Circulating Tumor Cell Clustering Shapes DNA Methylation to Enable Metastasis Seeding.

The ability of circulating tumor cells (CTCs) to form clusters has been linked to increased metastatic potential. Yet biological features and vulnerabilities of CTC clusters remain largely unknown. Here, we profile the DNA methylation landscape of single CTCs and CTC clusters from breast cancer patients and mouse models on a genome-wide scale. We find that binding sites for stemness- and proliferation-associated transcription factors are specifically hypomethylated in CTC clusters, including binding sites for OCT4, NANOG, SOX2, and SIN3A, paralleling embryonic stem cell biology. Among 2,486 FDA-approved compounds, we identify Na+/K+ ATPase inhibitors that enable the dissociation of CTC clusters into single cells, leading to DNA methylation remodeling at critical sites and metastasis suppression. Thus, our results link CTC clustering to specific changes in DNA methylation that promote stemness and metastasis and point to cluster-targeting compounds to suppress the spread of cancer.

The metastatic spread of breast cancer accelerates during sleep.

The metastatic spread of cancer is achieved by the haematogenous dissemination of circulating tumour cells (CTCs). Generally, however, the temporal dynamics that dictate the generation of metastasis-competent CTCs are largely uncharacterized, and it is often assumed that CTCs are constantly shed from growing tumours or are shed as a consequence of mechanical insults1. Here we observe a striking and unexpected pattern of CTC generation dynamics in both patients with breast cancer and mouse models, highlighting that most spontaneous CTC intravasation events occur during sleep. Further, we demonstrate that rest-phase CTCs are highly prone to metastasize, whereas CTCs generated during the active phase are devoid of metastatic ability. Mechanistically, single-cell RNA sequencing analysis of CTCs reveals a marked upregulation of mitotic genes exclusively during the rest phase in both patients and mouse models, enabling metastasis proficiency. Systemically, we find that key circadian rhythm hormones such as melatonin, testosterone and glucocorticoids dictate CTC generation dynamics, and as a consequence, that insulin directly promotes tumour cell proliferation in vivo, yet in a time-dependent manner. Thus, the spontaneous generation of CTCs with a high proclivity to metastasize does not occur continuously, but it is concentrated within the rest phase of the affected individual, providing a new rationale for time-controlled interrogation and treatment of metastasis-prone cancers.

Hepatic stellate cells suppress NK cell-sustained breast cancer dormancy.

The persistence of undetectable disseminated tumour cells (DTCs) after primary tumour resection poses a major challenge to effective cancer treatment1-3. These enduring dormant DTCs are seeds of future metastases, and the mechanisms that switch them from dormancy to outgrowth require definition. Because cancer dormancy provides a unique therapeutic window for preventing metastatic disease, a comprehensive understanding of the distribution, composition and dynamics of reservoirs of dormant DTCs is imperative. Here we show that different tissue-specific microenvironments restrain or allow the progression of breast cancer in the liver-a frequent site of metastasis4 that is often associated with a poor prognosis5. Using mouse models, we show that there is a selective increase in natural killer (NK) cells in the dormant milieu. Adjuvant interleukin-15-based immunotherapy ensures an abundant pool of NK cells that sustains dormancy through interferon-γ signalling, thereby preventing hepatic metastases and prolonging survival. Exit from dormancy follows a marked contraction of the NK cell compartment and the concurrent accumulation of activated hepatic stellate cells (aHSCs). Our proteomics studies on liver co-cultures implicate the aHSC-secreted chemokine CXCL12 in the induction of NK cell quiescence through its cognate receptor CXCR4. CXCL12 expression and aHSC abundance are closely correlated in patients with liver metastases. Our data identify the interplay between NK cells and aHSCs as a master switch of cancer dormancy, and suggest that therapies aimed at normalizing the NK cell pool might succeed in preventing metastatic outgrowth.

Neutrophils escort circulating tumour cells to enable cell cycle progression.

