Leptomeningeal metastases in patients with human epidermal growth factor receptor 2 positive breast cancer: Real-world data from a multicentric European cohort.

In patients with human epidermal growth factor receptor 2 positive (HER2+) breast cancer, leptomeningeal metastases (LM) are a rare but often a fatal clinical scenario. In this multicentric study, clinical and pathologic characteristics of patients with HER2+ breast cancer developing LM were described, as well as survival outcomes. Data were gathered retrospectively from medical records of 82 patients with advanced HER2+ breast cancer and LM treated between August 2005 and July 2020. Following LM diagnosis, 79 (96.3%) patients received at least one line of anti-HER2 therapy, 25 (30.5%) patients received intrathecal therapy and 58 (70.7%) patients received radiotherapy. Overall survival (OS) was 8.3 months (95% confidence interval [CI] 5.7-11), 1-year OS was 42%, and 2-year OS was 21%. At univariate analysis, patients who were treated after 2010, had better Karnofsky performance status, were free of neurological symptoms, had better prognostic, received chemotherapy (OS difference 9.4 months, P = .024), or monoclonal antibodies (trastuzumab ± pertuzumab; OS difference 6.1 months; P = .013) after LM diagnosis, had a statistically significantly longer OS. Presence of neurological symptoms (hazard ratio 3.32, 95% CI 1.26-8.73; P = .015) and not having received radiotherapy (hazard ratio 2.02, 95% CI 1.09-3.72; P = .024) were all associated with poorer OS at multivariate analysis. To summarize, not having neurological symptoms and receiving RT at LM diagnosis were associated with prolonged OS in our cohort. Survival seemed to be prolonged with multimodality treatment, which included targeted therapy, chemotherapy, and RT to the LM sites.

No evidence of disease versus residual disease in long-term responders to first-line HER2-targeted therapy for metastatic breast cancer.

BACKGROUND: Long-term response to HER2-targeted therapies is infrequent in metastatic breast cancer (MBC). We evaluated clinical characteristics of HER2-positive MBC patients with no evidence of disease (NED) vs residual disease (RES) experiencing long-term response to first-line HER2-targeted therapy. METHODS: Patients receiving first-line chemotherapy-trastuzumab (CT) or taxane-trastuzumab-pertuzumab (THP) with response duration ≥2-fold higher than in phase II/III trials (CT [18.2 months]; THP [40.4 months]) were included. Clinical characteristics and radiographic review for NED or RES was evaluated by Cox-regression (hazard ratio; HR) or Kaplan-Meier (log-rank). Characteristics associated with NED were evaluated by logistic regression (Odds; OR). RESULTS: From 01/2005-01/2016, N = 103 (4.6%) patients were identified. In multivariate analyses, NED (N = 46) showed improved progression-free (PFS) and overall survival (OS) [p < 0.001] versus RES (N = 57), with high 5-year PFS/OS for NED (93.2%/97.4%) relative to RES (10.6%/61.3%). Premenopausal status (p = 0.006), de-novo metastases (p = 0.002), and no palliative radiotherapy (p = 0.01) were associated with NED. Overall, 6/7 (85.7%) patients with NED were alive and disease-free after discontinuing HER2 treatment (≥1 year) versus 1/17 (5.9%) with RES. CONCLUSIONS: Long-term responders with NED have better survival compared to RES. Premenopausal status and de novo metastatic disease are associated with NED. Prospective studies of HER2 therapy discontinuation with NED in MBC are warranted.

Impact of Cumulative Chemotherapy Dose on Survival With Adjuvant FEC-D Chemotherapy for Breast Cancer.

