App-based support for breast cancer patients to reduce psychological distress during therapy and survivorship - a multicentric randomized controlled trial.

Introduction: The negative impact of unmanaged psychological distress on quality of life and outcome in breast cancer survivors has been demonstrated. Fortunately, studies indicate that distress can effectively be addressed and even prevented using evidence-based interventions. In Germany prescription-based mobile health apps, known as DiGAs (digital health applications), that are fully reimbursed by health insurances, were introduced in 2020. In this study, the effectiveness of an approved breast cancer DiGA was investigated: The personalized coaching app PINK! Coach supports and accompanies breast cancer patients during therapy and follow-up. Methods: PINK! Coach was specifically designed for breast cancer (BC) patients from the day of diagnosis to the time of Follow-up (aftercare). The app offers individualized, evidence-based therapy and side-effect management, mindfulness-based stress reduction, nutritional and psychological education, physical activity tracking, and motivational exercises to implement lifestyle changes sustainably in daily routine. A prospective, intraindividual RCT (DRKS00028699) was performed with n = 434 patients recruited in 7 German breast cancer centers from September 2022 until January 2023. Patients with BC were included independent of their stage of diseases, type of therapy and molecular characteristics of the tumor. Patients were randomized into one of two groups: The intervention group got access to PINK! over 12 weeks; the control group served as a waiting-list comparison to "standard of care." The primary endpoint was psychological distress objectified by means of Patient Health Questionnaire-9 (PHQ-9). Subgroups were defined to investigate the app's effect on several patient groups such as MBC vs. EBC patients, patients on therapy vs. in aftercare, patients who received a chemotherapy vs. patients who did not. Results: Efficacy analysis of the primary endpoint revealed a significant reduction in psychological distress (least squares estimate -1.62, 95% confidence interval [1.03; 2.21]; p<0.001) among intervention group patients from baseline to T3 vs, control group. Subgroup analysis also suggested improvements across all clinical situations. Conclusion: Patients with breast cancer suffer from psychological problems including anxiety and depression during and after therapy. Personalized, supportive care with the app PINK! Coach turned out as a promising opportunity to significantly improve psychological distress in a convenient, accessible, and low-threshold manner for breast cancer patients independent of their stage of disease (EBC/MBC), therapy phase (aftercare or therapy) or therapy itself (chemotherapy/other therapy options). The app is routinely available in Germany as a DiGA. Clinical Trial Registration: DRKS Trial Registry (DRKS00028699).

ABC7 Consensus: Assessment by a German Group of Experts.

Background: The "International Consensus Conference for Advanced Breast Cancer" was initiated more than 10 years ago. The rationale was to standardize treatment of advanced breast cancer (ABC) based on available evidence and to ensure that all ABC patients worldwide receive adequate treatment and access to new therapies. Topics of ABC7: The 7th International Consensus Conference for ABC (ABC7) took place from November 9 to 11, 2023 - as in previous years in Lisbon/Portugal. ABC7 focused not only on metastatic disease but also on locally advanced and inflammatory breast cancer. Special topics were the management of oligometastatic disease, leptomeningeal disease, brain metastases, and pregnant women with ABC. Due to the current situation worldwide, there was a special interest to patients living in conflict zones. As in previous years, patient advocates from around the world were integrated into the ABC conference and had a major input to the consensus. Rationale for the Manuscript: A German breast cancer expert panel comments on the voting results of the ABC7 panelists regarding their relevance for routine clinical practice in Germany. As with previous meetings, the ABC7 votes focused on modified or new statements. Regarding the statements not modified for the ABC7 consensus, they are discussed in the published manuscript from 2021 in which the German experts commented on the ABC6 consensus. The German comments are always based on the current recommendations of the "Breast Committee" of the Gynecological Oncology Working Group (Arbeitsgemeinschaft Gynäkologische Onkologie, AGO Mamma).

App-Based Lifestyle Intervention (PINK! Coach) in Breast Cancer Patients-A Real-World-Data Analysis.

