Current Clinical Practice Guidelines for the Treatment of Renal Cell Carcinoma: A Systematic Review and Critical Evaluation.

The landscape of local and systemic therapy of renal cell carcinoma (RCC) is rapidly changing. The increase in the incidental finding of small renal tumors has increased the application of nephron-sparing procedures, while ten novel agents targeting the vascular endothelial growth factor (VEGF) or the mammalian target of rapamycin pathways, or inhibiting the interaction of the programmed death 1 receptor with its ligand, have been approved since 2006 and have dramatically improved the prognosis of metastatic RCC (mRCC). These rapid developments have resulted in continuous changes in the respective Clinical Practice Guidelines/Expert Recommendations. We conducted a systematic review of the existing guidelines in MEDLINE according to the Preferred Reporting Items for Systematic Review and Meta-Analyses statement, aiming to identify areas of agreement and discrepancy among them and to evaluate the underlying reasons for such discrepancies. Data synthesis identified selection criteria for nonsurgical approaches in renal masses; the role of modern laparoscopic techniques in the context of partial nephrectomy; selection criteria for cytoreductive nephrectomy and metastasectomy in mRCC; systemic therapy of metastatic non-clear-cell renal cancers; and optimal sequence of available agents in mRCC relapsed after anti-VEGF therapy as the major areas of uncertainty. Agreement or uncertainty was not always correlated with the availability of data from phase III randomized controlled trials. Our review suggests that the combination of systematic review and critical evaluation can define practices of wide applicability and areas for future research by identifying areas of agreement and uncertainty among existing guidelines. IMPLICATIONS FOR PRACTICE: Currently, there is uncertainity on the role of surgery in MRCC and on the choice of available guidelines in relapsed RCC. The best practice is individualization of targeted therapies. Systematic review of guidelines can help to identify unmet medical needs and areas of future research.

The Utility of NGS Analysis in Homologous Recombination Deficiency Tracking.

Several tumor types have been efficiently treated with PARP inhibitors (PARPis), which are now approved for the treatment of ovarian, breast, prostate, and pancreatic cancers. The BRCA1/2 genes and mutations in many additional genes involved in the HR pathway may be responsible for the HRD phenomenon. The aim of the present study was to investigate the association between genomic loss of heterozygosity (gLOH) and alterations in 513 genes with targeted and immuno-oncology therapies in 406 samples using an NGS assay. In addition, the %gLOHs of 24 samples were calculated using the Affymetrix technology in order to compare the results obtained via the two methodologies. HR variations occurred in 20.93% of the malignancies, while BRCA1/2 gene alterations occurred in 5.17% of the malignancies. The %LOH was highly correlated with alterations in the BRCA1/2 genes, since 76.19% (16/21) of the BRCA1/2 positive tumors had a high %LOH value (p = 0.007). Moreover, the LOH status was highly correlated with the TP53 and KRAS statuses, but there was no association with the TMB value. Lin's concordance correlation coefficient for the 24 samples simultaneously examined via both assays was 0.87, indicating a nearly perfect agreement. In conclusion, the addition of gLOH analysis could assist in the detection of additional patients eligible for treatment with PARPis.

Ribociclib and palbociclib-induced erythema multiforme: a case report.

Cyclin-dependent kinase 4/6 inhibitors (CKIs), ribociclib, palbocilb and abemaciclib, have been approved in combination with endocrine therapy for the treatment of hormone receptor-positive and human epidermal growth factor 2-negative advanced or metastatic breast cancer. Severe dermatological adverse events are rare with these agents; however, they require direct recognition and management in order not to become life-threatening. Erythema multiforme (EM) belongs to a dermatopathic spectrum that includes immune-mediated, widespread hypersensitivity reaction, which occurs with varying degrees of severity and affects the skin and/or the mucosa. We hereby present a case of ribociclib- and palbociclib-related EM. We sought to report this case given the implication of two agents from the same drug class in EM onset. We also aim to emphasize the breadth of mechanisms of actions of CKIs, with an impingement in the immune system as well, and the importance of promptly identifying and handling such skin toxicities.

Prognostic Significance of Low HER2 Expression in Patients With Early Hormone Receptor Positive Breast Cancer.

BACKGROUND/AIM: A possible role of antibody-drug conjugates against tumors with low HER2-expression, leads to the emergence of a new "low-HER2" classification in breast cancer, encompassing tumors from the hormonal-receptor-positive and the triple-negative subgroups. There is a need for data (clinical trial data and real-world evidence) that will accurately describe this population, the risk of recurrence and the possible benefit of HER2 targeted therapies. PATIENTS AND METHODS: We retrospectively analyzed 949 patients from our Department databases, with hormonal receptor-positive and HER2-negative early breast cancer, for whom detailed data for immunohistochemical HER2-staining could be retrieved. RESULTS: HER2-low expression was detected in 66.6% of patients (472 IHC +1 and 160 IHC +2 and ISH-negative). Lobular, or mixed lobular and ductal cancers had a statistically significantly lower chance of being HER2-low when compared to pure infiltrative ductal carcinomas (53.1% vs. 69.3% respectively). HER2-low status was not prognostic for recurrence-free survival or response to neoadjuvant chemotherapy. There was a non-significant trend for increased risk of recurrence for HER2-low, compared to HER2-0, in patients with lobular or mixed lobular and ductal carcinomas (HR=2.192, 95% CI=0.819-5.912). CONCLUSION: Low expression of HER2 in hormonal receptor-positive early breast cancer does not affect prognosis but may lead to a shorter progression-free-survival in lobular and mixed ductal and lobular cancers. Despite optimal management, a large proportion of hormonal receptor-positive patients will relapse. Targeting HER2 in HER2-low cancers may offer a potential additional treatment strategy to improve survival of this group.

