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.

Smartphone-Based Psychotherapeutic Interventions in Blended Care of Cancer Survivors: Nested Randomized Clinical Trial.

BACKGROUND: Cancer is related to not only physical but also mental suffering. Notably, body image disturbances are highly relevant to cancer-related changes often persisting beyond recovery from cancer. Scalable and low-barrier interventions that can be blended with face-to-face psychotherapy for cancer survivors are highly warranted. OBJECTIVE: The aim of the study is to investigate whether smartphone-based bodily interventions are more effective to improve the mood of patients with cancer than smartphone-based fairy tale interventions (control intervention). METHODS: We recruited patients with cancer in 2 Swiss hospitals and conducted daily, fully automated smartphone-based interventions 6 times a week for 5 consecutive weeks, blended with weekly face-to-face group body psychotherapy. We applied 2 types of smartphone-based interventions using a within-subject design, randomly assigning patients daily to either bodily interventions or fairy tales. Each intervention type was presented 3 times a week. For this secondary analysis, 3-level mixed models were estimated with mood assessed by the 3 Multidimensional Mood Questionnaire subscales for good-bad mood, wakefulness, and calmness as key indicators. In addition, the effects on experience of presence, vitality, and burden assessed with visual analog scales were investigated. RESULTS: Based on the data from s=732 interventions performed by 36 participants, good-bad mood improved (ß=.27; 95% CI 0.062-0.483), and participants became calmer (ß=.98; 95% CI 0.740-1.211) following smartphone-based interventions. Wakefulness did not significantly change from pre- to postsmartphone-based intervention (ß=.17; 95% CI -0.081 to 0.412). This was true for both intervention types. There was no interaction effect of intervention type with change in good-bad mood (ß=-.01; 95% CI -0.439 to 0.417), calmness (ß=.22; 95% CI -0.228 to 0.728), or wakefulness (ß=.14; 95% CI -0.354 to 0.644). Experience of presence (ß=.34; 95% CI 0.271-0.417) and vitality (ß=.35; 95% CI 0.268-0.426) increased from pre- to postsmartphone-based intervention, while experience of burden decreased (ß=-0.40; 95% CI -0.481 to 0.311). Again, these effects were present for both intervention types. There were no significant interaction effects of intervention type with pre- to postintervention changes in experience of presence (ß=.14; 95% CI -0.104 to 0.384), experience of vitality (ß=.06; 95% CI -0.152 to 0.265), and experience of burden (ß=-.16; 95% CI -0.358 to 0.017). CONCLUSIONS: Our results suggest that both smartphone-based audio-guided bodily interventions and fairy tales have the potential to improve the mood of cancer survivors. TRIAL REGISTRATION: ClinicalTrials.gov NCT03707548; https://clinicaltrials.gov/study/NCT03707548. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.1186/s40359-019-0357-1.

Group-based body psychotherapy improves appreciation of body awareness in post-treatment cancer patients: A non-randomized clinical trial.

Introduction: Cancer-related impairments often co-occur with bodily disturbances. Body psychotherapy (BPT) can improve bodily wellbeing, yet evidence in cancer survivors is scarce. Hence, we aimed to evaluate whether blended group BPT alleviates bodily disturbances in post-treatment cancer patients. Methods: We conducted a bi-center study (registered in ClinicalTrials.gov, under No. NCT03707548), applying a pre-post convergent parallel design of weekly group BPT interspersed with smartphone-based ambulatory interventions using a waiting-period comparator. We included patients with completed curatively intended treatment for malignant neoplasms, suffering from bodily disturbances. The primary outcome was body image disturbances. Secondary outcomes were experiencing and appreciating body awareness, mental wellbeing, and health-related quality of life. Results: Forty patients (mean age 51.7 years) attended group BPT. Mixed-effect linear regression models contrasting intervention with the waiting period did not show statistically significant differences regarding the primary outcome [Pre-post difference contrasts: 1.44, 95% confidence interval (CI): -1.51 to 4.93, p = 0.339]. However, patients showed greater improvements in appreciating body awareness, measured by the "Body Mindfulness Questionnaire" (BMQ), from pre- to post-intervention as compared to the waiting period (pre-post difference contrasts: 7.31 95% CI: 4.15-10.47, Bonferroni-Holm corrected q = 0.0002). Discussion: We found no evidence that blended group BPT was effective in improving body image disturbances in post-treatment cancer patients, but found indications for an increase in body awareness appreciation. Clinical trial registration: ClinicalTrials.gov, identifier NCT03707548.

