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.

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.

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.

Desensitization in patients with hypersensitivity to platinum and taxane in gynecological cancers.

BACKGROUND: Exposure to paclitaxel and carboplatin has the risk of developing hypersensitivity reactions (HSRs), which could necessitate using less effective treatments to avoid anaphylaxis. Desensitization to platinum and taxane HSRs can be used to complete chemotherapy according to the standard regimen; therefore, this study investigated rates and benefits of successful desensitization in patients with gynecologic cancers (GC). METHODS: We collected data from 241 patients with GC who had at least one cycle of platinum or taxane chemotherapy. The rate of HSRs and successful desensitization were evaluated, and an outcome analysis was conducted. RESULTS: The rate of HSRs to platinum and taxane was 6.39% and 13.07%, respectively. We observed a 100% success rate of desensitization in our cohort. Patients with HSR were significantly younger (57.1 vs. 64.9 years, p = 0.030) in the taxane cohort. Importantly, the overall survival (OS) of patients with platinum and taxane HSRs who underwent desensitization was comparable to that of patients with no HSRs (platinum vs. controls; median OS 60.36 vs. 60.39 months, p = 0.31; taxane vs. controls; OS 80.29 vs. 60.00 months, p = 0.59). CONCLUSION: Thus, we show that desensitization for platinum and taxane HSRs is safe and effective, resulting in an outcome that is well comparable to patients without HSR. Based on these observations, desensitization procedures might be considered as standard of care before switching to less effective treatment for patients with GC.

[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.

Clinical and pathological factors and outcome of central nervous system metastasis in breast cancer.

Background: In Switzerland, approximately 6000 new breast cancer cases and 1300 deaths are reported annually. Brain metastasis from breast cancer (BMBC) has a major effect on prognosis. This study aimed to identify prognostic factors for overall survival (OS) in a cohort of Swiss patients with BMBC. This study evaluated the prognosis on older BMBC, which has not been completely addressed in the literature. Methods: We performed a retrospective chart review analysis with the primary endpoint of OS after a diagnosis of BMBC. The study population was divided into 2 groups based on an OS cut-off value of 12 months after diagnosis. Univariate and multivariate analyses of several risk factors, including age, were performed. To evaluate differences in OS according to age, we performed a secondary analysis to examine the prognostic value of clinical symptoms, metastatic pattern, and lymph node involvement in an older (≥65 years) vs. younger (<65 years) cohort. Results: From 1989 to 2019, 55 patients were identified as having BMBC, among whom 47 patients were confirmed to be dead. The median patient age was 58 years (range 25-83 years). Comorbidities were present in 45 (81.8%) patients. The median survival in the OS <12 and OS ≥12 months groups was 4.3 and 30.7 months, respectively (p<0.001). Multivariate analysis revealed no significant differences in terms of comorbidities, medication use, M-stage, and symptomatology between the 2 groups. Additionally, there was no significant difference in OS in the 2 subgroups of patients aged <65 and ≥65 years. Discussion: We concluded that age should not be a decisive factor in therapy planning for advanced breast cancer patients with BMBC.

Upfront Taxane Could Be Superior to Pegylated Liposomal Doxorubicin (PLD): A Retrospective Real-World Analysis of Treatment Sequence Taxane-PLD versus PLD-Taxane in Patients with Metastatic Breast Cancer.

Background: Patients with endocrine-resistant metastatic breast cancer (MBC) require cytostatic therapy. Single-agent taxanes and anthracyclines, including pegylated liposomal doxorubicin (PLD), are standard treatment options. There are no prospective data regarding optimal treatment sequences, and real-world data regarding both treatment options are limited. Methods: We analyzed electronic records of all patients with Her2-negative MBC treated with either first-line PLD or first-line taxane and subsequent crossover at the University Hospital Basel between 2003 and 2021. The primary endpoint was time to next chemotherapy or death (TTNC). Secondary endpoints were overall survival (OS), progression-free survival (PFS), and objective response rate (ORR). We used the Kaplan-Meyer method and logrank test to compare time-to-event endpoints and the Fisher exact test to compare discrete variables. Results: We retrospectively identified 42 patients with Her2-negative MBC who have received either single-agent PLD or single-agent taxane as first-line chemotherapy with subsequent crossover, including 23 patients who received first-line PLD and 19 patients who received first-line taxane. Baseline characteristics were similar between treatment groups. Treatment sequence PLD-taxane was significantly inferior to taxane-PLD regarding all endpoints: median TTNC 4.9 vs. 9.9 months (p = 0.006), median OS 17.8 vs. 24.6 months (p = 0.05), median PFS 4.4 vs. 9.0 months (p = 0.005), and ORR 13% vs. 53% (p = 0.01). Conclusions: Here, we report a first retrospective head-to-head comparison of the treatment sequence PLD-taxane versus taxane-PLD in patients with MBC, showing a substantial advantage of using taxanes first, followed by PLD. An inherent treatment bias in favor of first-line taxanes cannot be excluded, thus calling for prospective validation.