INTRODUCTION: Overweight and a lack of physical activity not only increase the risk of recurrence in breast cancer patients but also negatively impact overall and long-term survival, as well as quality of life. The results presented here are the first real-world data from the DiGA PINK! Coach examining the physical activity and BMI of app users. Based on the literature, an approximate weight gain of 10% over 6 months and a decrease in physical activity can be expected. The purpose of this study is to retrospectively investigate the effects of the PINK! Coach in a real-world setting on patients' BMI and physical activity level during acute therapies. such as chemotherapy (CHT) and antihormone therapy (AHT). MATERIAL AND METHODS: The PINK! Coach app accompanies breast cancer patients during and after acute therapy to bring about a sustainable lifestyle change. The patients are encouraged to establish a healthy diet, become physically active, and make informed decisions. In this study, real-world data from the app were analyzed over 6 months from baseline to T1 (after 12 weeks) and T2 (after 24 weeks). The patients were under acute therapy or in follow-up care receiving either CHT or AHT. RESULTS: The analyzed data indicate that all patients were able to maintain a consistent BMI over 6 months independent of pre-defined subgroups such as AHT, CHT, or BMI subgroups. In the subgroup of patients undergoing AHT, overweight patients were even able to significantly reduce their BMI by 1-score-point over 6 months (p < 0.01). The subgroup of patients undergoing CHT also showed an significant overall reduction in BMI (p = 0.01). All patients were also able to significantly increase their daily step count as well as their physical activity minutes per day. After the first 12 weeks, 41.4% of patients experienced weight gain, 33.4% were able to maintain their weight, and 24.2% reduced their weight. CONCLUSION: The presented data provides intriguing insights into the users of the PINK! Coach app and the impact of this usage in regards to BMI and physical activity. At the current time, there are only a few effective concepts for encouraging all breast cancer patients to engage in moderate physical activity and reduce body weight. Often, these concepts apply to selected patient groups. The data presented here include all age groups, tumor stages, and therapies, providing an initial insight into a comprehensive approach. Data over an even longer period would be one way to better contextualize the results in current research.

Neratinib as Extended Adjuvant Treatment of HER2-Positive/HR-Positive Early Breast Cancer Patients in Germany, Austria, and Switzerland: Interim Results of the Prospective, Observational ELEANOR Study.

Introduction: Prognosis of patients diagnosed with HER2+ early breast cancer (eBC) has substantially improved, but distant recurrences impacting quality of life and survival still occur. One treatment option for extended adjuvant treatment of patients with HER2+/HR+ eBC is neratinib, available in Europe for patients who completed adjuvant trastuzumab-based therapy within 1 year. The ELEANOR study is investigating the real-world use of neratinib in Germany, Austria, and Switzerland. Results from an interim analysis of the first 200 patients observed for ≥3 months are reported. Methods: The primary objective of this prospective, multicenter, observational study is to assess patient adherence to neratinib (defined as the percentage of patients taking neratinib on ≥75% prescribed days). Secondary objectives are patient characteristics and treatment outcomes. Results: At cut-off (May 2, 2022), a total of 202 patients had been observed for ≥3 months, with neratinib treatment documented for 187 patients (median age: 53.0 years; 67.9% at increased risk of disease recurrence). In total, 151 (80.7%) patients had received prior neoadjuvant treatment; of these, 82 (54.3%) patients achieved a pathologically complete response. Neratinib was initiated at a median 3.6 months after trastuzumab-based treatment, with 36.4% starting at a dose <240 mg/day. Treatment is ongoing for 46.0% of patients, with median treatment duration of 11.2 (interquartile range 0.9-12.0) months. Diarrhea was the most common adverse event (78.6% any grade, 20.3% grade ≥3); pharmacologic prophylaxis was used in 85.6% of patients. Conclusions: The pattern of anti-HER2 pretreatment observed reflected the current treatment for HER2+/HR+ eBC in Germany, Austria, and Switzerland. These interim results suggest that neratinib as an extended adjuvant is a feasible option after various anti-HER2 pretreatments and that its tolerability can be managed and improved with proactive diarrhea management.