A multicenter phase II trial of anti-EGFR-immunoliposomes loaded with doxorubicin in patients with advanced triple negative breast cancer.

Advanced triple negative breast cancer (TNBC) is an aggressive, but initially chemo-sensitive disease. The prognosis is poor and more than three quarters of patients experience progression 12 months after the initiation of conventional first-line chemotherapy. Approximately two thirds of TNBC express epidermal growth factor receptor 1 (EGFR). We have developed an anti-EGFR targeted nanocontainer drug by inserting anti-EGFR antibody fragments into the membrane of pegylated liposomes (anti-EGFR-ILs-dox). The payload consists of doxorubicin, a standard drug for TNBC. In a first-in-human phase I trial in 26 patients with various advanced solid malignancies, anti-EGFR-ILs-dox has shown little toxicity and encouraging efficacy. In this single-arm phase II trial, we assessed the efficacy of anti-EGFR-ILs-dox as first-line therapy in patients with advanced, EGFR + TNBC. The primary endpoint was progression-free survival at 12 months (PFS12m). Secondary endpoints included overall response rate (ORR), duration of response (DOR), time to progression (TTP), overall survival (OS) and adverse events (AEs). 48 patients received anti-EGFR-ILs-dox 50 mg/m2 iv, on day one of a 28 days-cycle until progression. The Kaplan-Meier estimate for PFS12m was 13% (one-sided 90% CI 7%, 95% CI [5%, 25%]), median PFS was 3.5 months (95% CI 1.9, 5.4). The trial has not reached its primary endpoint. There were no new toxicity signals. Based on these results, anti-EGFR-ILs-dox should not be further developed for TNBC. It remains an open question whether anti-EGFR-ILs-dox would offer more opportunities in other EGFR-expressing malignancies, where targeting this receptor has already shown anticancer effects.Trial registration: This trial was registered at clinicaltrials.gov: NCT02833766. Registered 14/07/2016.

Eribulin as first-line treatment in older patients with advanced breast cancer: A multicenter phase II trial [SAKK 25/14].

INTRODUCTION: Standard-dose eribulin mesylate (1.4 mg/m2 d1 + 8) achieves clinical benefit rates of 26%-52% in patients with metastatic breast cancer (mBC). <10% of patients in the registration trial were ≥ 70 years old; dose reductions were common in these older patients. MATERIALS AND METHODS: This single-arm phase II trial explored the efficacy of reduced starting dosing of first-line eribulin at 1 mg/m2 d1 + 8 q3 weeks in patients with mBC aged ≥70 years. The primary endpoint was a disease control rate (DCR) ≥55%. The secondary endpoints were objective response (OR), progression-free survival (PFS), overall survival (OS), and patient-reported neurotoxicity. RESULTS: Overall, 77 patients were accrued; their median age was 76 years and Eastern Cooperative Oncology Group performance status was 0-1 in 90%. The DCR was 40% (90% confidence interval [CI]: 31-50); therefore, the primary endpoint was not reached. The overall response rate was 22% (95%CI: 13-33), median PFS 5.4 months (95%CI: 4.5-7.7), and median OS 16.1 months (95%CI: 13.5-26.9). Dose modifications were necessary in 35% of patients. In nine patients, more than fifteen cycles were given; 48 patients (62%) experienced at least one grade 3 toxicity. Median patient-reported neurotoxicity scores remained stable for at least fifteen cycles. The main reason for treatment discontinuation was disease progression (57%). DISCUSSION: We report the first prospective data on first-line eribulin in older patients. The reduced starting dose of 1.1 mg/m2 was safe, with prolonged treatment and DC achieved in a considerable proportion of patients (but less than the 55% assumed), without cumulative neurotoxicity. The reduced dose was apparently within the range of the minimal effective dose, as shown by the efficacy lack in patients requiring further dose reductions. Thus, our results do not support the approach of a reduced starting dose for older patients.