Cardiac safety of neoadjuvant chemotherapy with epirubicin and cyclophosphamide followed by docetaxel/pertuzumab/trastuzumab for HER2-positive breast cancer patients.

PURPOSE: Early-stage, HER2-positive breast cancer is increasingly treated with neoadjuvant chemotherapy (NAC). After the positive results of the Neosphere trial, the standard of care has been the combination of chemotherapy with two anti-HER2 agents, trastuzumab and pertuzumab. Many oncologists use the sequence of four cycles of anthracycline-containing regimen followed by four cycles of taxane with the two monoclonals. We report here the cardiac safety of four cycles of epirubicin with cyclophosphamide followed by four cycles of docetaxel with trastuzumab and pertuzumab, given at the neoadjuvant setting in early, HER2-positive breast cancer. METHODS: We retrospectively collected data from the medical records of patients treated at our clinic between 2014 and 2020. RESULTS: It total, 55 patients treated with the same regimen were identified. There were 20 estrogen receptor (ER)-negative and 35 ER-positive patients. Complete pathologic response was observed in 64.8% of the patients. After a median cardiac follow-up of 2.61 years, and a total of 283 echocardiograms, there was only one recorded asymptomatic Left Ventricular Ejection Fraction (LVEF) fall > 25% and no symptomatic left ventricular systolic dysfunction. LVEF consistently dropped during treatment, but the drop was not significant enough to necessitate treatment interruption, and improved during follow-up. CONCLUSION: Our data confirm the effectiveness and cardiac safety of the aforementioned neoadjuvant regimen.

Prognostic stratification of patients with advanced renal cell carcinoma treated with sunitinib: comparison with the Memorial Sloan-Kettering prognostic factors model.

BACKGROUND: The treatment paradigm in advanced renal cell carcinoma (RCC) has changed in the recent years. Sunitinib has been established as a new standard for first-line therapy. We studied the prognostic significance of baseline characteristics and we compared the risk stratification with the established Memorial Sloan Kettering Cancer Center (MSKCC) model. METHODS: This is a retrospective analysis of patients treated in six Greek Oncology Units of HECOG. Inclusion criteria were: advanced renal cell carcinoma not amenable to surgery and treatment with Sunitinib. Previous cytokine therapy but no targeted agents were allowed. Overall survival (OS) was the major end point. Significance of prognostic factors was evaluated with multivariate cox regression analysis. A model was developed to stratify patients according to risk. RESULTS: One hundred and nine patients were included. Median follow up has been 15.8 months and median OS 17.1 months (95% CI: 13.7-20.6). Time from diagnosis to the start of Sunitinib (12 months, p = 0.001), number of metastatic sites (1 vs. >1, p = 0.003) and performance status (PS) (1, p = 0.001) were independently associated with OS. Stratification in two risk groups ("low" risk: 0 or 1 risk factors; "high" risk: 2 or 3 risk factors) resulted in distinctly different OS (median not reached [NR] vs. 10.8 [95% confidence interval (CI): 8.3-13.3], p < 0.001). The application of the MSKCC risk criteria resulted in stratification into 3 groups (low and intermediate and poor risk) with distinctly different prognosis underlying its validity. Nevertheless, MSKCC model did not show an improved prognostic performance over the model developed by this analysis. CONCLUSIONS: Studies on risk stratification of patients with advanced RCC treated with targeted therapies are warranted. Our results suggest that a simpler than the MSKCC model can be developed. Such models should be further validated.

Real-world experience of neoadjuvant chemotherapy for early breast cancer patients: an observational non-interventional study in Thessaloniki, Greece.

PURPOSE: Neoadjuvant chemotherapy has been increasingly used in early-stage breast cancer. The results of large randomized clinical trials suggest the need for the wider use of preoperative therapy as it can result in a more conservative surgery, and can guide physicians to a more individualized approach in the adjuvant setting. METHODS: We aimed to analyze the outcomes of 203 patients with early-stage breast cancer who had received neoadjuvant chemotherapy at our institutions. RESULTS AND CONCLUSION: Pathological complete responses (pCR) were obtained in 42.4% of all patients, with the highest percentage in hormonal receptor (HR)-negative and human epidermal growth factor receptor-2 (HER2)-positive cancers. Conversion of a clinically and/or cytologically node-positive to node-negative disease was achieved in 55.8% of patients. Patients who achieved a pCR had a significantly better outcome in terms of disease-free and distant disease-free survival. Patients with residual disease experienced a worse prognosis if they had HR-negative cancer compared to HR-positive patients for whom the use of adjuvant endocrine treatment likely led to better outcomes. These results are encouraging as they show that outcomes from large randomized clinical trials can be reproduced in the everyday clinical setting. Neoadjuvant chemotherapy may be the treatment of choice for HR-negative and/or HER2-positive early breast cancer patients. This may also be the case for the majority of HR-positive and HER2-negative patients with either locally advanced disease or disease extending to the axillary lymph nodes, as it may result in more conservative surgical interventions with fewer post-operative complications.

