse events was similar in cohort A versus cohort B as well (22.5% versus 19.4%; p = 0.54). CONCLUSION: Shorter duration of neoadjuvant anthracycline-taxane ChT was not associated with worse clinical outcomes in patients with stage II-III BC. Prospective studies are needed to evaluate whether the duration of neoadjuvant anthracycline-taxane-based ChT can be reduced in specific patient subgroups without negatively affecting clinical outcomes.

Health-related quality of life in patients with RAS wild-type metastatic colorectal cancer treated with panitumumab-based first-line treatment strategy: A pre-specified secondary analysis of the Valentino study.

BACKGROUND: Quality of life (QoL) patient-reported outcomes (PROs) data from pivotal first-line trials in metastatic colorectal cancer (mCRC) are poor. The Valentino study showed that de-escalation to single-agent panitumumab after 4-month induction with panitumumab-FOLFOX is inferior to panitumumab-5-FU/LV in patients with RAS wild-type mCRC, although slightly reducing toxicity. We report QoL, a secondary end-point. METHODS: PROs were assessed by European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire - Core 30 (QLQ-C30), EORTC QLQ-CR29, EuroQol EQ-5D questionnaires, at baseline and every 8 weeks until disease progression. First two evaluations correspond to induction treatment (identical in both arms), while subsequent to maintenance. To describe QoL changes over time, mean changes from baseline at each time point were calculated in overall population. To compare maintenance between two arms, mean changes and proportion of improved/stable/worse patients versus baseline were compared for each item. RESULTS: In arm A/B, 91.5%/92.0% of enrolled patients completed questionnaires at baseline. No significant differences in the two arms were reported in compliance, baseline scores and mean changes versus baseline for the three questionnaires during maintenance (24/32/40 weeks). Overall, mean changes versus baseline showed an early deterioration during induction with partial recovering during maintenance for global QoL, functional scales and several symptoms/items of QLQ-C30 (fatigue, nausea/vomiting, appetite loss, diarrhoea) and QLQ-CR29 (body image, dry mouth, hair loss, taste, faecal incontinence, sore skin), and EQ-5D Visual Analogue Scale (VAS) score. CONCLUSION: In patients with RAS wild-type mCRC, induction with oxaliplatin-containing chemotherapy plus anti-EGFRs induces a transient significant QoL deterioration. After induction phase, treatment deintensification determines an overall recovery of health-related QoL, besides the expected prevention of oxaliplatin-related neurotoxicity.

Safety and activity of radium-223 in metastatic castration-resistant prostate cancer: the experience of Istituto Nazionale dei Tumori.

INTRODUCTION: Therapeutic decision-making in metastatic castration-resistant prostate cancer (mCRPC) represents an open challenge. Radium-223 is approved for patients with symptomatic bone metastases, no visceral involvement, progressing after at least 2 lines of systemic therapy, or ineligible for any other systemic treatment. METHODS: We performed a retrospective, observational study on patients with mCRPC treated with radium-223 at our institution outside of clinical trials, to assess the safety and activity in a real-world population. Data regarding baseline patient/disease characteristics and treatment outcomes (number of cycles, treatment-related adverse events [AEs], cause of discontinuation, and best response) were collected. RESULTS: Overall, 41 patients were treated from September 2015 to September 2018. Median age was 73 years; baseline Eastern Cooperative Oncology Group Performance Status (ECOG PS) was 0, 1, or 2 in 15%, 80%, and 5% of cases, respectively; and 3%, 41%, 44%, and 12% of patients had <6, 6-20, >20, and superscan bone lesions, respectively. A median number of 5 cycles (interquartile range 3-6) with median dose 19.52 MBq (interquartile range 12.87-24.83) was received. Treatment schedule was completed in 49% of cases; discontinuations due to AEs, disease-related death, or disease progression occurred in 24%, 33%, and 43% of patients, respectively. Any-grade AEs occurred in 73% and grade 3/4 treatment-related AEs occurred in 29% of patients, mainly anemia, decreased platelet count, and fatigue. No skeletal-related events or treatment-related deaths were recorded. After treatment, 66%, 2%, and 32% of patients had a stable, improved, or deteriorated ECOG PS versus baseline, respectively, and 24%, 61%, and 15% reported a stable, improved, or worsened pain symptom control. Post-treatment versus baseline alkaline phosphatase was reduced or stable in 46% and increased in 54% of patients, whereas prostate-specific antigen was decreased or stable in 83% and increased in 17% of patients. CONCLUSIONS: Our study provides clinically useful real-world data on radium-223, highlighting the importance of multidisciplinary patient management to guarantee the best continuum of care for patients with mCRPC.