Use of the Gene Expression Test Prosigna® in Premenopausal Patients with HR+, HER2- Early Breast Cancer: Correlation of the Results with the Proliferation Marker Ki-67.

Introduction: In hormone receptor-positive (ER+/PR+) and human epidermal growth factor receptor 2-negative (HER2-) early-stage breast cancer (EBC), gene expression tests such as the Prosigna are increasingly used since classic clinicopathological parameters and the proliferation factor Ki-67 often do not allow a definite therapy decision regarding an adjuvant chemotherapy. While the Prosigna test has been validated for postmenopausal patients, few data are available regarding its use in premenopausal patients. The present study compared the Prosigna test with the Ki-67 index in premenopausal patients. Materials and Methods: Premenopausal patients with HR+ HER2-, pN0-1, G1-2 EBC were retrospectively enrolled (n = 55). The Prosigna assay was performed in formalin-fixed paraffin-embedded tumor samples of surgical resection specimens. Ki-67 was reassessed in original diagnostic core needle biopsy specimens and defined as low, intermediate, or high with the threshold of <10%, 10-24%, ≥25%. Results: According to Ki-67, patients were in the low (LR)-, intermediate (IR)-, and high-risk (HR) groups in 40%, 36%, and 24% of the cases. The Prosigna gene signature assay assessed the risk of recurrence as LR for 45% of the patients, IR for 35%, and HR for 20%. The most frequent intrinsic subtypes were luminal A in 73% and luminal B in 24% of the patients. A moderate correlation was found between Prosigna and Ki-67 scores with a Pearson correlation coefficient of 0.51. In the overall cohort, 47% of the Ki-67-based therapy decision would correspond to those based on the Prosigna score. After exclusion of IR patients, matching of low/low or high/high results was observed in 57% of the cases. Conclusion: According to the present study, there is only limited concordance regarding the risk group stratification between Ki-67 and Prosigna-based risk assessment. The relevance and frequency of premenopausal breast cancer emphasizes the need for further evaluation of gene expression analyses in this setting and the correlation with classic clinicopathological parameters regarding therapy decision-making.

Genetics and beyond: Precision Medicine Real-World Data for Patients with Cervical, Vaginal or Vulvar Cancer in a Tertiary Cancer Center.

Advances in molecular tumor diagnostics have transformed cancer care. However, it remains unclear whether precision oncology has the same impact and transformative nature across all malignancies. We conducted a retrospective analysis of patients with human papillomavirus (HPV)-related gynecologic malignancies who underwent comprehensive molecular profiling and subsequent discussion at the interdisciplinary Molecular Tumor Board (MTB) of the University Hospital, LMU Munich, between 11/2017 and 06/2022. We identified a total cohort of 31 patients diagnosed with cervical (CC), vaginal or vulvar cancer. Twenty-two patients (fraction: 0.71) harbored at least one mutation. Fifteen patients (0.48) had an actionable mutation and fourteen (0.45) received a recommendation for a targeted treatment within the MTB. One CC patient received a biomarker-guided treatment recommended by the MTB and achieved stable disease on the mTOR inhibitor temsirolimus for eight months. Factors leading to non-adherence to MTB recommendations in other patient cases included informed patient refusal, rapid deterioration, stable disease, or use of alternative targeted but biomarker-agnostic treatments such as antibody-drug conjugates or checkpoint inhibitors. Despite a remarkable rate of actionable mutations in HPV-related gynecologic malignancies at our institution, immediate implementation of biomarker-guided targeted treatment recommendations remained low, and access to targeted treatment options after MTB discussion remained a major challenge.

Arbeitsgemeinschaft Gynäkologische Onkologie Recommendations for the Diagnosis and Treatment of Patients with Early Breast Cancer: Update 2023.

Background: Each year the interdisciplinary Arbeitsgemeinschaft Gynäkologische Onkologie (AGO), German Gynecological Oncology Group Breast Committee on Diagnosis and Treatment of Breast Cancer provides updated state-of-the-art recommendations for early and metastatic breast cancer. Summary: The updated evidence-based treatment recommendation for early and metastatic breast cancer has been released in March 2023. Key Messages: This paper concisely captures the updated recommendations for early breast cancer chapter by chapter.