BACKGROUND: Reductions in adjuvant chemotherapy dose <85% for historical regimens (ie, cyclophosphamide/methotrexate/fluorouracil) are known to affect breast cancer survival. This threshold, in addition to early versus late dose reductions, are poorly defined for third-generation anthracycline/taxane-based chemotherapy. In patients with breast cancer receiving adjuvant 5-fluorouracil/epirubicin/cyclophosphamide followed by docetaxel (FEC-D), we evaluated the impact of chemotherapy total cumulative dose (TCD), and early (FEC) versus late (D only) dose reductions, on survival outcomes. PATIENTS AND METHODS: Women with stage I-III, hormone receptor-positive/negative, HER2-negative breast cancer treated with adjuvant FEC-D chemotherapy from 2007 through 2014 in Alberta, Canada, were included. TCD for cycles 1 to 6 of <85% or ≥85% was calculated. Average cumulative dose was also calculated for early (cycles 1-3) and late (cycles 4-6) chemotherapy. Survival outcomes (disease-free survival [DFS] and overall survival [OS]) were estimated using Kaplan-Meier and multivariate analysis. Cohorts were evaluated for uniformity. RESULTS: Characteristics were reasonably balanced for all cohorts. Overall, 1,302 patients were evaluated for dose reductions, with 16% being reduced <85% (n=202) relative to ≥85% (n=1,100; 84%). Patients who received TCD ≥85% relative to <85% had superior 5-year DFS (P=.025) and OS (P<.001) according to Kaplan-Meier analysis, which remained significant on univariate and multivariate analyses. In stratified late and early dose reduction cohorts, DFS and OS showed a significant inferior survival trend for dose reduction early in treatment administration in 5-year Kaplan-Meier (P=.002 and P<.001, respectively) and multivariate analyses (hazard ratio [HR], 1.46; P=.073, and HR, 1.77; P=.011, respectively). Dose delays of <14 or ≥14 days and granulocyte colony-stimulating factor use did not affect outcomes. CONCLUSIONS: Chemotherapy TCD <85% for adjuvant FEC-D affects breast cancer survival. Late reductions (D only) were not shown to adversely affect DFS or OS. Conversely, early reductions (FEC±D) negatively affected patient outcomes.

Real-World Outcomes of Adjuvant Chemotherapy for Node-Negative and Node-Positive HER2-Positive Breast Cancer.

Background: Comparative real-world outcomes for patients with HER2-positive (HER2+) breast cancer receiving adjuvant trastuzumab outside of clinical trials are lacking. This study sought to retrospectively characterize outcomes for patients with node-negative and node-positive breast cancer receiving adjuvant trastuzumab in combination with docetaxel/cyclophosphamide (DCH), docetaxel/carboplatin/trastuzumab (TCH), or fluorouracil/epirubicin/cyclophosphamide followed by docetaxel/trastuzumab (FEC-DH) chemotherapy in Alberta, Canada, from 2007 through 2014. Methods: Disease-free survival and overall survival (OS) analyses for node-negative cohorts receiving DCH (n=111) or TCH (n=371) and node-positive cohorts receiving FEC-DH (n=146) or TCH (n=315) were compared using chi-square, Kaplan-Meier, or Cox multivariable analysis where appropriate. Results: Median follow-up was similar in node-negative (63.9 months) and node-positive (69.0 months) cohorts. The 5-year OS rates in patients with node-negative disease receiving DCH or TCH were similar (95.2% vs 96.9%; P=.268), whereas 5-year OS rates were higher but nonsignificant for patients with node-positive disease treated with FEC-DH compared with TCH (95.2% vs 91.4%; P=.160). Subgroup analysis of node-positive cohorts showed significantly improved OS with FEC-DH versus TCH in patients with estrogen receptor (ER)/progesterone receptor (PR)-positive breast cancer (98.3% vs 91.6%, respectively; P=.014). Conversely, patients with ER/PR-negative disease showed a nonsignificant trend toward higher OS rates with TCH versus FEC-DH (91.6% vs 83.3%, respectively; P=.298). Given the retrospective design, we were unable to capture all potential covariates that may have impacted treatment assignment and/or outcomes. Furthermore, cardiac toxicity data were unavailable. Conclusions: Survival rates of patients with HER2+ breast cancer in our study are comparable to those seen in clinical trials. Our findings support chemotherapy de-escalation in patients with node-negative disease and validate the efficacy of FEC-DH in those with node-positive disease.

Influence of control group therapy on the benefit from dose-dense chemotherapy in early breast cancer: a systemic review and meta-analysis.