Fertility preservation in male cancer patients: A mixed methods assessment of experiences and needs.

INTRODUCTION: As fertility may be impaired due to gonadotoxic cancer treatment, fertility preservation should be offered to young cancer patients. Despite affirmative guidelines, sperm cryopreservation rates are still unsatisfying. OBJECTIVE: To examine how male cancer patients experience the current practice of counseling regarding fertility preservation and the needs they have for additional online support tools. METHODS: A cross-sectional mixed methods study of men above 18 years old with a cancer diagnosis within the last 10 years. The quantitative part was a retrospective questionnaire-based online survey; the qualitative part used focus-group methodology. The mean age of participants (n=72) was 32.94 years (SD 8.38) and the predominant cancer types were testicular cancer (55.6%), lymphomas (16.7%), and leukemias (13.9%). RESULTS: Participants rated the significance of the counseling as high (M=4.2, SD=1.05) and experienced professionals as supportive (M=4.37, SD=0.66). A majority of participants (70.8%) stated that they would use an additional support tool designed for male cancer patients. The tool should contain not only information about fertility preservation, but also about sexuality, virility, consequences for partners, and experience reports from other patients. CONCLUSIONS: Cancer patients undergoing gonadotoxic therapies should be counseled about fertility preservation. Professional, individualized information and a well-organized fertility preservation process improve the subjective experience of cancer patients. An online support tool that provides information about fertility preservation and general reproductive health was considered as a helpful, low-threshold offer that would be appreciated.

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.

An In Vivo CRISPR Screen Identifies Stepwise Genetic Dependencies of Metastatic Progression.

Blood-borne metastasis of breast cancer involves a series of tightly regulated sequential steps, including the growth of a primary tumor lesion, intravasation of circulating tumor cells (CTC), and adaptation in various distant metastatic sites. The genes orchestrating each of these steps are poorly understood in physiologically relevant contexts, owing to the rarity of experimental models that faithfully recapitulate the biology, growth kinetics, and tropism of human breast cancer. Here, we conducted an in vivo loss-of-function CRISPR screen in newly derived CTC xenografts, unique in their ability to spontaneously mirror the human disease, and identified specific genetic dependencies for each step of the metastatic process. Validation experiments revealed sensitivities to inhibitors that are already available, such as PLK1 inhibitors, to prevent CTC intravasation. Together, these findings present a new tool to reclassify driver genes involved in the spread of human cancer, providing insights into the biology of metastasis and paving the way to test targeted treatment approaches. SIGNIFICANCE: A loss-of-function CRISPR screen in human CTC-derived xenografts identifies genes critical for individual steps of the metastatic cascade, suggesting novel drivers and treatment opportunities for metastatic breast cancers.

The Alkaline Phosphatase Flare Phenomenon: A Transient Substantial Increase in Alkaline Phosphatase Concentration in a Prostate Cancer Patient after Starting GnRH Agonist Treatment.

A 78-year-old man with metastatic prostate cancer was referred to the hospital 5 weeks after the initiation of systemic therapy with goserelin (GnRH agonist) because of a significant increase in alkaline phosphatase (ALP) concentration despite clinical improvement. Further workup revealed a decrease in prostate-specific antigen levels and a lack of radiological signs of disease progression. Subsequently, the ALP dropped spontaneously. This case report is an example for an early ALP flare after initiation of endocrine therapy in patients with bone metastasis which is consistent with a treatment response. Clinicians should be familiar with the ALP flare phenomenon in this setting, which does not reflect disease progression or treatment failure, in order to prevent unnecessary investigations, hospital admissions, or even erroneous termination of successful therapy.