A better understanding of the features that define the interaction between cancer cells and immune cells is important for the development of new cancer therapies1. However, focus is often given to interactions that occur within the primary tumour and its microenvironment, whereas the role of immune cells during cancer dissemination in patients remains largely uncharacterized2,3. Circulating tumour cells (CTCs) are precursors of metastasis in several types of cancer4-6, and are occasionally found within the bloodstream in association with non-malignant cells such as white blood cells (WBCs)7,8. The identity and function of these CTC-associated WBCs, as well as the molecular features that define the interaction between WBCs and CTCs, are unknown. Here we isolate and characterize individual CTC-associated WBCs, as well as corresponding cancer cells within each CTC-WBC cluster, from patients with breast cancer and from mouse models. We use single-cell RNA sequencing to show that in the majority of these cases, CTCs were associated with neutrophils. When comparing the transcriptome profiles of CTCs associated with neutrophils against those of CTCs alone, we detect a number of differentially expressed genes that outline cell cycle progression, leading to more efficient metastasis formation. Further, we identify cell-cell junction and cytokine-receptor pairs that define CTC-neutrophil clusters, representing key vulnerabilities of the metastatic process. Thus, the association between neutrophils and CTCs drives cell cycle progression within the bloodstream and expands the metastatic potential of CTCs, providing a rationale for targeting this interaction in treatment of breast cancer.

Single-cell Analysis Reveals Inter- and Intratumour Heterogeneity in Metastatic Breast Cancer.

Metastasis is the leading cause of cancer-related deaths of breast cancer patients. Some cancer cells in a tumour go through successive steps, referred to as the metastatic cascade, and give rise to metastases at a distant site. We know that the plasticity and heterogeneity of cancer cells play critical roles in metastasis but the precise underlying molecular mechanisms remain elusive. Here we aimed to identify molecular mechanisms of metastasis during colonization, one of the most important yet poorly understood steps of the cascade. We performed single-cell RNA-Seq (scRNA-Seq) on tumours and matched lung macrometastases of patient-derived xenografts of breast cancer. After correcting for confounding factors such as the cell cycle and the percentage of detected genes (PDG), we identified cells in three states in both tumours and metastases. Gene-set enrichment analysis revealed biological processes specific to proliferation and invasion in two states. Our findings suggest that these states are a balance between epithelial-to-mesenchymal (EMT) and mesenchymal-to-epithelial transitions (MET) traits that results in so-called partial EMT phenotypes. Analysis of the top differentially expressed genes (DEGs) between these cell states revealed a common set of partial EMT transcription factors (TFs) controlling gene expression, including ZNF750, OVOL2, TP63, TFAP2C and HEY2. Our data suggest that the TFs related to EMT delineate different cell states in tumours and metastases. The results highlight the marked interpatient heterogeneity of breast cancer but identify common features of single cells from five models of metastatic breast cancer.

[New treatment options in system therapy for breast carcinoma and associated new side effects].

INTRODUCTION: Breast cancer today has a significantly better prognosis than two to three decades ago. Treatment options have improved significantly. However, new systemic therapy has also resulted in side effects that clinicians must first become familiar with in order to be able to treat them optimally. This article gives an overview of the most important innovations in the last 10 years in the field of systemic therapy in breast cancer and also shows the most important side effects and their management.

Maintenance Therapy with Aromatase Inhibitor in epithelial Ovarian Cancer (MATAO): study protocol of a randomized double-blinded placebo-controlled multi-center phase III Trial.

BACKGROUND: A high percentage of epithelial ovarian cancers (EOC) express the estrogen receptor (ER), which is an ideal target for endocrine therapy. Letrozole is a proven, potent aromatase inhibitor, extensively tested and used in the treatment of ER positive breast cancer. In addition, it seems a potent drug for patients with heavily pre-treated OC as demonstrated in several distinctive settings. However, it has never been evaluated prospectively in a maintenance setting for ovarian cancer after standard of care. The here proposed trial aims to define a population of EOC patients, who would benefit from the effectiveness of the generic agent letrozole, with little expected toxicity and thus beneficial impact on overall quality of life (QoL). METHODS: In this international multicenter randomized, placebo-controlled phase III trial at clinical centers in Switzerland, Germany and Austria, we plan to include 540 patients with primary, newly diagnosed FIGO Stage II to IV and histologically confirmed low- or high-grade serous or endometrioid epithelial ovarian/fallopian tube/peritoneal cancer. Patients are randomized in a 1:1 ratio into two groups: receiving blinded study treatment (letrozole or placebo tablets). When assuming a HR of 0.7, a median PFS of 18 months in the control arm and a median PFS of 25.7 months in the treatment arm, a two-sided alpha level of 5%, 3.5 years recruitment and 1.5 years observation time, we expect 330 events to have occurred within these 5 years in the total cohort yielding a power of 90%. Follow-up data for the whole cohort will be collected for up to 10 years and for the low-grade cancer for up to 12 years. DISCUSSION: The here proposed randomized phase III trial aims to identify patients with EOC in the maintenance setting, who benefit from the effectiveness of the letrozole, by proving its efficacy whilst maintaining a high standard of QoL due to the limited toxicity expected in comparison to the current alternative drugs on the market for this treatment phase. TRIAL REGISTRATION: This trial is registered at clinicaltrials.gov under the identifier NCT04111978 . Registered 02 October 2019.