PURPOSE: Results from clinical trials of adjuvant dose-dense chemotherapy in patients with breast cancer are inconsistent. METHODS: A systematic search of MEDLINE identified studies comparing the efficacy of dose-dense adjuvant chemotherapy to a standard treatment. The primary analysis included studies that used identical regimens in the experimental and control groups, but varied only dose density. A secondary analysis included studies that used either different drugs or doses in the experimental and the control groups. Hazard ratios (HRs) and 95% confidence intervals were computed for disease-free survival (DFS) and overall survival (OS) and pooled in a meta-analysis. Subgroup analyses and meta-regression explored drug schedules utilized in control groups and the influence of clinicopathologic variables on benefit from dose-dense therapy. RESULTS: The primary analysis included 5 studies comprising 9819 patients while the secondary analysis included 6 studies comprising 9679 patients. Dose-dense treatment significantly improved DFS (HR 0.85, p < 0.001) and OS (HR 0.86, p = 0.008) in the primary analysis. Similar results were observed in the secondary analysis. Dose-dense schedule was important primarily in studies utilizing paclitaxel every 3 weeks as the control group (interaction p = 0.04 for DFS interaction p = 0.001 for OS). A significantly greater relative magnitude of benefit was observed in pre-menopausal women and those with nodal involvement, but there was no influence of hormone receptor status on results. CONCLUSIONS: Adjuvant dose-dense regimens improve breast cancer outcomes. It remains uncertain whether the observed benefit reflects the impact of dose density or the inferiority of paclitaxel every 3 weeks as a control group.

Reporting of Randomized Trials in Common Cancers in the Lay Media.

BACKGROUND: Limited data exist about the role of the lay media in the dissemination of results of randomized controlled trials (RCTs) in common cancers. METHODS: Completed phase III RCTs evaluating new drugs in common cancers between January 2005 and October 2016 were identified from ClinicalTrials.gov. Lay media reporting was identified by searching LexisNexis Academic. Scientific reporting was defined as presentation at an academic conference or publication in full. Associations between reporting in the lay media before scientific reporting and study design and sponsorship were evaluated using logistic regression. RESULTS: Of 180 RCTs identified, 52% were reported in the lay media and in 27%, lay media reporting occurred before scientific reporting with an increasing trend over time (p = 0.009). Reporting in the lay media before scientific reporting was associated with positive results (OR: 2.10, p = 0.04), targeted therapy compared to chemotherapy (OR: 4.75, p = 0.006), immunotherapy compared to chemotherapy (OR: 7.60, p = 0.02), and prostate cancer compared to breast cancer (OR: 3.25, p = 0.02). CONCLUSIONS: Over a quarter of all RCTs in common cancers are reported in the lay media before they are reported scientifically with an increasing proportion over time. Positive trials, studies in prostate cancer, and trials of immunotherapy are associated with early reporting in the lay media.

General Overview and Treatment Recommendations for Young Women with Breast Cancer.

Breast cancer in young women is a complex disease to manage due to its biological heterogeneity and special issues related to toxicity of different treatment strategies. Defining a cut-off for young age has been challenging since it is not clear whether the prognostic effect of age is continuously variable or whether there are certain thresholds at which the prognosis changes (e.g. those < 50 years of age or ≤ 35 years of age). In this review article, we define young patients as those being premenopausal. In addition, we discuss the most recent data of the biological diversity of breast cancer arising in premenopausal patients and current treatment modalities in early and advanced settings. Survivorship, with special emphasis on the importance of early supportive care, is also discussed.

The trajectory of sarcopenia following diagnosis of prostate cancer: A systematic review and meta-analysis.