Long-term effectiveness of an online decision aid for female cancer patients regarding fertility preservation: Knowledge, attitude, and decisional regret.

INTRODUCTION: The decision, whether to undergo fertility preservation or not is highly demanding for cancer patients. Decision aids may act as an additional source of support. So far, only a limited number of decision aids regarding fertility preservation for female cancer patients exist and have been evaluated systematically. This paper presents the results of secondary analyses of the first randomized controlled trial evaluating an online decision aid for female cancer patients affected by different types of cancer. It focuses on fertility-related knowledge, attitude toward fertility preservation, and long-term effectiveness regarding decisional regret. MATERIAL AND METHODS: Young female cancer patients between 18 and 40 years of age were recruited after fertility counseling with a reproductive specialist. They were assigned to either the control group (counseling only) or the intervention group (counseling followed by the additional use of the decision aid). Both groups had to complete a questionnaire after counseling as well as 1 and 12 months later, covering topics such as fertility-related knowledge, attitude towards fertility preservation, decisional conflict and regret. Recruitment was ongoing during 18 months in eight fertility centers located in Switzerland and Germany. RESULTS: Mean age of participating women was 29.31 years (SD 4.57). Of the entire sample (n = 51) 53% were affected with breast cancer, 27.4% with lymphoma, and 19.6% with various other types of cancer. Knowledge regarding the most common fertility preservation methods was high and comparable in both groups. Positive attitude significantly exceeded negative attitude among all participants (p = 0.001). Although the altogether low scores for decisional regret were on a higher level in the control group (T2: mean = 19.00, SD = 13.24; T3: mean = 22.0, SD = 20.67) than in the intervention group (T2: mean = 14.12, SD = 11.07; T3: mean = 12.94, SD = 13.24), there were no statistically significant differences between and within both groups. There was a positive association between decisional conflict and decisional regret at T3 (p = 0.001, r = 0.510). CONCLUSIONS: This decision aid was suitable as an additional source of knowledge and may positively impact decisional regret in the long term. Results suggest that the provision of an online decision aid as a complement to fertility counseling may facilitate decision-making.

Hypoxia Triggers the Intravasation of Clustered Circulating Tumor Cells.

Circulating tumor cells (CTCs) are shed from solid cancers in the form of single or clustered cells, and the latter display an extraordinary ability to initiate metastasis. Yet, the biological phenomena that trigger the shedding of CTC clusters from a primary cancerous lesion are poorly understood. Here, when dynamically labeling breast cancer cells along cancer progression, we observe that the majority of CTC clusters are undergoing hypoxia, while single CTCs are largely normoxic. Strikingly, we find that vascular endothelial growth factor (VEGF) targeting leads to primary tumor shrinkage, but it increases intra-tumor hypoxia, resulting in a higher CTC cluster shedding rate and metastasis formation. Conversely, pro-angiogenic treatment increases primary tumor size, yet it dramatically suppresses the formation of CTC clusters and metastasis. Thus, intra-tumor hypoxia leads to the formation of clustered CTCs with high metastatic ability, and a pro-angiogenic therapy suppresses metastasis formation through prevention of CTC cluster generation.

Long-term responders to trastuzumab monotherapy in first-line HER-2+ advanced breast cancer: characteristics and survival data.