Sunitinib treatment for patients with clear-cell metastatic renal cell carcinoma: clinical outcomes and plasma angiogenesis markers.

BACKGROUND: Sunitinib is a protein tyrosine kinase-inhibitor targeting VEGFR, c-kit and PDGFR. It has been approved for the treatment of metastatic renal-cell carcinoma and gastrointestinal stromal tumors. Although it has been shown to prolong disease-free and overall survival in renal-cell carcinoma patients, only 70% of the treated population receive a clinical benefit (CB) from the treatment. Markers that could predict clinical benefit to sunitinib would be an important aid in monitoring and following their treatment. We assessed the outcome and plasma proangiogenic factors in patients with metastatic renal cell carcinoma (mRCC) treated with sunitinib in our institution. METHODS: We have treated 42 patients with metastatic clear-cell renal carcinoma with sunitinib. Plasma concentrations of VEGF-A, sVEGFR2 and PDGF were determined by ELISA. RESULTS: At the time of analysis 39 patients were evaluable for response and 30 patients had obtained a clinical benefit (CB). Median progression-free survival was 268 days (8.93 months) and median overall survival was 487 days (16.23 months). Interestingly, disease stabilization or objective response resulted in comparable overall survival. Most treatment-related adverse events were of mild-to-moderate intensity with one treatment-related death. Plasma sVEGFR2 and PDGF levels had no predictive value. Fold-increase in plasma VEGF was significantly lower in patients that obtained a CB as compared to patients that progressed after two cycles of treatment. Plasma VEGF did not increase in patients with initial CB at the time of progression. CONCLUSION: Sunitinib showed substantial activity in mRCC. Disease stabilization or objective response resulted in comparable overall survival and both outcomes should be considered positive. Fold-increase in plasma VEGF predicts for CB and could be a candidate marker. Progression after initial CB is not associated with elevated plasma VEGF, implying a different mechanism of resistance.

Erythropoiesis-stimulating agents are associated with reduced survival in patients with multiple myeloma.

The impact of erythropoiesis-stimulating agent (ESA) on cancer patients' survival has recently become a matter of extensive discussion. Studies in solid tumors demonstrated that ESA adversely affects survival. This issue has not been sufficiently studied in patients with multiple myeloma. In this study, which included 323 multiple myeloma patients followed in our Institution between 1988 and 2007, we demonstrated by using a proportional hazards model including multiple covariates (age, LDH, Hb, platelets, serum creatinine, ISS score, beta2 microglobulin, and ESA administration) that ESA administration is associated with reduced survival (hazards ratio: 1.88, 95% CI: 1.28-2.77). Anemia, which is considered a predictor for survival, platelets, serum creatinine, ISS score, and LDH, were not significant, whereas, age and beta2 microglobulin confirmed their predicting value in the multivariate analysis. With a median follow-up of 31 months (range 1-238), the median survival of patients in the ESA group was 31 months (95% CI: 25-37), whereas in the group without ESA administration it was 67 months (95% CI: 55-79) (P < 0.001). The median progression-free survival for patients in the ESA group was 14 months (95% CI: 12-16), and for the group without ESA it was 30 months (95% CI: 24-36) (P < 0.001). These results indicate that ESA may have a detrimental impact on MM patients' outcomes and, thus, in this context, they should be used with rigorous criteria.

Sequential treatment with sorafenib and sunitinib in metastatic renal cell carcinoma: clinical outcomes from a retrospective clinical study.

Sorafenib and sunitinib are inhibitors of receptor protein tyrosine kinases (TKIs) and are approved for the treatment of metastatic renal cell carcinoma (mRCC). Although the mTOR inhibitor everolimus is effective for the treatment of patients who have failed TKI therapy, it is important to consider all available treatment options before switching therapy mode of action. Herein, we report outcomes in patients with mRCC switched to sorafenib following disease progression on sunitinib treatment. The medical records of 35 patients treated between November 2006 and November 2009 at two large referral centers in Greece were retrospectively analyzed for time-to-progression (TTP), overall survival (OS), and tolerability of sorafenib after sunitinib. Median TTP and OS on sorafenib were 4.9 and 11.5 months, respectively. Among 33 patients evaluable for tumor response, three had a partial response and 17 achieved disease stabilization (objective response rate 8.5%; total clinical benefit rate 57%). Sorafenib was well tolerated, with mostly grade 1/2 adverse events and no treatment-related deaths. Sorafenib was effective and well tolerated in this group of patients. The TTP with sorafenib following sunitinib was comparable to outcomes reported previously, providing further support that TKIs should be used in sequence before switching to an mTOR inhibitor.