INTRODUCTION: Sarcopenia is a common skeletal muscle disorder in older people. Here we explore the prevalence of sarcopenia and its impact on men with prostate cancer. MATERIALS AND METHODS: We searched PubMed, Embase, and Web of Science databases for relevant studies with an explicit definition of sarcopenia in men with prostate cancer which were published between years 2000 and 2022. Prevalence of sarcopenia and its association with time to biochemical recurrence (BCR), progression-free survival (PFS), non-cancer mortality, overall survival (OS), and treatment-related complications in men with prostate cancer were explored. The summary prevalence, hazard ratios (HRs), and 95% confidence intervals (CIs) were calculated. RESULTS: A total of 24 studies comprising 3,616 patients with early and advanced prostate cancer were included. The prevalence of sarcopenia and sarcopenic obesity was 43.8% (95% CI 19.2%-68.5%) and 24.0% (95% CI 5.0%-43.1%), respectively. Sarcopenia was not associated with a shorter time to BCR (HR 0.89, 95% CI 0.64-1.23, p = 0.48), a shorter PFS (HR 1.20, 95% CI 0.73-1.97, p = 0.48), or a shorter OS (HR 1.29, 95% CI 0.90-1.85, p = 0.16). In contrast, sarcopenia was significantly associated with a higher non-cancer mortality (HR 1.85, 95% CI 1.23-2.80, p = 0.003). In four out of five studies eligible for assessment, sarcopenia was not associated with an increased risk of treatment-related complications. DISCUSSION: Sarcopenia increases the risk of death from other causes in men with prostate cancer. Patients with prostate cancer should be assessed and managed for sarcopenia in everyday clinical practice.

Association between PIK3CA activating mutations and outcomes in early-stage invasive lobular breast carcinoma treated with adjuvant systemic therapy.

BACKGROUND: The aim of the study was to evaluate the independent prognostic role of PIK3CA activating mutations and an association between PIK3CA activating mutations and efficacy of adjuvant endocrine therapy (ET) in patients with operable invasive lobular carcinoma (ILC). PATIENTS AND METHODS: A single institution study of patients with early-stage ILC treated between 2003 and 2008 was performed. Clinicopathological parameters, systemic therapy exposure and outcomes (distant metastasis-free survival [DMFS] and overall survival [OS]) were collected based on presence or absence of PIK3CA activating mutation in the primary tumor determined using a quantitative polymerase chain reaction (PCR)-based assay. An association between PIK3CA mutation status and prognosis in all patient cohort was analyzed by Kaplan-Meier survival analysis, whereas an association between PIK3CA mutation and ET was analyzed in estrogen receptors (ER) and/or progesterone receptors (PR)-positive group of our patients by the Cox proportional hazards model. RESULTS: Median age at diagnosis of all patients was 62.8 years and median follow-up time was 10.8 years. Among 365 patients, PIK3CA activating mutations were identified in 45%. PIK3CA activating mutations were not associated with differential DMFS and OS (p = 0.36 and p = 0.42, respectively). In patients with PIK3CA mutation each year of tamoxifen (TAM) or aromatase inhibitor (AI) decreased the risk of death by 27% and 21% in comparison to no ET, respectively. The type and duration of ET did not have significant impact on DMFS, however longer duration of ET had a favourable impact on OS. CONCLUSIONS: PIK3CA activating mutations are not associated with an impact on DMFS and OS in early-stage ILC. Patients with PIK3CA mutation had a statistically significantly decreased risk of death irrespective of whether they received TAM or an AI.

New Insights in the Era of Clinical Biomarkers as Potential Predictors of Systemic Therapy-Induced Cardiotoxicity in Women with Breast Cancer: A Systematic Review.

Cardiotoxicity induced by breast cancer therapies is a potentially serious complication associated with the use of various breast cancer therapies. Prediction and better management of cardiotoxicity in patients receiving chemotherapy is of critical importance. However, the management of cancer therapy-related cardiac dysfunction (CTRCD) lacks clinical evidence and is based on limited clinical studies. AIM: To provide an overview of existing and potentially novel biomarkers that possess a promising predictive value for the early and late onset of CTRCD in the clinical setting. METHODS: A systematic review of published studies searching for promising biomarkers for the prediction of CTRCD in patients with breast cancer was undertaken according to PRISMA guidelines. A search strategy was performed using PubMed, Google Scholar, and Scopus for the period 2013-2023. All subjects were >18 years old, diagnosed with breast cancer, and received breast cancer therapies. RESULTS: The most promising biomarkers that can be used for the development of an alternative risk cardiac stratification plan for the prediction and/or early detection of CTRCD in patients with breast cancer were identified. CONCLUSIONS: We highlighted the new insights associated with the use of currently available biomarkers as a standard of care for the management of CTRCD and identified potentially novel clinical biomarkers that could be further investigated as promising predictors of CTRCD.