BACKGROUND: The impact of HER2-targeted therapy alone followed by the addition of chemotherapy at disease progression (PD) versus upfront combination was investigated by the SAKK 22/99 trial. The aim of this exploratory analysis of the SAKK 22/99 trial was to characterize the specific subset of patients deriving long-term benefit from trastuzumab monotherapy alone and to identify potential predictive factors of long-term response. METHODS: This is an unplanned post-hoc analysis of patients randomized to Arm A (trastuzumab monotherapy). Patients were divided in two groups: patients with durable clinical benefit from trastuzumab monotherapy and short-term responders without durable clinical benefit from trastuzumab monotherapy Univariate and multivariate analyses of clinical characteristics correlating with response duration was performed. RESULTS: Eighty six patients were randomized in arm A, 24 patients (28%) were long-term responders and 62 (72%) were short-term responders with a 5y-overall survival (OS) of 54% (95% CI 31-72) and of 18% (95%CI 10-30), respectively. Absence of ER expression, absence of PgR expression and presence of visceral disease emerged as possible negative predictive factors for durable clinical benefit. CONCLUSION: Durable clinical benefit can be achieved with trastuzumab monotherapy in a subgroup of HER2-positive patients with advanced disease and it is predictive for longer OS. Further investigations of predictive biomarkers are necessary to better characterize this subgroup of patients and develop further de-escalating strategies. TRIAL REGISTRATION: NCT00004935 ; first posted 27.01.2003, retrospectively registered.

Randomized controlled trial on the effect of an online decision aid for young female cancer patients regarding fertility preservation.

STUDY QUESTION: Does the use of an online decision aid (DA) about fertility preservation (FP), in addition to standard counselling by a specialist in reproductive medicine, reduce decisional conflict compared to standard counselling alone? SUMMARY ANSWER: Female cancer patients who could make use of the online DA had a significantly lower short-term decisional conflict score. WHAT IS KNOWN ALREADY: Nowadays, female cancer patients have several options for preserving fertility, but having to decide whether to opt for FP within a short time frame after cancer diagnosis and before the start of treatment is challenging. According to previous studies focussing mainly on breast cancer patients, decisional conflict among these women is high, and they have expressed the need for additional support. STUDY DESIGN, SIZE, DURATION: The study was a randomized controlled trial including female cancer patients who were referred by their treating oncologist to a specialist in reproductive medicine for fertility counselling. Participants were randomly assigned to the control group (counselling only) or to the intervention group (counselling and additional use of the online DA immediately after counselling). Recruitment was ongoing from July 2016 to December 2017 at eight fertility centres in Switzerland and Germany. PARTICIPANTS/MATERIALS, SETTING, METHODS: The online DA was developed by an interdisciplinary team of specialists in reproductive medicine, gynaecologists, oncologists and psychologists. Of 79 recruited participants, 59 completed the first assessment and could therefore be enrolled in the study. They were asked to complete an online questionnaire at three time points: at T1, after counselling (control group, n = 27) or after counselling and the additional use of the DA (intervention group, n = 24); at T2, 1 month later (N = 41: control group, n = 23; intervention group, n = 18); and at T3, 12 months later (N = 37: control group, n = 20; intervention group, n = 17). The survey comprised questions about fertility-related knowledge, attitude towards FP, willingness to undergo FP and socio-demographic data, as well as the decisional conflict and decisional regret scales. MAIN RESULTS AND THE ROLE OF CHANCE: All participants showed low decisional conflict scores. Women who used the online DA in addition to counselling (intervention group) showed a significantly lower total score on the Decisional Conflict Scale (DCS) compared to the control group at T1 (P = 0.008; M = 12.15, SD = 4.38; 95% CI, 3.35-20.95) and at T2 (P = 0.043; M = 9.35, SD = 4.48; 95% CI, 0.31-18.38). At T3, the mean total score of the DCS was still lower in the intervention group compared to the control group; however, this group difference was no longer significant (P = 0.199, M = 6.86, SD = 5.24; 95% CI, -3.78 to 17.51). The majority of participants had already made a decision regarding FP (yes or no) at T1 (72.5%): 91.7% in the intervention group compared to 55.6% in the control group (P = 0.014). Those who had decided already at T1 showed significantly lower decisional conflict (P = 0.007; M = 13.69, SD = 4.89; 95% CI, 3.86-23.52). The average number of DA sessions per user was 2.23, and 80.8% of the participants completed the DA's value clarification exercises. Participants in the intervention group were satisfied with the DA and would recommend it to other patients. LIMITATIONS, REASONS FOR CAUTION: The recruitment of participants was challenging because of the emotionally difficult situation patients were in. This led to the limited sample size for final analysis. Education levels were high in two-thirds of the participants. It is difficult to say whether the DA would be equally effective in women with a lower educational background. WIDER IMPLICATIONS OF THE FINDINGS: There is evidence that the DA served as a helpful complement to the decision-making process for young female cancer patients qualifying for FP. This is, to our knowledge, the first randomized controlled trial evaluating a DA targeted at patients with several cancer types and in a language other than English (i.e. German). This study contributes to extending the range of the still limited number of DAs in the context of FP. STUDY FUNDING/COMPETING INTEREST(S): The study was supported by a research grant of the Swiss Cancer Research. The authors declare that no competing interests exist. TRIAL REGISTRATION NUMBER: Clinicaltrials.gov, trial no. NCT02404883. TRIAL REGISTRATION DATE: 19 March 2015. DATE OF FIRST PATIENT'S ENROLMENT: 4 July 2016.