App-Based Lifestyle Coaching (PINK!) Accompanying Breast Cancer Patients and Survivors to Reduce Psychological Distress and Fatigue and Improve Physical Activity: A Feasibility Pilot Study.

Introduction: This pilot study aimed to investigate the effects of using an app-based certified medical product named PINK! on breast cancer patients and survivors. The objectives were to measure psychological distress, physical activity, and therapy-related fatigue of patients using PINK! to identify trends and develop a study design for a subsequent multicentric proof of efficacy RCT. Materials and Methods: PINK! offers individualized, evidence-based therapy and side-effect management, mindfulness-based stress reduction, nutritional and psychological education, physical activity tracking, and motivational exercises to implement lifestyle changes sustainably in daily routine. A prospective, intraindividual RCT was performed with n = 60 patients in 2021 at Comprehensive Cancer Center Munich. Patients with BC were included independent of the stage of diseases. The intervention group got access to PINK! over 12 weeks. Control group served as a waiting-list comparison to "standard of care." Results: Primary efficacy variable analysis revealed a relative average decrease of 32.9% in psychological distress, which corresponds to a statistically significant reduction (p < 0.001) within 12 weeks compared to the control group. Linear regressions within usage groups showed a correlation of high app usage and a reduction of psychological distress. Fatigue data presented a statistically significant antifatigue efficacy (p < 0.001) and physical activity increased by 63.9%. Conclusion: App-based supportive care offers a promising, low-threshold, and cost-efficient opportunity to improve psychological well-being, quality of life, fatigue, and physical activity. More research is needed to implement eHealth solutions in clinical cancer care.

Biologically Based Complementary and Alternative Medicine Use in Breast Cancer Patients and Possible Drug-Drug Interactions.

Purpose: Biologically based complementary and alternative medicine (BB-CAM) is gaining importance. Cancer patients in particular are at risk of interactions between the prescribed medications (intravenous or oral anticancer therapy, concomitant medication, medication for pre-existing illnesses) and BB-CAM. This investigation aims to identify potentially clinically relevant interactions between both BB-CAM and conventional medicine and two BB-CAM products in breast cancer patients (n = 47). Methods: From March 2020 to January 2021, consecutive breast cancer patients (n = 47) completed a questionnaire about their medication and BB-CAM intake at the beginning of a new intravenous or oral tumor therapy (time point 1) and again after 10 to 12 weeks (time point 2) at the LMU Breast Center in Munich. The collective was divided into two subgroups based on the time after initial diagnosis; a cutoff of 6 months was used. The survey was available through an eHealth application called CANKADO as electronic patient-reported outcome only. Lexicomp® and AiD Klinik® databases were used for evaluating potentially clinically relevant interactions. As part of routine care, the collected data were evaluated and cross-checked in interdisciplinary cooperation with the University Hospital Pharmacy LMU. Results: 43 of the 47 included breast cancer patients (91%) used BB-CAM at some point during their treatment period. We found a significant increase from time point 1 (n = 27) to time point 2 (n = 40) (p = 0.004). Moreover, in the subgroup of newly diagnosed patients, the number significant rose from 17 at time point 1 to 28 at time point 2 (p = 0.007). Overall, we found potentially clinically relevant interactions in 30 of 43 patients (70%). Sixty interactions were detected at both times of investigations. Twenty-three different kinds of BB-CAM-to-BB-CAM (time point 1 [n = 12], time point 2 [n = 11]) or conventional medicine-to-BB-CAM interactions (time point 1 [n = 15], time point 2 [n = 22]) were discovered. Importantly, there was not a single interaction between BB-CAM and an anticancer drug. Conclusion: Breast cancer patients frequently use BB-CAM. Interactions were detected at both time points of investigation (time point 1 [n = 27], time point 2 [n = 33]). Interactions were particularly evident between BB-CAM substances as well as between BB-CAM and the patients' medication for pre-existing illnesses. Although no interaction between BB-CAM and an anticancer therapy was found, the use of BB-CAM should be evaluated at the beginning and regularly during therapy in view of the substantial number of interactions detected and the large number of upcoming targeted therapies.