BAP1-defficient breast cancer in a patient with BAP1 cancer syndrome.

BAP1 cancer syndrome is a rare and highly penetrant hereditary cancer predisposition. Uveal melanoma, mesothelioma, renal cell carcinoma (RCC) and cutaneous melanoma are considered BAP1 cancer syndrome core cancers, whereas association with breast cancer has previously been suggested but not confirmed so far. In view of BAP1 immunomodulatory functions, BAP1 alterations could prove useful as possible biomarkers of response to immunotherapy in patients with BAP1-associated cancers. We present a case of a patient with BAP1 cancer syndrome who developed a metastatic breast cancer with loss of BAP1 demonstrated on immunohistochemistry. She carried a germline BAP1 likely pathogenic variant (c.898_899delAG p.(Arg300Glyfs*6)). In addition, tumor tissue sequencing identified a concurrent somatic variant in BAP1 (partial deletion of exon 12) and a low tumor mutational burden. As her triple negative tumor was shown to be PD-L1 positive, the patient was treated with combination of atezolizumab and nab-paclitaxel. She had a complete and sustained response to immunotherapy even after discontinuation of nab-paclitaxel. This case strengthens the evidence for including breast cancer in the BAP1 cancer syndrome tumor spectrum with implications for future cancer prevention programs. It also indicates immune checkpoint inhibitors might prove to be an effective treatment for BAP1-deficient breast cancer.

Safety of CDK4/6 inhibitors and concomitant radiation therapy in patients affected by metastatic breast cancer.

PURPOSE: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) currently represent the standard of care for the initial treatment of patients with metastatic hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) breast cancer. The aim of our study is to evaluate the safety of the use of concomitant radiation therapy (RT) in a consecutive series of HR+/HER2- patients treated in two academic institutions with CDK4/6i in the metastatic setting. METHODS AND MATERIALS: From September 2017 to February 2020, we retrospectively collected and analysed data on a sequential series of patients treated with CDK4/6i, receiving RT or not, at two European institutions. Primary outcome of the study was the association between RT and any adverse events (AEs) ≥ G3. Secondary outcomes were the association between RT and any AEs (any grade), CDK4/6i dose reduction rate, and CDK4/6i treatment discontinuation rate. RESULTS: We analysed a total of 132 consecutive women; RT was prescribed in 57 (43.2%) patients (70 irradiated lesions). The median age of the series was 52.1 years (range 32.3-78.2). Concomitant RT administration was not significantly related to higher AEs ≥ G3 (p = 0.19) and any grade AEs (p = 1.0); there was no association with RT and CDK4/6i dose reduction (p = 0.49) and discontinuation rates (p = 0.14). At a median follow-up of 18.8 months, the progression-free survival (PFS) rate was 35% and the overall survival (OS) rate was 38.7% in the whole group. The use of concomitant RT did not affect both PFS (p = 0.71) and OS rates (p = 0.55). CONCLUSIONS: Our data are encouraging regarding the safety of this combination, showing that concurrent RT did not increase severe toxicity and did not have an impact on systemic treatment conduction.

Efficacy, safety and tolerability of drugs studied in phase 3 randomized controlled trials in solid tumors over the last decade.