Hormone Receptor Expression in Primary and Recurrent High-Grade Serous Ovarian Cancer and Its Implications in Early Maintenance Treatment.

Endocrine therapy is an effective treatment for low-grade serous ovarian cancer. However, the role of estrogen and progesterone receptors as biomarkers for high-grade serous ovarian cancer (HGSOC) is yet to be elucidated because not all estrogen and progesterone receptor-positive tumors benefit from anti-estrogen therapy. The degree of expression is presumed to play a vital role; however, that role is not well-defined in ovarian cancer. We aimed to determine the role of estrogen and progesterone receptor expression in primary and paired relapsed HGSOC. In this study, primary and matched relapsed tumor samples were collected from 80 patients with International Federation of Gynecology and Obstetrics Stage II-IV HGSOC. Tissue microarray was conducted and immunohistochemistry for estrogen and progesterone receptor expression was performed. Two independent pathologists performed the tissue microarray analysis with the Immunoreactive Score and Allred Total score. In the paired analysis, no significant difference in estrogen receptor expression was observed. However, progesterone receptor expression was significantly lower in patients with recurrent platinum-sensitive HGSOC. We conclude that anti-estrogen therapy targeting estrogen receptor positive HGSOC could be administered in primary and relapsed settings. The use of endocrine maintenance with an aromatase inhibitor in patients with estrogen receptor positive HGSOC needs to be further evaluated and validated in a randomized controlled trial.

Palbociclib with adjuvant endocrine therapy in early breast cancer (PALLAS): interim analysis of a multicentre, open-label, randomised, phase 3 study.

BACKGROUND: Palbociclib added to endocrine therapy improves progression-free survival in hormone-receptor-positive, HER2-negative, metastatic breast cancer. The PALLAS trial aimed to investigate whether the addition of 2 years of palbociclib to adjuvant endocrine therapy improves invasive disease-free survival over endocrine therapy alone in patients with hormone-receptor-positive, HER2-negative, early-stage breast cancer. METHODS: PALLAS is an ongoing multicentre, open-label, randomised, phase 3 study that enrolled patients at 406 cancer centres in 21 countries worldwide with stage II-III histologically confirmed hormone-receptor-positive, HER2-negative breast cancer, within 12 months of initial diagnosis. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group performance score of 0 or 1. Patients were randomly assigned (1:1) in permuted blocks of random size (4 or 6), stratified by anatomic stage, previous chemotherapy, age, and geographical region, by use of central telephone-based and web-based interactive response technology, to receive either 2 years of palbociclib (125 mg orally once daily on days 1-21 of a 28-day cycle) with ongoing standard provider or patient-choice adjuvant endocrine therapy (tamoxifen or aromatase inhibitor, with or without concurrent luteinising hormone-releasing hormone agonist), or endocrine therapy alone, without masking. The primary endpoint of the study was invasive disease-free survival in the intention-to-treat population. Safety was assessed in all randomly assigned patients who started palbociclib or endocrine therapy. This report presents results from the second pre-planned interim analysis triggered on Jan 9, 2020, when 67% of the total number of expected invasive disease-free survival events had been observed. The trial is registered with ClinicalTrials.gov (NCT02513394) and EudraCT (2014-005181-30). FINDINGS: Between Sept 1, 2015, and Nov 30, 2018, 5760 patients were randomly assigned to receive palbociclib plus endocrine therapy (n=2883) or endocrine therapy alone (n=2877). At the time of the planned second interim analysis, at a median follow-up of 23·7 months (IQR 16·9-29·2), 170 of 2883 patients assigned to palbociclib plus endocrine therapy and 181 of 2877 assigned to endocrine therapy alone had invasive disease-free survival events. 3-year invasive disease-free survival was 88·2% (95% CI 85·2-90·6) for palbociclib plus endocrine therapy and 88·5% (85·8-90·7) for endocrine therapy alone (hazard ratio 0·93 [95% CI 0·76-1·15]; log-rank p=0·51). As the test statistic comparing invasive disease-free survival between groups crossed the prespecified futility boundary, the independent data monitoring committee recommended discontinuation of palbociclib in patients still receiving palbociclib and endocrine therapy. The most common grade 3-4 adverse events were neutropenia (1742 [61·3%] of 2840 patients on palbociclib and endocrine therapy vs 11 [0·3%] of 2903 on endocrine therapy alone), leucopenia (857 [30·2%] vs three [0·1%]), and fatigue (60 [2·1%] vs ten [0·3%]). Serious adverse events occurred in 351 (12·4%) of 2840 patients on palbociclib plus endocrine therapy versus 220 (7·6%) of 2903 patients on endocrine therapy alone. There were no treatment-related deaths. INTERPRETATION: At the planned second interim analysis, addition of 2 years of adjuvant palbociclib to adjuvant endocrine therapy did not improve invasive disease-free survival compared with adjuvant endocrine therapy alone. On the basis of these findings, this regimen cannot be recommended in the adjuvant setting. Long-term follow-up of the PALLAS population and correlative studies are ongoing. FUNDING: Pfizer.