Oral Capecitabine-Vinorelbine is Associated with Longer Overall Survival When Compared to Single-Agent Capecitabine in Patients with Hormone Receptor-Positive Advanced Breast Cancer.

Background: Single-agent capecitabine (C) is a moderately effective chemotherapeutic compound in the treatment of patients with HER2-negative metastatic breast cancer (mBC). The capecitabine-vinorelbine (CV) combination is also used due to a good tolerability profile, but no studies have demonstrated its superiority over single-agent C. Methods: We conducted a retrospective analysis to compare overall response rate (ORR), progression-free survival (PFS), overall survival (OS) and incidence of adverse events (AEs) in patients with HER2-negative mBC treated with CV vs. single-agent C. Results: Out of 290 patients included in this study, 127 (43.8%) received single-agent C, while 163 (56.2%) patients were treated with CV. Median PFS was similar in patients treated with single-agent C or CV, while CV was associated with significantly longer OS in patients with hormone receptor-positive (HR+) BC. This OS advantage was confirmed at multivariable analysis also after propensity score-based matching of patients according to relevant clinical or tumor characteristics. When compared with single-agent C, CV was associated with higher incidence of G3/G4 and any-grade nausea/vomiting, diarrhea and increased transaminases. Conclusions: While prospective studies are needed to confirm our findings, the potential OS advantage of CV over single-agent C in HR+ mBC patients must be weighed against a significantly higher incidence of AEs.

A novel circulating tumor cell subpopulation for treatment monitoring and molecular characterization in biliary tract cancer.

In biliary tract cancer (BTC), tissue biopsies to guide treatment are rarely feasible, thus implementing liquid biopsy approaches to improve patient management represents a priority. So far, studies on circulating tumor cells (CTCs) in BTC are insufficient to promote their use in patient clinical management and are limited to EpCAM-enriched CTCs evaluated with the CellSearch. We applied a single-cell protocol allowing identification not only of epithelial CTCs (eCTCs), but also of nonconventional CTCs (ncCTCs) lacking epithelial and leukocyte markers, but presenting aberrant genomes as confirmed by copy number alterations and therefore representing a distinct subpopulation of bona fide CTCs. In 41 blood samples longitudinally collected from 21 patients with advanced-stage BTC, addition of ncCTC to classic eCTC led to a CTC-positivity increase from 19% to 83%. Patients presenting with at least 1 eCTC/10 ml of blood at baseline prior to treatment start had a significantly shorter median disease-specific survival (DSS) compared to those lacking eCTCs (9 months vs. 19 months, p = 0.03 by log-rank test). No differences in DSS were observed according to ncCTC-positivity, conversely, variations in ncCTC counts during, and at the end of treatment, were associated with the RECIST response supporting their role in treatment monitoring. Moreover, in 88 ncCTCs collected at different times during treatment, unsupervised clustering evidenced segregation of cells by patient's best response, allowing identification of genomic regions possibly involved in resistance mechanisms. The presence of ncCTCs beside eCTCs opens the way to exploiting liquid biopsy for optimizing clinical management in BTC.

Cabozantinib in Renal Cell Carcinoma With Brain Metastases: Safety and Efficacy in a Real-World Population.

BACKGROUND: Cabozantinib showed efficacy and manageable toxicity in patients with metastatic renal cell carcinoma (mRCC). In this study we aimed to describe the safety and to collect evidence on the potential efficacy of cabozantinib in mRCC patients with brain metastases (BM) in a real-world experience. MATERIALS AND METHODS: We retrospectively collected data of patients treated with cabozantinib within the Italian Managed Access Program. Patients were selected for the presence of BM before the start of treatment and for at least 1 previous tyrosine kinase inhibitor (TKI) treatment regimen for metastatic disease. Safety data were reported, and overall response rate (ORR), brain-specific response, progression-free survival (PFS), and median overall survival (OS) were analyzed. RESULTS: Overall, 12 patients treated with cabozantinib were evaluated. Any grade adverse events (AEs) accounted for 92%, Grade 3/4 AEs rated at 36% with no major neurological side effects. The most common AEs included hypertension (33%), fatigue (24%), aminotransferase elevation (25%), hypothyroidism (16%), and gastrointestinal toxicity (16%). The ORR was 50% with a disease control rate of 75%. All 5 patients treated with a combined systemic and brain-directed approach obtained intracranial disease control, without increased toxicity. Median PFS and median OS were 5.8 and 8.8 months, respectively. Comparable safety and tolerability results for other TKI regimens were reported from the literature. CONCLUSION: Cabozantinib showed safety, acceptable tolerability, and promising antitumor activity in a population of mRCC patients with BM from a real-world experience. A combined modality approach for renal cell carcinoma with BM, whenever feasible, could be recommended to improve oncological outcomes.