Data suggest that for newly approved cancer drugs safety and tolerability are worse than in control arms of registration trials. Less is known about the balance between efficacy and toxicity of drugs studied in unselected phase 3 randomized controlled trials (RCTs) including those not resulting in regulatory approval. We searched Clinicaltrials.gov to identify phase 3 RCTs in patients with advanced breast, colorectal, lung, or prostate cancer completed between January 2005 and October 2016. We extracted efficacy and safety data from publications. For efficacy hazard ratios (HRs) for progression-free survival (PFS) and overall survival (OS) were extracted. For safety, we computed odds ratios (ORs) and 95% confidence intervals (CIs) for toxic death, treatment discontinuation without progression and commonly reported grade 3/4 adverse events (AEs). Data were then pooled in a meta-analysis. Of 377 RCTs identified initially, 143 RCTs comprising 88,603 patients were included in the analysis. Of these, 79 (57%) trials met their primary endpoint. Compared to control groups, both PFS (HR 0.80; 95% CI 0.78-0.82) and OS (HR 0.87; 95% CI 0.85-0.89) were improved with experimental drugs. Toxic death (OR 1.14; 95% CI 1.03-1.27), treatment discontinuation without progression (OR 1.64; 95% CI 1.56-1.71) and grade 3/4 AEs were also more common with experimental drugs compared to respective control group therapy. Just over half of phase 3 RCTs in common solid tumors met their primary endpoint and in nearly half, experimental therapy had worse safety compared to control arms.

Association of Obesity With Breast Cancer Outcome in Relation to Cancer Subtypes: A Meta-Analysis.

BACKGROUND: Obesity at breast cancer (BC) diagnosis has been associated with poor outcome, although the magnitude of effect in different BC subtypes is uncertain. We report on the association of obesity or overweight at diagnosis of nonmetastatic BC with disease-free (DFS) and overall survival (OS) in the following defined subtypes: hormone receptor positive/HER2 negative (HR+HER2-), HER2 positive (HER2+), and triple negative (TNBC). METHODS: We searched MEDLINE, EMBASE, and COCHRANE databases up to January 1, 2019. Study eligibility was performed independently by 2 authors. Studies reporting hazard ratios (HRs) of OS and/or DFS for obesity or overweight in BC subtypes were included. The pooled hazard ratio was computed and weighted using generic inverse variance and random effects models. RESULTS: Twenty-seven studies were included. Obese compared with nonobese women had worse DFS in all subtypes: the hazard ratios were 1.26 (95% confidence interval [CI] = 1.13 to 1.41, P < .001) for HR+HER2- BC, 1.16 (95% CI = 1.06 to 1.26, P < .001) for HER2+ BC, and 1.17 (95% CI = 1.06 to 1.29, P = .001) for TNBC. OS was also worse in obese vs nonobese women (HR+HER2- BC HR = 1.39, 95% CI = 1.20 to 1.62, P < .001; HER2+ BC HR = 1.18, 95% CI = 1.05 to 1.33, P = .006; and TNBC HR = 1.32, 95% CI = 1.13 to 1.53, P < .001). As opposed to obesity, overweight was not associated with either DFS or OS in HER2+ BC (HR = 1.02, 95% CI = 0.81 to 1.28, P = .85; and HR = 0.96, 95% CI = 0.76 to 1.21, P = .99, respectively) or TNBC (HR = 1.04, 95% CI = 0.93 to 1.18, P = .49; and HR = 1.08, 95% CI = 0.81 to 1.44, P = .17), respectively. In HR+HER2- BC, being overweight was associated with worse OS (HR = 1.14, 95% CI = 1.07 to 1.22, P < .001). CONCLUSIONS: Obesity was associated with modestly worse DFS and OS in all BC subtypes.

Associations between safety, tolerability, and toxicity and the reporting of health-related quality of life in phase III randomized trials in common solid tumors.