Denosumab treatment is associated with the absence of circulating tumor cells in patients with breast cancer.

BACKGROUND: The presence of circulating tumor cells (CTCs) in patients with breast cancer correlates to a bad prognosis. Yet, CTCs are detectable in only a minority of patients with progressive breast cancer, and factors that influence the abundance of CTCs remain elusive. METHODS: We conducted CTC isolation and enumeration in a selected group of 73 consecutive patients characterized by progressive invasive breast cancer, high tumor load and treatment discontinuation at the time of CTC isolation. CTCs were quantified with the Parsortix microfluidic device. Clinicopathological variables, blood counts at the time of CTC isolation and detailed treatment history prior to blood sampling were evaluated for each patient. RESULTS: Among 73 patients, we detected at least one CTC per 7.5 ml of blood in 34 (46%). Of these, 22 (65%) had single CTCs only, whereas 12 (35%) featured both single CTCs and CTC clusters. Treatment with the monoclonal antibody denosumab correlated with the absence of CTCs, both when considering all patients and when considering only those with bone metastasis. We also found that low red blood cell count was associated with the presence of CTCs, whereas high CA 15-3 tumor marker, high mean corpuscular volume, high white blood cell count and high mean platelet volume associated specifically with CTC clusters. CONCLUSIONS: In addition to blood count correlatives to single and clustered CTCs, we found that denosumab treatment associates with most patients lacking CTCs from their peripheral circulation. Prospective studies will be needed to validate the involvement of denosumab in the prevention of CTC generation.

SAKK 24/09: safety and tolerability of bevacizumab plus paclitaxel vs. bevacizumab plus metronomic cyclophosphamide and capecitabine as first-line therapy in patients with HER2-negative advanced stage breast cancer - a multicenter, randomized phase III trial.