Health-related quality of life and patient-centred outcomes with COVID-19 vaccination in patients with breast cancer and gynaecological malignancies.

Introduction: Safety and tolerability of COVID-19 vaccines were demonstrated by several clinical trials which led to the first FDA/EMA approvals in 2021. Because of mass immunizations, most social restrictions were waived with effects on quality of life. Therefore, our a-priori hypothesis was that COVID-19 vaccination impacted the health-related quality of life (HR-QoL) in patients with breast and gynecological cancer. Methods: From March 15th until August 11th, 2022, fully vaccinated patients with breast and gynecological cancer treated in the oncological outpatient clinics of the Department of Obstetrics and Gynecology, LMU University Hospital, Munich, Germany filled out a vaccine related QoL survey. Patients were asked about demographics (age, comorbidities), clinical parameters related to previous COVID-19 infections, and HR-QoL related parameters (living situation, responsibilities in everyday life). Subsequently, a questionnaire with 12 items was designed using a 5-point Likert scale (0 - strongly disagree/4 - strongly agree), covering the aspects health and therapy, social environment, participation in everyday life and overall assessment. Results: By August 11th, 2022, 108 out of 114 (94.7%) patients had received at least three doses of COVID-19 vaccine and six patients at least two doses. More than half of the surveyed patients were >55y (52.6%; mean: 55.1y, range 29-86y). Patients with breast cancer (n= 83) had early (59.0%) or metastatic cancer (41.0%); gynecological cancers (n=31) also included metastatic (54.8%) and non-metastatic cancer (45.2%). 83.3% of the patients stated that COVID-19 vaccination had a positive impact on their HR-QoL. Furthermore, 29 patients (25.4%) had undergone a COVID-19 infection. These patients reported self-limiting symptoms for a median duration of 5.9 days and no hospital admissions were registered. Conclusions: Our study demonstrates that vaccination against COVID-19 was positively associated with HR-QoL in patients with breast and gynecological cancer. Furthermore, vaccinated patients who underwent COVID-19 disease experienced only self-limiting symptoms.

Favorable impact of therapy management by an interactive eHealth system on severe adverse events in patients with hormone receptor-positive, HER2-negative locally advanced or metastatic breast cancer treated by palbociclib and endocrine therapy.

BACKGROUND: Oral cancer medications offer advantages but also pose challenges for therapy management and adherence. An eHealth-based platform such as CANKADO can help to support therapy management by probing the patient's quality of life (QoL) continuously throughout the course of treatment. MATERIAL AND METHODS: AGO-B WSG PreCycle (NCT03220178) is a multicenter, randomized phase IV intergroup trial evaluating the impact of eHealth-based Patient-Reported Outcome (ePRO) assessment on QoL in patients with hormone receptor-positive (HR + )/HER2-negative (HER2-) advanced breast cancer treated with palbociclib and endocrine therapy. Patients were randomized (2:1) to CANKADO-active arm (supported by CANKADO PRO-React) or CANKADO-inform arm (drug intake documentation only) This exploratory analysis reports the impact of CANKADO PRO-React on safety. Time to first serious adverse event (SAE) was estimated taking competing risks into account. RESULTS: While distributions of adverse events (AEs) were similar by arm overall, patients in the CANKADO-active arm had a favorable hazard ratio of 0.67 (95%CI 0.46-0.97; p = 0.04) for time to first SAE and were significantly less likely overall to suffer an SAE than patients in the inform arm. At 24 months, 22.9% [17.9%-27.8%] of patients in CANKADO-active had suffered an SAE vs. 30.3% [22.6%-38.0%] in CANKADO-inform. AE-related dose reductions affected approximately 20% of patients (CANKADO-active: 18.2%, CANKADO-inform: 21.1%). CONCLUSION: Exploratory safety analysis of PreCycle demonstrates for the first time in a randomized prospective trial that interactive autonomous eHealth-based support has a substantial favorable impact on the risk of SAEs and mitigates their severity for patients with advanced HR+/HER2- breast cancer on oral tumor therapy.