Changes in the quality of life of early breast cancer patients and comparison with the normative Slovenian population.

BACKGROUND: We aimed to identify changes in quality of life after breast cancer treatment and compare them with the normative population data for the Slovenian population. PATIENTS AND METHODS: A prospective, single-group, cohort design was used. A total of 102 early breast cancer patients treated with chemotherapy at the Institute of Oncology Ljubljana were included. Of those, 71% returned the questionnaires after one-year post-chemotherapy. The Slovenian versions of the European Organisation for Research and Treatment of Cancer (EORTC) QLQ C30 and BR23 questionnaires were used. Primary outcomes were a comparison of global health status/quality of life (GHS) and C30 Summary Score (C30-SumSc) at baseline and one-year post-chemotherapy with the normative Slovenian population. The exploratory analysis evaluated the differences in symptoms and functional scales of QLQ C-30 and QLQ BR-23 between baseline and one-year post-chemotherapy. RESULTS: At baseline and one-year post-chemotherapy, C30-SumSc of patients was lower than the predicted C30-SumSc from the normative Slovenian population by 2.6 points (p = 0.04) and 6.5 points (p < 0.001), resp. On the contrary, GHS was not statistically different from predicted either at baseline or after one year. Exploratory analysis revealed that one-year post-chemotherapy compared to the beginning of chemotherapy, patients had statistically significantly and clinically meaningful lower scores in body image and cognitive functioning, and increased symptom scores for pain, fatigue, and arm symptoms. CONCLUSIONS: The C30-SumSc is reduced one-year post-chemotherapy. Early interventions should be directed toward the prevention of the decline of cognitive functioning and body image, and to alleviate fatigue, pain, and arm symptoms.

Pertuzumab as second­ or later­line therapy for human epidermal growth factor receptor 2­positive metastatic breast cancer: A clinical experience.

Trastuzumab and pertuzumab with taxane-based chemotherapy are considered the first-line standard therapy for human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (mBC). Pertuzumab is also a later-line therapy for mBC in Switzerland, although limited safety and efficacy data are available. The present study assessed the therapeutic regimens, toxicities and clinical outcomes after second- or later-line pertuzumab therapy in patients with mBC who did not receive pertuzumab as a first-line therapy. Physicians from nine major Swiss oncology centers retrospectively completed a questionnaire for each pertuzumab-naive patient who was treated with pertuzumab as a second- or later-line therapy. Of 35 patients with HER2-positive mBC (median age, 49 years; range, 35-87 years), 14 received pertuzumab as a second-line therapy, 6 as a third-line therapy, and 15 as a fourth- or later-line therapy. A total of 20 patients (57%) died during the study period. The median overall survival was 74.2 months (95% confidence interval, 47.6-139.8 months). Grade (G) 3/4 adverse events (AEs) were reported in 14% of patients, with only 1 patient discontinuing therapy due to pertuzumab-related toxicities. The most common AE was fatigue (overall, 46%; G3, 11%). Overall, congestive heart disease occurred in 14% of patients (G3, 6%), nausea in 14% of patients (all G1), and myelosuppression in 12% of patients (G3, 6%). In conclusion, the median overall survival of patients who underwent second- or later-line pertuzumab treatment was similar to that reported for patients who underwent first-line pertuzumab treatment, and the safety profile was acceptable. These data support the use of pertuzumab for second- or later-line therapy when it was not administered as first-line therapy.

Therapeutic approaches in patients with bone metastasis due to endometrial carcinoma - A systematic review.