BACKGROUND: Adding bevacizumab to chemotherapy improves response rates and progression-free survival (PFS) in metastatic breast cancer (mBC). We aimed to demonstrate decreased toxicity with metronomic chemotherapy/bevacizumab compared with paclitaxel/bevacizumab. METHODS: This multicenter, randomized phase III trial compared bevacizumab with either paclitaxel (arm A) or daily oral capecitabine-cyclophosphamide (arm B) as first-line treatment in patients with HER2-negative advanced breast cancer. The primary endpoint was the incidence of selected grade 3-5 adverse events (AE) including: febrile neutropenia, infection, sensory/motor neuropathy, and mucositis. Secondary endpoints included objective response rate, disease control rate, PFS, overall survival (OS), quality of life (QoL), and pharmacoeconomics. The study was registered prospectively with ClinicalTrials.gov, number NCT01131195 on May 25, 2010. RESULTS: Between September 2010 and December 2012, 147 patients were included at 22 centers. The incidence of primary endpoint-defining AEs was similar in arm A (25 % [18/71]; 95 % CI 15-35 %) and arm B (24 % [16/68]; 95 % CI 13-34 %; P = 0.96). Objective response rates were 58 % (42/73; 95 % CI 0.46-0.69) and 50 % (37/74; 95 % CI 0.39-0.61) in arms A and B, respectively (P = 0.45). Median PFS was 10.3 months (95 % CI 8.7-11.3) in arm A and 8.5 months (95 % CI 6.5-11.9) in arm B (P = 0.90). Other secondary efficacy endpoints were not significantly different between study arms. The only statistically significant differences in QoL were less hair loss and less numbness in arm B. Treatment costs between the two arms were equivalent. CONCLUSION: This trial failed to meet its primary endpoint of a reduced rate of prespecified grade 3-5 AEs with metronomic bevacizumab, cyclophosphamide and capecitabine.

Personal or first-degree family breast cancer history: which has higher impact on tumor detection and tumor size in breast cancer.

PURPOSE: A woman's risk of developing breast cancer (BC) is increased if she has a personal history (PH) or family history (FH) of the disease. We compared the impact of the two risk factors PH and FH on tumor detection and tumor size at diagnosis in a cohort of BC patients. METHODS: The study cohort comprised 1,037 invasive BC patients (≤70 years at diagnosis). From these, 92 patients (8.5%) had a positive PH and 151 patients (13.7%) had a positive first-degree FH. RESULTS: Compared to the tumors of patients without PH or FH, the lesions of patients who had a positive PH or a positive FH were more often found by radiologic breast examinations (RBE) (PH: 49.4%, FH: 43.4%, no PH/FH: 26.2%; both comparisons p < 0.001). In patients with a positive FH, the tumors were slightly less often found by RBE as in patients with a positive PH (p = 0.468). Patients with a positive PH or FH had smaller tumors compared with those without such a history (PH: 19.7 mm, FH: 19.6 mm, no PH/FH: 26.7 mm; p = 0.015/p < 0.001). The tumor sizes of patients with a positive PH were almost identical to those of patients with a positive FH (p = 0.999). CONCLUSIONS: In women with a positive FH or PH of BC, the increased awareness of BC risk led to the detection of smaller tumors compared to women who have not had this experience. However, comparison of the two risk factors showed that they had a similar impact on the RBE detection rate of BC lesions and that the tumor sizes were nearly identical.

Pulmonary Tumor Thrombotic Microangiopathy in a Patient with Rapid Progressive Triple-Negative Breast Cancer.

Introduction: Pulmonary tumor thrombotic microangiopathy (PTTM) is a rare complication of metastatic carcinoma, which occurs in patients with pulmonary arterial hypertension, and is mostly fatal. Circulating tumor cell clusters have been recognized as critical factors during breast cancer progression. Case Presentation: An 80-year-old woman with triple-negative breast cancer was admitted to our hospital with progressive dyspnea and lower back pain. Breast cancer treatment included mastectomy, neoadjuvant and adjuvant chemotherapy as well as adjuvant radiotherapy, receiving her last cycle of radiotherapy 8 days before death. At admission, D-dimers were strongly elevated and platelets were low. NT-pro-BNP was moderately elevated. A CT scan of the chest did not show pulmonary embolism but revealed interlobular septal thickening, centrilobular consolidation, and distension of the pulmonary arteries. Moreover, new skeletal and most likely lymphatic metastasis was described. Treatment with oxygen and oral glucocorticoids was initiated, assuming radiotherapy-induced pneumonitis. Due to low expression of PD-L1 and her markedly bad performance status, tumor-specific therapy was not possible, and the treatment regimen was changed to best supportive care. The patient died 8 days after admission. Autopsy revealed numerous events consistent with tumor emboli in the pulmonary vessels, suggesting PTTM. Conclusion: PTTM is a rare and mostly fatal complication in malignant breast cancer. As an early detection is difficult, further investigation is needed. Circulating tumor cluster cells may be one way to detect PTTM early and improve patients' survival.