Clinical relevance of potential self-medication drug interactions in antineoplastic and immune-modulating therapy among online pharmacy customers.

Background: Modern oral antineoplastic and immune-modulating drugs offer an array of therapeutic advantages, and yet pose challenges in daily use for patients, physicians and pharmacists. In contrast to intravenous administration, these drugs are not subject to direct medical control. Recently, we have seen a huge rise in sales of non-prescription over-the-counter (OTC) medicines via the internet without any advice from a healthcare professional. Objectives: The aim of this study was to investigate whether the risk of known potential drug-drug interactions between modern oral antineoplastic and immune-modulating drugs and OTC drugs differs between sales in traditional community pharmacies versus online pharmacies. Design: Real-life sales data from community and online pharmacies were used as basis for the analysis. Methods: We determined the most frequently purchased antineoplastic and immune-modulating drug-substances in 14 local community pharmacies within the Munich area, Germany and identified the OTC substance groups that could potentially cause interactions with oncological therapies. Using sales data from 11 local community pharmacies and three online pharmacies, we investigated whether OTC purchases differed between the two sales channels. Results: We identified 10 relevant OTC substance classes and detected significant variations in patients' preferred sales channels between the drug classes. Certain OTC drugs, which seem to be bought more often over the internet, pose risks during antineoplastic and immune-modulating therapy. Conclusion: Patients should therefore be proactively made aware of the corresponding risks in order not to jeopardize the activity of the antineoplastic and immune-modulating drugs and thus the success of their therapy.

Comparing Community and Online Pharmacies: Investigating Potential Interactions Between Cancer and Immune-Modulating Drugs with Over-the-Counter Medications, and the Importance of Patient Awareness and Healthcare Professional Guidance in Minimizing Adverse Effects and Maintaining Treatment Efficacy Modern anticancer and immune-modulating drugs have the advantage of often being taken orally, but they present other challenges in daily use. Unlike intravenously administered drugs, these are usually not administered by a physician but taken by the patient at home. In these cases, patients may be more likely to buy and take self-medicating drugs over-the-counter (OTC) without consulting a healthcare professional. This study aimed to investigate whether there is a different risk of drug interactions between cancer or immune-modulating drugs and OTC drugs when bought in a community pharmacy versus an online pharmacy. Therefore, we looked at the most common cancer and immune-modulating drugs purchased in 14 local community pharmacies in Munich and identified which OTC drugs could cause problems when used simultaneously. Additionally, we analyzed the sales data from 11 local and 3 online pharmacies to determine if people were more likely to buy different OTC drugs from the two types of pharmacies. As a result, this study showed 10 relevant OTC drug types that potentially cause problems and influence effectiveness when used with cancer or immune-modulating drugs. Furthermore, we observed that some of these OTC drugs were purchased more often online than in community pharmacies and thus are more distant from the control of a physician or pharmacist. It is therefore essential for patients to be aware of the risks associated with easily accessible OTC drugs in combination with their cancer or immune-modulating medication, as serious side effects or decreased efficacy may develop. Patients should remember to consult their doctor or pharmacist if there is any uncertainty about potential drug interactions. At the same time, healthcare professionals should proactively draw their patients' attention to these potential risks, especially when purchasing online.

Significance of molecular diagnostics for therapeutic decision-making in recurrent glioma.