Prognostic impact of ATM mutations in patients with metastatic colorectal cancer.

Tumors bearing homologous recombination deficiency are extremely sensitive to DNA double strand breaks induced by several chemotherapeutic agents. ATM gene, encoding a protein involved in DNA damage response, is frequently mutated in colorectal cancer (CRC), but its potential role as predictive and prognostic biomarker has not been fully investigated. We carried out a multicenter effort aimed at defining the prognostic impact of ATM mutational status in metastatic CRC (mCRC) patients. Mutational profiles were obtained by means of next-generation sequencing. Overall, 35 out of 227 samples (15%) carried an ATM mutation. At a median follow-up of 56.6 months, patients with ATM mutated tumors showed a significantly longer median overall survival (OS) versus ATM wild-type ones (64.9 vs 34.8 months; HR, 0.50; 95% CI, 0.29-0.85; P = 0.01). In the multivariable model, ATM mutations confirmed the association with longer OS (HR, 0.57; 95% CI, 0.33-0.98; P = 0.04). The prognostic impact of ATM mutations was independent from TP53 mutational status and primary tumor location. High heterogeneity score for ATM mutations, possibly reflecting the loss of wild-type allele, was associated with excellent prognosis. In conclusion, we showed that ATM mutations are independently associated with longer OS in patients with mCRC.

Safety and Efficacy of Cabozantinib for Metastatic Nonclear Renal Cell Carcinoma: Real-world Data From an Italian Managed Access Program.

OBJECTIVE: The activity of cabozantinib in nonclear cell histologies has not been evaluated. MATERIALS AND METHODS: Data were collected across 24 Italian hospitals. Patients were aged 18 years and older with advanced nonclear cell renal cell carcinoma (RCC), with an Eastern Cooperative Oncology Group Performance Status 0 to 2, who had relapsed after previous systemic treatments for metastatic disease. Cabozantinib was administered orally at 60 mg once a day in 28 days cycles. Dose reductions to 40 or 20 mg were made due to toxicity. Adverse events (AEs) were monitored using CTCAE version 4.0. RESULTS: Seventeen patients were enrolled. Three (18%) patients were diagnosed type I papillary RCC, 9 (53%) type II papillary, 3 (18%) chromophobe, and 2 (11%) with Bellini duct carcinoma. In total, 11 patients started with 60 mg. Six patients started a lower dose of 40 mg. Median progression-free survival was 7.83 months (0.4 to 13.4 mo), while median overall survival was not reached but 1-year overall survival was about 60%. Six patients (35%) experienced a partial response to treatment and 6 patients (35%) showed a stable disease. In the remaining 5 (30%), we observed a progressive disease. Grade 3 and 4 AEs were observed in 41% of patients. Among 20 patients, only 1 (6%) discontinued treatment due to AEs. Asthenia (41%), diarrhea (35%), aminotransferase increasing (35%), mucosal inflammation (35%), hand and foot syndrome (24%), and hypothyroidism (24%) were the most frequently AEs. CONCLUSIONS: Our data showed that, cabozantinib is a active and feasible treatment in patient with nonclear cell RCC.

Treatment of Advanced Merkel Cell Carcinoma: Current Therapeutic Options and Novel Immunotherapy Approaches.