Background: Bone metastases (BM) are uncommon in endometrial carcinoma (EC), without information on the optimal oncologic management of patients with BM in EC. Here, we systematically review clinical characteristics, treatment approaches and prognosis in patients with BM in EC. Methods: We conducted a systematic literature search until 27th March 2022 on PubMed, MEDLINE, Embase and clinicaltrials.gov. Outcomes included treatment frequency and survival after BM with comparators being treatment approaches (local cytoreductive bone surgery, systemic therapy, and local radiotherapy). Risk of bias was assessed using the NIH Quality Assessment Tool and Navigation Guide methodology. Results: We retrieved 1096 records of which 112 retrospective studies (12 cohort studies, 12/12 fair quality; 100 case studies, 100/100 low quality) with a total of 1566 patients were included. The majority had a primary diagnosis of FIGO stage IV, grade 3 endometrioid EC. Singular BM were present in a median of 39.2%, multiple BM in 60.8% and synchronous additional distant metastases in 48.1% of patients respectively. In patients with secondary BM median time to bone recurrence was 14 months. Median survival after BM was 12 months. Local cytoreductive bone surgery was assessed in 7/13 cohorts and performed in a median of 15.8% (interquartile range [IQR] 10.3-43.0) of patients. Chemotherapy was assessed in 11/13 cohorts and administered in a median of 55.5% (IQR 41.0-63.9), hormonal therapy (7/13 cohorts) in 24.7% (IQR 16.3-36.0), and osteooncologic therapy (4/13 cohorts) in 2.7% (IQR 0.0-7.5) of patients respectively. Local radiotherapy was assessed in 9/13 cohorts and performed in a median of 66.7% (IQR 55.6-70.0) of patients. Survival benefits were seen in 2/3 cohorts after local cytoreductive bone surgery, and in 2/7 cohorts after chemotherapy without survival benefits in the remaining cohorts and investigated therapies. Limitations include the lack of controlled intervention studies, the heterogeneity and retrospective nature of the investigated populations. Conclusions: This systematic review shows heterogenous therapeutic approaches in clinical practice without clear evidence for optimal oncologic management for patients with BM in EC.

Distinct Cognitive Function Profiles Are Associated With a Higher Presurgery Symptom Burden in Patients With Breast Cancer.

BACKGROUND: Cancer-related cognitive impairment (CRCI) is a common symptom in patients with breast cancer. In our previous study of 397 women with breast cancer, we identified 3 groups of patients with distinct CRCI profiles (ie, high, moderate, and low-moderate attentional function). Compared with the other 2 classes, the low-moderate class was younger, had more comorbidities, and with lower functional status. OBJECTIVES: In this study, we expand on this work and evaluate for differences among these latent classes in the severity of psychological (depression and anxiety) and physical (fatigue, decrements in energy, sleep disturbance, and pain) symptoms before surgery. METHODS: Cancer-related cognitive impairment was assessed using the Attentional Functional Index from before through 6 months after surgery. Lower Attentional Functional Index scores indicate higher levels of CRCI. Psychological and physical symptoms were assessed with valid instruments. Parametric and nonparametric tests were used to evaluate for differences in symptom severity scores among the latent classes. RESULTS: Approximately 60% of patients experienced CRCI (ie, moderate and low-moderate classes). Significant differences were found among the 3 classes in the severity of trait and state anxiety, depressive symptoms, fatigue, and sleep disturbance (ie, high < moderate < low-moderate). In addition, compared with the other 2 classes, the low-moderate class reported higher pain interference scores. CONCLUSIONS: These findings suggest that women with clinically meaningful levels of persistent CRCI have a relatively high symptom burden before surgery. IMPLICATIONS FOR PRACTICE: Clinicians need to routinely perform preoperative assessments of CRCI and associated symptoms and initiate therapeutic interventions.

Application of a 21-Gene Recurrence Score in a Swiss Single-Center Breast Cancer Population: A Comparative Analysis of Treatment Administration before and after TAILORx.

In patients with hormone receptor positive, human epidermal receptor 2 negative (HR+/HER2-) negative breast cancer (BC), the TAILORx study showed the benefit of adding chemotherapy (CHT) to endocrine therapy (ET) in a subgroup of patients under 50 years with an intermediate Oncotype DX recurrence score (RS 11-25). The aim of the present study was to determine if the TAILORx findings, including the changes in the RS categories, impacted CHT use in the intermediate RS (11-25) group in daily practice, as well as to identify the main factors for CHT decisions. We conducted a retrospective study on 326 BC patients (59% node-negative), of which 165 had a BC diagnosis before TAILORx (Cohort A) and 161 after TAILORx publication (Cohort B). Changes in the RS categories led to shifts in patient population distribution, thereby leading to a 40% drop in the low RS (from 60% to 20%), which represented a doubling in the intermediate RS (from 30% to 60%) and an increase of 5% in the high RS (from 8-10% to 15%). The overall CHT recommendation and application did not differ significantly between cohort B when compared with A (19% vs. 22%, resp., p = 0.763). In the intermediate RS (11-25), CHT use decreased by 5%, while in the high-risk RS category (>25), there was an increase of 13%. The tumor board recommended CHT for 90% of the patients according to the new RS guidelines in cohort A and for 85% in cohort B. The decision for CHT recommendation was based on age (OR 0.93, 95% CI 0.08-0.97, p = 0.001), nodal stage (OR 4.77, 95% CI 2.03-11.22, p < 0.001), and RS categories (RS 11-25 vs. RS 0-10: OR 0.06 (95% CI 0.02-0.17), p < 0.001; RS > 26 vs. RS 11-25: OR 618.18 95% CI 91.64-4169.91, p < 0.001), but did not depend on the cohort. In conclusion, while the tumor board recommendation for CHT decreased in the intermediate RS category, there was an increase being reported in the high RS category, thus leading to overall minor changes in CHT application. As expected, among the younger women with intermediate RS and unfavorable histopathological factors, CHT use increased.