Background: Targeted therapies have substantially improved survival in cancer patients with malignancies outside the brain. Whether in-depth analysis for molecular alterations may also offer therapeutic avenues in primary brain tumors remains unclear. We herein present our institutional experience for glioma patients discussed in our interdisciplinary molecular tumor board (MTB) implemented at the Comprehensive Cancer Center Munich (LMU). Methods: We retrospectively searched the database of the MTB for all recurrent glioma patients after previous therapy. Recommendations were based on next-generation sequencing results of individual patient's tumor tissue. Clinical and molecular information, previous therapy regimens, and outcome parameters were collected. Results: Overall, 73 consecutive recurrent glioma patients were identified. In the median, advanced molecular testing was initiated with the third tumor recurrence. The median turnaround time between initiation of molecular profiling and MTB case discussion was 48 ± 75 days (range: 32-536 days). Targetable mutations were found for 50 recurrent glioma patients (68.5%). IDH1 mutation (27/73; 37%), epidermal growth factor receptor amplification (19/73; 26%), and NF1 mutation (8/73; 11%) were the most detected alterations and a molecular-based treatment recommendation could be made for all of them. Therapeutic recommendations were implemented in 12 cases (24%) and one-third of these heavily pretreated patients experienced clinical benefit with at least disease stabilization. Conclusions: In-depth molecular analysis of tumor tissue may guide targeted therapy also in brain tumor patients and considerable antitumor effects might be observed in selected cases. However, future studies to corroborate our results are needed.

Efficacy of Endocrine Therapy Plus Trastuzumab and Pertuzumab vs De-escalated Chemotherapy in Patients with Hormone Receptor-Positive/ERBB2-Positive Early Breast Cancer: The Neoadjuvant WSG-TP-II Randomized Clinical Trial.

Importance: Combination of chemotherapy with (dual) ERBB2 blockade is considered standard in hormone receptor (HR)-positive/ERBB2-positive early breast cancer (EBC). Despite some promising data on endocrine therapy (ET) combination with dual ERBB2 blockade in HR-positive/ERBB2-positive BC, to our knowledge, no prospective comparison of neoadjuvant chemotherapy vs ET plus ERBB2 blockade in particular with focus on molecular markers has yet been performed. Objective: To determine whether neoadjuvant de-escalated chemotherapy is superior to endocrine therapy, both in combination with pertuzumab and trastuzumab, in a highly heterogeneous HR-positive/ERBB2-positive EBC. Design, Setting, and Participants: This prospective, multicenter, neoadjuvant randomized clinical trial allocated 207 patients with centrally confirmed estrogen receptor-positive and/or progesterone receptor-positive (>1%) HR-positive/ERBB2-positive EBC to 12 weeks of standard ET (n = 100) vs paclitaxel (n = 107) plus trastuzumab and pertuzumab. A total of 186 patients were required to detect a statistically significant difference in pathological complete response (pCR) (assumptions: 19% absolute difference in pCR; power, ≥80%; 1-sided Fisher exact test, 2.5% significance level). Interventions: Standard ET (aromatase inhibitor or tamoxifen) or paclitaxel, 80 mg/m2, weekly plus trastuzumab and pertuzumab every 21 days. Main Outcomes and Measures: The primary end point was pCR (ypT0/is, ypN0). Secondary end points included safety, translational research, and health-related quality of life. Omission of further chemotherapy was allowed in patients with pCR. PAM50 analysis was performed on baseline tumor biopsies. Results: Of the 207 patients included (median [range] age, 53 [25-83] years), 121 (58%) had cT2 to cT4 tumors, and 58 (28%) had clinically node-positive EBC. The pCR rate in the ET plus trastuzumab and pertuzumab arm was 23.7% (95% CI, 15.7%-33.4%) vs 56.4% (95% CI, 46.2%-66.3%) in the paclitaxel plus trastuzumab and pertuzumab arm (odds ratio, 0.24; 95% CI, 0.12-0.46; P < .001). Both immunohistochemical ERBB2 score of 3 or higher and ERBB2-enriched subtype were independent predictors for pCR in both arms. Paclitaxel was superior to ET only in the first through third quartiles but not in the highest ERBB2 quartile by messenger RNA. In contrast with the paclitaxel plus trastuzumab and pertuzumab arm, no decrease in health-related quality of life after 12 weeks was observed in the ET plus trastuzumab and pertuzumab arm. Conclusions and Relevance: The WSG-TP-II randomized clinical trial is, to our knowledge, the first prospective trial comparing 2 neoadjuvant de-escalation treatments in HR-positive/ERBB2-positive EBC and demonstrated an excellent pCR rate after 12 weeks of paclitaxel plus trastuzumab and pertuzumab that was clearly superior to the pCR rate after ET plus trastuzumab and pertuzumab. Trial Registration: ClinicalTrials.gov Identifier: NCT03272477.