BACKGROUND: Anti-cancer drugs are approved typically on the basis of efficacy and safety as evaluated in phase III randomized trials (RCTs). Health-related quality of life (HRQoL) is a direct measure of patient benefit, but is under-reported. Here we explore associations with reporting of HRQoL data in phase III RCTs in common solid tumors. METHODS: We searched ClinicalTrials.gov to identify phase III RCTs evaluating new drugs in adults with advanced cancers that completed accrual between January 2005 and October 2016. Data on HRQoL, safety, and tolerability comprising treatment-related death, treatment discontinuation and commonly reported grade 3 or 4 adverse events (AEs) were extracted. Associations between these measures and reporting of HRQoL data were explored using logistic regression. RESULTS: Of 377 phase III RCTs identified initially, 143 studies were analysed and comprised 55% positive trials and 90% industry sponsored trials. HRQoL was listed as an endpoint in 59% trials; and of these, only 65% reported HRQoL data. There were higher odds of reporting HRQoL data for positive trials (OR 2.05, P = .04) and trials published in journals with higher impact factor (OR 1.35, P = .01). Reporting of HRQoL was not associated with treatment-related death (OR 1.25, P = .40) or treatment discontinuation (OR 1.12, P = .61), but was positively associated with dyspnea and dermatological adverse events. CONCLUSIONS: HRQoL is reported in only two-thirds of RCTs that describe collecting such data. Reporting of HRQoL is associated with positive trial outcome and higher journal impact factor, but not associated with overall safety and tolerability of anti-cancer drugs.

The Prognostic Value of Neutrophil-to-Lymphocyte Ratio in Metastatic Testicular Cancer.

We investigated the prognostic utility of pre-chemotherapy neutrophil-to-lymphocyte ratio (NLR) in patients with metastatic germ cell tumors (GCTs) undergoing first-line chemotherapy. We utilized two institutional databases to analyze the pretreatment-derived NLR (dNLR). Predictive accuracy was evaluated using the Cox proportional hazard model adjusted for the international germ cell cancer collaborative group (IGCCCG) risk classification. Discriminatory accuracy was evaluated by determining the area under the receiver operating characteristic curve (AUROC). In total, 569 of 690 patients had available dNLR (IGCCCG: good, 64%; intermediate, 21%; poor, 16%). The 5-year and 10-year overall survivals (OSs) for good, intermediate, and poor risk groups were 96.2%, 92.8%, and 62.7% and 93.9%, 90.3%, and 62.7%, respectively. A dNLR of 2 provided the best discriminatory accuracy with an AUROC of 0.58 (95% CI: 0.52-0.65, p = 0.01) for progression-free survival (PFS), whereas for OS, a dNLR of 3 provided the best discriminatory accuracy with an AUROC of 0.62 (95% CI: 0.53-0.70, p < 0.01). A dNLR > 2 was associated with a hazard ratio (HR) of 1.99 (95% CI: 1.27-3.12, p < 0.01) for PFS, which lost its effect after adjustment for IGCCCG (HR: 1.44, 95% CI: 0.90-2.30, p = 0.13). For OS, a dNLR >3 was associated with an HR of 3.00 (95% CI: 1.79-5.01, p < 0.01), but lost its effect after adjustment for IGCCCG. Systemic inflammation plays a role in metastatic GCT, but its prognostic utility beyond established algorithms is limited. The general prognostic value of NLR can be seen across a number of tumors, although the consistency and magnitude of the effect differ according to cancer type, disease stage, and treatment received. We identified that an elevated NLR was associated with an adverse PFS and OS, but not independent of the IGCCCG risk classification. dNLRs >2 and >3 were associated with an adverse PFS and OS, respectively, in patients with metastatic GCT receiving first-line chemotherapy, but not independent of the IGCCCG risk classification.

Cyclin-Dependent Kinase 4/6 Inhibitors Combined With Radiotherapy for Patients With Metastatic Breast Cancer.

BACKGROUND: The cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) represent the standard treatment for hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer. Data about the balance between efficacy and toxicity of combined palliative radiotherapy (RT) and CDK4/6 inhibition are lacking. PATIENTS AND METHODS: We undertook a review of 46 patients with metastatic breast cancer on systemic treatment with CDK4/6i who underwent 62 metastases-directed RT. Clinical, laboratory, and RT treatment planning data were collected. Statistical analyses included Student t test, paired sample t test, and logistic regression modeling. RESULTS: Thirty patients (65.2%) received palbociclib, 15 (32.6%) received ribociclib, and one patient received abemaciclib (2.2%). Median total prescribed RT dose was 20 Gy (range, 8-63 Gy). Sites of RT were bone (n = 50; 80.7%), visceral (n = 7; 11.3%), or brain metastases (n = 3; 4.8%), as well as primary tumor of the breast (n = 2; 3.2%). Overall, the rates of grade 3 or higher adverse events (AEs) were 6.5%, 4.3%, 15.2%, and 23.9% before the start of RT, during RT, 2 and 6 weeks after RT completion, respectively. We found no correlation between dose distribution to organs at risk and the development of AEs. The local control rates for the entire cohort were 98% at 6 months and 90% at 12 months. Overall, pain relief (complete or partial) was experienced by 80% (24/30) of patients who initially reported pain at the treated metastatic site. CONCLUSION: We observed a modest increase in the rates of grade 3 or higher AEs after combined RT and CDK4/6i, with maintained efficacy of concomitant RT.