Web-based counseling for families with parental cancer: Baseline findings and lessons learned.

Purpose: This is the first study in Switzerland to report on psychological adjustment in children of a parent with cancer using a web-based intervention during cancer therapy. Design/Sample: Twenty-two families participated in this randomized controlled web-based intervention program. Methods: Quality of life and emotional-behavioral well-being of children were examined using child self-reports, and parent proxy-reports. Furthermore, family communication and satisfaction and feedback on the web-based program were assessed. Findings: Children's first stage adjustment to parental cancer did not show detrimental patterns. The "lesson learned" in this setting emphasizes the challenge to reach families in need. The web-based program was appreciated as an additional source of information and support in this mostly highly functioning population. Conclusion: While feasibility was shown, it remains unclear how to contact families with lower psychosocial functioning.

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.

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.

Adjuvant Letrozole and Tamoxifen Alone or Sequentially for Postmenopausal Women With Hormone Receptor-Positive Breast Cancer: Long-Term Follow-Up of the BIG 1-98 Trial.

PURPOSE: Luminal breast cancer has a long natural history, with recurrences continuing beyond 10 years after diagnosis. We analyzed long-term follow-up (LTFU) of efficacy outcomes and adverse events in the Breast International Group (BIG) 1-98 study reported after a median follow-up of 12.6 years. PATIENTS AND METHODS: BIG 1-98 is a four-arm, phase III, double-blind, randomized trial comparing adjuvant letrozole versus tamoxifen (either treatment received for 5 years) and their sequences (2 years of one treatment plus 3 years of the other) for postmenopausal women with endocrine-responsive early breast cancer. When pharmaceutical company sponsorship ended at 8.4 years of median follow-up, academic partners initiated an observational, LTFU extension collecting annual data on survival, disease status, and adverse events. Information from Denmark was from the Danish Breast Cancer Cooperative Group Registry. Intention-to-treat analyses are reported. RESULTS: Of 8,010 enrolled patients, 4,433 were alive and not withdrawn at an LTFU participating center, and 3,833 (86%) had at least one LTFU report. For the monotherapy comparison of letrozole versus tamoxifen, we found a 9% relative reduction in the hazard of a disease-free survival event with letrozole (hazard ratio [HR], 0.91; 95% CI, 0.81 to 1.01). HRs for other efficacy end points were similar to those for disease-free survival. Efficacy of letrozole versus tamoxifen for contralateral breast cancer varied significantly over time (0- to 5-, 5- to 10-, and > 10-year HRs, 0.62, 0.47, and 1.35, respectively; treatment-by-time interaction P = .005), perhaps reflecting a longer carryover effect of tamoxifen. Reporting of specific long-term adverse events seemed more effective with national registry than with case-record reporting of clinical follow-up. CONCLUSION: Efficacy end points continued to show trends favoring letrozole. Letrozole reduced contralateral breast cancer frequency in the first 10 years, but this reversed beyond 10 years. This study illustrates the value of extended follow-up in trials of luminal breast cancer.