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.

Live slow-frozen human tumor tissues viable for 2D, 3D, ex vivo cultures and single-cell RNAseq.

Biobanking of surplus human healthy and disease-derived tissues is essential for diagnostics and translational research. An enormous amount of formalin-fixed and paraffin-embedded (FFPE), Tissue-Tek OCT embedded or snap-frozen tissues are preserved in many biobanks worldwide and have been the basis of translational studies. However, their usage is limited to assays that do not require viable cells. The access to intact and viable human material is a prerequisite for translational validation of basic research, for novel therapeutic target discovery, and functional testing. Here we show that surplus tissues from multiple solid human cancers directly slow-frozen after resection can subsequently be used for different types of methods including the establishment of 2D, 3D, and ex vivo cultures as well as single-cell RNA sequencing with similar results when compared to freshly analyzed material.

A RAS-Independent Biomarker Panel to Reliably Predict Response to MEK Inhibition in Colorectal Cancer.

Background: In colorectal cancer (CRC), mutations of genes associated with the TGF-ß/BMP signaling pathway, particularly affecting SMAD4, are known to correlate with decreased overall survival and it is assumed that this signaling axis plays a key role in chemoresistance. Methods: Using CRISPR technology on syngeneic patient-derived organoids (PDOs), we investigated the role of a loss-of-function of SMAD4 in sensitivity to MEK-inhibitors. CRISPR-engineered SMAD4R361H PDOs were subjected to drug screening, RNA-Sequencing, and multiplex protein profiling (DigiWest®). Initial observations were validated on an additional set of 62 PDOs with known mutational status. Results: We show that loss-of-function of SMAD4 renders PDOs sensitive to MEK-inhibitors. Multiomics analyses indicate that disruption of the BMP branch within the TGF-ß/BMP pathway is the pivotal mechanism of increased drug sensitivity. Further investigation led to the identification of the SFAB-signature (SMAD4, FBXW7, ARID1A, or BMPR2), coherently predicting sensitivity towards MEK-inhibitors, independent of both RAS and BRAF status. Conclusion: We identified a novel mutational signature that reliably predicts sensitivity towards MEK-inhibitors, regardless of the RAS and BRAF status. This finding poses a significant step towards better-tailored cancer therapies guided by the use of molecular biomarkers.

Pre-Surgery Demographic, Clinical, and Symptom Characteristics Associated with Different Self-Reported Cognitive Processes in Patients with Breast Cancer.

Cancer related cognitive impairment (CRCI) is a common and persistent symptom in breast cancer patients. The Attentional Function Index (AFI) is a self-report measure that assesses CRCI. AFI includes three subscales, namely effective action, attentional lapses, and interpersonal effectiveness, that are based on working memory, inhibitory control, and cognitive flexibility. Previously, we identified three classes of patients with distinct CRCI profiles using the AFI total scores. The purpose of this study was to expand our previous work using latent class growth analysis (LCGA), to identify distinct cognitive profiles for each of the AFI subscales in the same sample (i.e., 397 women who were assessed seven times from prior to through to 6 months following breast cancer surgery). For each subscale, parametric and non-parametric statistics were used to determine differences in demographic, clinical, and pre-surgical psychological and physical symptoms among the subgroups. Three-, four-, and two-classes were identified for the effective action, attentional lapses, and interpersonal effectiveness subscales, respectively. Across all three subscales, lower functional status, higher levels of anxiety, depression, fatigue, and sleep disturbance, and worse decrements in energy were associated with worse cognitive performance. These and other modifiable characteristics may be potential targets for personalized interventions for CRCI.

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.