Targeting CDK4/6 pathways and beyond in breast cancer.

Metastatic or advanced breast cancer (mBC/ABC) remains incurable despite many different systemic treatment options. Hormone receptor positive (HR+) disease represents the most common subtype in both early and advanced disease. A better understanding of the biology of this BC subtype, in particular regarding potential mechanisms of endocrine resistance, has led to the development of CDK4/6 inhibitors. All three selective CDK4/6 inhibitors, palbociclib, ribociclib and abemaciclib have shown to significantly improve progression-free survival (PFS) when combined to endocrine therapy as first-line treatment for patients with HR+/HER-2 negative ABC, who have progressed on or after adjuvant endocrine therapy. All three of them have also shown an improved PFS as 2nd line therapy for HR+/Her2 negative ABC. Their toxicity profile is favorable, with hematological toxicity (mainly neutropenia) being predominant, followed by diarrhea and fatigue. Quality of life has been maintained in the 1st line setting or improved in the 2nd line setting. Overall survival (OS) has been reported so far only in 2 out of 7 trials as first line therapy and the difference did not reach statistical significance. In this article we review the biology of CDK signaling pathway and its inhibitors, preclinical and clinical data of all three investigated selective CDK4/6 inhibitors and their toxicity. We also discuss how these agents are being included in current international guidelines and future directions for these agents in other subtypes of breast cancer, in both advanced disease and early-stage disease.

Deescalating Adjuvant Trastuzumab in HER2-Positive Early-Stage Breast Cancer: A Systemic Review and Meta-Analysis.

BACKGROUND: One year of adjuvant trastuzumab in combination with chemotherapy is the standard of care in early-stage human epidermal growth factor receptor 2 (HER2)-positive breast cancer. Existing data on shortening trastuzumab treatment show conflicting results. METHODS: A search of PubMed and abstracts from key conferences identified randomized trials that compared abbreviated trastuzumab therapy to 1 year of treatment in early-stage HER2-positive breast cancer. Hazard ratios (HRs) and 95% confidence intervals (CIs) were extracted for disease-free survival (DFS) and overall survival (OS). Subgroup analyses evaluated the effect of nodal involvement, estrogen receptor expression, and the duration of abbreviated trastuzumab (9-12 weeks vs 6 months). Odds ratios (ORs) and 95% confidence intervals were computed for prespecified cardiotoxicity events including cardiac dysfunction and congestive heart failure. P values were two-sided. RESULTS: Analysis included six trials comprising 11 603 patients. Shorter trastuzumab treatment was associated with worse DFS (HR = 1.14, 95% CI = 1.05 to 1.25, P = .002) and OS (HR = 1.15, 95% CI = 1.02 to 1.29. P = .02). The effect on DFS was not influenced by estrogen receptor status (P for the subgroup difference = .23), nodal involvement (P = .44), or the different duration of trastuzumab in the experimental arm (P = .09). Shorter trastuzumab treatment was associated with lower odds of cardiac dysfunction (OR = 0.67, 95% CI = 0.55 to 0.81, P < .001) and congestive heart failure (OR = 0.66, 95% CI = 0.50 to 0.86, P = .003). CONCLUSIONS: Compared with 1 year, shorter duration of adjuvant trastuzumab is associated with statistically significantly worse DFS and OS despite favorable cardiotoxicity profile. One year of targeted HER2 treatment should remain the standard adjuvant treatment in early-stage HER2-positive disease with appropriate cardiac monitoring.