Prognostic Importance of Axillary Lymph Node Response to Neoadjuvant Systemic Therapy on Axillary Surgery in Breast Cancer-A Single Center Experience.

Neoadjuvant systemic treatment (NST) is the standard treatment for HER2+, triple-negative (TN), and highly proliferative luminal HER2- early breast cancer. Pathologic complete response (pCR) after NST is associated with improved outcomes. We evaluated the predictive factors for axillary-pCR (AXpCR) and its impact on the extent of axillary node surgery. This retrospective study included 92 patients (median age of 50.4 years) with an initially node-positive disease. Patients were treated with molecular subtype-specific NST (4.3% were luminal A-like, 28.3% luminal HER2-, 26.1% luminal HER2+, 18.5% HER2+ non-luminal, and 22.8% TN). Axillary-, breast- and total-pCR were achieved in 52.2%, 48.9%, and 38% of patients, respectively. In a binary logistic regression model for the whole population, the only independent factor significantly associated with AXpCR was breast-pCR (OR 7.4; 95% CI 2.6-20.9; p < 0.001). In patients who achieved breast-pCR, aggressive subtypes (HER2+ and TN; OR 11.24) and clinical tumor stage (OR 0.10) had a significant impact on achieving AXpCR. Axillary lymph node dissection was avoided in 53.3% of patients. In conclusion, in node-positive patients with HER2+ and TN subtypes, who achieved breast-pCR after NST, de-escalation of axillary surgery could be considered in most cases.

Management of Patients with Hypersensitivity to Platinum Salts and Taxane in Gynecological Cancers: A Cross-Sectional Study by the European Network of Young Gynaecologic Oncologists (ENYGO).

Platinum and taxane chemotherapy is associated with the risk of hypersensitivity reactions (HSRs), which may require switching to less effective treatments. Desensitization to platinum and taxane HSRs can be used to complete chemotherapy according to the standard regimen. Therefore, we aimed to investigate the current management of HSRs to platinum and/or taxane chemotherapy in patients with gynecologic cancers. We conducted an online cross-sectional survey among gynecological and medical oncologists consisting of 33 questions. A total of 144 respondents completed the survey, and 133 respondents were included in the final analysis. Most participants were gynecologic oncologists (43.6%) and medical oncologists (33.8%), and 77.4% (n = 103) were involved in chemotherapy treatment. More than 73% of participants experienced >5 HSRs to platinum and taxane per year. Premedication and a new attempt with platinum or taxane chemotherapy were used in 84.8% and 92.5% of Grade 1-2 HSRs to platinum and taxane, respectively. In contrast, desensitization was used in 49.4% and 41.8% of Grade 3-4 HSRs to platinum and taxane, respectively. Most participants strongly emphasized the need to standardize the management of platinum and taxane HSRs in gynecologic cancer. Our study showed that HSRs in gynecologic cancer are common, but management is variable and the use of desensitization is low. In addition, the need for guidance on the management of platinum- and taxane-induced HSRs in gynecologic cancer was highlighted.

Leave no one behind: A global survey of the current state of geriatric oncology practice by SIOG national representatives.

INTRODUCTION: The Sustainable Development Goals of the United Nations include a commitment to "leave no one behind" as a universal goal. To achieve this in geriatric oncology (GO) worldwide, it is important to understand the current state of GO at an international level. The International Society of Geriatric Oncology (SIOG) has several National Representatives (NRs) who act as SIOG's delegates in their respective countries. The NRs took part in this international survey exploring the state of GO practice, identifying barriers and solutions. MATERIALS AND METHODS: The NRs answered open-ended questions by email from February 2020 to October 2022. The questionnaire domains included the demographic information of older adults for their countries, and the NRs' opinions on whether GO is developing, what the barriers are to developing GO, and proposed actions to remove these barriers. The demographic data of each country reported in the survey was adjusted using literature and database searches. RESULTS: Twenty-one of thirty countries with NRs (70%) participated in this questionnaire study: 12 European, four Asian, two North American, two South American, and one Oceanian. The proportion of the population aged ≥75 years varied from 2.2% to 15.8%, and the average life expectancy also varied from 70 years to 86 years. All NRs reported that GO was developing in their country; four NRs (18%) reported that GO was well developed. Although all NRs agreed that geriatric assessment was useful, only three reported that it was used day-to-day in their countries' clinical practice (14%). The major barriers identified were the lack of (i) evidence to support GO use, (ii) awareness and interest in GO, and (iii) resources (time, manpower, and funding). The major proposed actions were to (i) provide new evidence through clinical trials specific for GO patients, (ii) stimulate awareness through networking, and (iii) deliver educational materials and information to healthcare providers and medical students. DISCUSSION: This current survey has identified the barriers to GO and proposed actions that could remove them. Broader awareness seems to be essential to implementing GO. Additional actions are needed to develop GO within countries and can be supported through international partnerships.