Advanced Merkel cell carcinoma (MCC) is a very aggressive, rare neuroendocrine tumor of the skin with a high frequency of locoregional recurrence and metastasis, and a high mortality rate. Surgical resection, sentinel lymph node biopsy, and radiotherapy represent the gold standard of treatment in patients with localized disease, while chemotherapy has a significant role in the treatment of advanced disease. However, no definitive evidence on the survival impact of radiotherapy in the advanced stages has been provided to date, and response to chemotherapy remains brief in the majority of cases, indicating an urgent need for alternative approaches. Biological and genome sequencing studies have implicated multiple molecular pathways in MCC, thus leading to the development of new agents that target angiogenic factors, anti-apoptosis molecules, poly-ADP ribose polymerase, intracellular signal proteins such as the PI3K/AKT/mTOR pathway, and peptide receptors such as somatostatin receptors. More recently, immunotherapy agents such as avelumab, pembrolizumab, and nivolumab, which act by blocking the programmed cell-death (PD)-1/PD-L1 immune checkpoint, have shown promising results, especially in the advanced setting, and should now be considered standard of care for metastatic MCC. Current research is focusing on developing new immunotherapeutic strategies, identifying predictive biomarker to aid in the selection of patients responsive to immunotherapy, and defining combination approaches to increase efficacy in refractory patients.

Genomic markers of resistance to targeted treatments in gastric cancer: potential new treatment strategies.

Gastric cancer is a highly heterogeneous disease, displaying a complex genomic landscape and an unfavorable outcome with standard therapies. Based on distinctive genomic alterations, novel targeted agents have been developed with the aim of personalizing treatments and improving patient outcome. However, a subgroup of patients is primarily treatment-resistant, and even in the initially sensitive population, secondary resistance emerges, thus limiting therapeutic benefit. In this review, we summarize the clinical data about standard targeted agents in gastric cancer, specifically anti-HER2 treatments and antivascular therapies. We also illustrate the available evidence regarding molecular mechanisms of resistance to these agents and we discuss potential strategies for new targeted treatments that could overcome such resistance.

Incidence of nausea and vomiting in breast cancer patients treated with anthracycline plus cyclophosphamide-based chemotherapy regimens in Italy: NAVY observational study.

PURPOSE: Chemotherapy-induced nausea and vomiting (CINV) is a common adverse event with cancer chemotherapy, despite the availability of effective antiemetic agents. This is a prospective observational study of Italian breast cancer patients treated with anthracycline plus cyclophosphamide (AC), assessed CINV incidence, adherence to national antiemetic guidelines (AIOM 2012), and the relationship with CINV outcomes. METHODS: Patients with breast cancer scheduled to receive their first cycle of an AC-based regimen were enrolled at 12 Italian centers and their clinical data prospectively recorded. CINV incidence was assessed from patient diaries after the first chemotherapy cycle. The relationship between guideline adherence and CINV outcomes was examined using multiple logistic regression. RESULTS: The overall incidence rates of nausea and vomiting among 246 evaluable patients were 63.0 and 25.4%, respectively. Most patients received a 5-HT3-RA agent and dexamethasone for acute phase CINV prophylaxis, whereas a triple combination including aprepitant (NK1-RA), consistent with national guidelines, was used in only 45.5% of cases. In the delayed phase, the guideline adherence was 48.8%, while the overall adherence was 43.5%. After adjusting for confounding factors, adherence to antiemetic prophylaxis guidelines was associated with a significant reduction in the odds of three endpoints, namely any nausea, "significant nausea," and vomiting (OR = 0.49, OR = 0.54, and OR = 0.48, respectively), and a 90% increase in the odds of overall complete protection (OR = 1.90). CONCLUSIONS: CINV is still a critical issue in AC-treated patients, despite antiemetic treatment. Non-adherence to antiemetic guidelines may lead to poorer outcomes and indicates the need for strategies to enhance the use of guidelines in clinical practice.

Pure small cell recurrent prostate cancer developing syndrome of inappropriate antidiuretic hormone secretion.

PURPOSE: Pure small cell neuroendocrine carcinoma of the prostate is a rare entity characterized by a poor prognosis due to early metastatic spread as well as resistance to treatment. Considering its increasing occurrence, clinicians should be aware of its aggressive behavior, the relevance of an early diagnosis, and proper management. METHODS: A 71-year-old man treated with brachytherapy for localized low-risk prostate cancer developed widespread disease 7 years later with a prostate-specific antigen-negative neuroendocrine small cell phenotype. He was also diagnosed with syndrome of inappropriate antidiuretic hormone secretion (SIADH) soon after starting chemotherapy. RESULTS: A substantial radiologic and clinical response to chemotherapy was observed and the paraneoplastic SIADH was successfully treated with oral vaptan therapy. CONCLUSIONS: Secondary small cell prostate carcinoma is an underestimated entity with high sensitivity to chemotherapy, although a standard treatment has not yet been defined. Moreover, oral vaptans demonstrated prompt efficacy and simple management in correcting SIADH-related hyponatremia.