Oncologist recommendation matters!-Predictors of psycho-oncological service uptake in oncology outpatients.

OBJECTIVE: Highly distressed cancer patients often do not use psycho-oncological services (POS). Research on predictors of POS uptake has mainly focused on patient-related variables and less on communication variables, so we examined the link between patient-oncologist communication (ie, talking about psychosocial distress, providing detailed information, and recommending POS) and POS uptake. METHODS: We conducted a prospective, observational study in an Oncology Outpatient Clinic in Switzerland. Predictors (ie, patient-related variables and patient's reports of the patient-oncologist communication) were assessed via semistructured interviews, and information on outpatient POS uptake was assessed after 4 months. For statistical analysis, a multivariate logistic regression was performed. RESULTS: Of 333 participants (mean age 61 years; 55% male; 54% distress thermometer ≥5), 77 (23%) had used POS during a 4-month period. Patients who reported an oncologist-recommended POS (odds ratio [OR] = 6.27, 95% confidence interval [CI] = 3.14-12.85) and those who were not sure if they had received a recommendation (OR = 4.64, 95% CI = 1.83-11.97) were more likely to attend POS than those who reported receiving no recommendation. Talking about psychosocial distress (OR = 0.74, 95% CI = 0.38-1.46) and providing detailed information about POS did not predict POS uptake (OR = 1.06, 95% CI = 0.46-2.38). CONCLUSIONS: Oncologists' expert recommendations to attend POS were strongly associated with patients' uptake of POS. The central role played by oncologists should be accounted for in stepped psycho-oncological care when POS referral pathways are defined.

A clinical trial of group-based body psychotherapy to improve bodily disturbances in post-treatment cancer patients in combination with randomized controlled smartphone-triggered bodily interventions (KPTK): study protocol.

BACKGROUND: Disturbances in bodily well-being represent one key source of suffering and impairment related to cancer. There is growing evidence that body psychotherapy (BPT) is efficacious for the treatment of various mental disorders. However, with regard to cancer patients, evidence is scarce. The aims of this project are to evaluate whether bodily disturbances in post-treatment cancer patients can be improved by group BPT, and to estimate the efficacy of intermittent smartphone-triggered bodily interventions. METHODS: The project is a bi-center study with two participating centers in Switzerland, applying a pre-post convergent parallel design of a weekly group BPT using a waiting-period comparator, including a nested RCT during the group BPT phase. During the BPT phase, either a smartphone-triggered bodily intervention or a smartphone-triggered control intervention is provided at random over 5 consecutive weeks, on 6 days weekly. Patients who had received curatively intended treatment for any malignant neoplasm (treatment being completed ≥3 months) and are suffering from bodily disturbances are screened to assess eligibility. Sample size estimation is based on an a priori power analysis. We plan to include a total of N = 88 subjects, aiming at at least 52 completers. Patients are surveyed three times (baseline assessment (T0), pre- (T1) and post-intervention assessment (T2)), and on a daily basis along BPT during five consecutive weeks. The primary outcome, bodily disturbances, is assessed using the 'Body Image Scale'(BIS). For the secondary outcomes standardized questionnaires are used to assess changes in experience of presence and vitality, mood, body mindfulness, somatic symptoms and somatic symptom disorder, quality of life, anxiety, and depression including suicidal tendency, vitality and mental health, as well as group cohesion. Using semi standardized interviews (at T0 and T2), we aim to explore the relation of BPT with bodily disturbances and body image in post-treatment cancer patients, as well as the acceptance and burden of the intervention. DISCUSSION: The proposed study has strong potential benefits for cancer patients, as it may pave the way for new therapeutic approaches to treat bodily disturbances, which persist despite curative tumor therapy. These may considerably improve patients' biopsychosocial well-being and quality of life. TRIAL REGISTRATION: ClinicalTrials.gov NCT03707548 (registered 9 October 2018; retrospectively registered).

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.