Breast cancer in women 80 years of age and older: a comprehensive analysis of an underreported entity.

BACKGROUND: Approximately 10% of breast cancer (BC) patients are over the age of 80. We present the first comprehensive review on this particular group of patients. PATIENTS AND METHODS: The treatments and disease courses of an unselected cohort of patients, whose age at first diagnosis was ≥ 80 years (n = 151), were compared to those of a group of women, who were aged 56-66 years (n = 372). RESULTS: The group of elderly patients had larger tumors at first diagnosis (25 mm vs. 18 mm, p < 0.001) and higher disease stages (I: 31.1% vs. 44.1%, IV: 11.9% vs. 5.4%; each p < 0.001). There were no significant differences between both groups in terms of histologic subtype, grading, hormonal receptor status and HER2 status. The tumors of older patients were more often detected by clinical examination (38.9% vs. 17.0%, p < 0.001) and less often by mammography/sonography (10.4% vs. 29.9%, p < 0.001). The rate of patients who died of BC were similar in both groups (21.2% vs. 21.5%, p = 1.00). In the patients who had no evidence of metastases and who opted for primary non-surgical management (n = 21), the tumor could be stabilized without considerable morbidity in only 42.9%. Persistence to adjuvant endocrine therapy was comparable (83.0% vs. 88.3%, p = 0.357). In the adjuvant as well as in the palliative settings, elderly patients received less chemotherapy than younger ones (adjuvant: 1.6% vs. 23.3%; palliative: 32.3% vs. 68.4%; each p < 0.001). For palliative treatments only, elderly patients received fewer treatment regimens (≥ 3 therapy lines: 16.0% vs. 54.9%, p < 0.001). In those patients who died of BC, elderly women had inferior overall (25 vs. 54.5 months, p < 0.001) as well as metastatic-disease survival (11.5 vs. 19 months, p = 0.062). CONCLUSION: It must be ensured that appropriate standard therapies should not be routinely withheld in older patients based on erroneous perceptions regarding the biological nature of BC in the elderly and lack of knowledge about available therapy regimens. Physicians should consider that preservation of current life circumstances and maintenance of quality of life are frequently more important than "classical" hard medical facts such as survival times.

Genome-wide RNA interference analysis of renal carcinoma survival regulators identifies MCT4 as a Warburg effect metabolic target.

Clear cell renal cell carcinoma (ccRCC) is the most common pathological subtype of kidney cancer. Here, we integrated an unbiased genome-wide RNA interference screen for ccRCC survival regulators with an analysis of recurrently overexpressed genes in ccRCC to identify new therapeutic targets in this disease. One of the most potent survival regulators, the monocarboxylate transporter MCT4 (SLC16A3), impaired ccRCC viability in all eight ccRCC lines tested and was the seventh most overexpressed gene in a meta-analysis of five ccRCC expression datasets. MCT4 silencing impaired secretion of lactate generated through glycolysis and induced cell cycle arrest and apoptosis. Silencing MCT4 resulted in intracellular acidosis, and reduction in intracellular ATP production together with partial reversion of the Warburg effect in ccRCC cell lines. Intra-tumoural heterogeneity in the intensity of MCT4 protein expression was observed in primary ccRCCs. MCT4 protein expression analysis based on the highest intensity of expression in primary ccRCCs was associated with poorer relapse-free survival, whereas modal intensity correlated with Fuhrman nuclear grade. Consistent with the potential selection of subclones enriched for MCT4 expression during disease progression, MCT4 expression was greater at sites of metastatic disease. These data suggest that MCT4 may serve as a novel metabolic target to reverse the Warburg effect and limit disease progression in ccRCC.