PRECYCLE: multicenter, randomized phase IV intergroup trial to evaluate the impact of eHealth-based patient-reported outcome (PRO) assessment on quality of life in patients with hormone receptor positive, HER2 negative locally advanced or metastatic breast cancer treated with palbociclib and an aromatase inhibitor or palbociclib and fulvestrant.

BACKGROUND: Efficacy and quality of life (QoL) are key criteria for therapy selection in metastatic breast cancer (MBC). In hormone receptor positive (HR +) human epidermal growth factor receptor 2 negative (HER2 -) MBC, addition of targeted oral agents such as everolimus or a cycline-dependent kinase 4/6 (CDK 4/6) inhibitor (e.g., palbociclib, ribociclib, abemaciclib) to endocrine therapy substantially prolongs progression-free survival and in the case of a CDK 4/6i also overall survival. However, the prerequisite is adherence to therapy over the entire course of treatment. However, particularly with new oral drugs, adherence presents a challenge to disease management. In this context, factors influencing adherence include maintaining patients' satisfaction and early detection/management of side effects. New strategies for continuous support of oncological patients are needed. An eHealth-based platform can help to support therapy management and physician-patient interaction. METHODS: PreCycle is a multicenter, randomized, phase IV trial in HR + HER2 - MBC. All patients (n = 960) receive the CDK 4/6 inhibitor palbociclib either in first (62.5%) or later line (37.5%) together with endocrine therapy (AI, fulvestrant) according to national guidelines. PreCycle evaluates and compares the time to deterioration (TTD) of QoL in patients supported by eHealth systems with substantially different functionality: CANKADO active vs. inform. CANKADO active is the fully functional CANKADO-based eHealth treatment support system. CANKADO inform is a CANKADO-based eHealth service with a personal login, documentation of daily drug intake, but no further functions. To evaluate QoL, the FACT-B questionnaire is completed at every visit. As little is known about relationships between behavior (e.g., adherence), genetic background, and drug efficacy, the trial includes both patient-reported outcome and biomarker screening for discovery of forecast models for adherence, symptoms, QoL, progression free survival (PFS), and overall survival (OS). DISCUSSION: The primary objective of PreCycle is to test the hypothesis of superiority for time to deterioration (TTD) in terms of DQoL = "Deterioration of quality of life" (FACT-G scale) in patients supported by an eHealth therapy management system (CANKADO active) versus in patients merely receiving eHealth-based information (CANKADO inform). EudraCT Number: 2016-004191-22.

De-Escalated Neoadjuvant Trastuzumab-Emtansine With or Without Endocrine Therapy Versus Trastuzumab With Endocrine Therapy in HR+/HER2+ Early Breast Cancer: 5-Year Survival in the WSG-ADAPT-TP Trial.

PURPOSE: Neoadjuvant chemotherapy is standard of care in human epidermal growth factor receptor 2-positive (HER2+) early breast cancer (EBC), irrespective of the hormone receptor status. Trastuzumab-emtansine (T-DM1), antibody-drug conjugate, is highly effective in HER2+ EBC; however, no survival data are available for de-escalated antibody-drug conjugate-based neoadjuvant therapy without conventional chemotherapy. PATIENTS AND METHODS: In the WSG-ADAPT-TP (ClinicalTrials.gov identifier: NCT01779206) phase II trial, 375 centrally reviewed patients with hormone receptor-positive (HR+)/HER2+ EBC (clinical stage I-III) were randomly assigned to 12 weeks of T-DM1 with or without endocrine therapy (ET) or trastuzumab + ET once every 3 weeks (ratio 1:1:1). Adjuvant chemotherapy (ACT) omission was allowed in patients with pathologic complete response (pCR). In this study, we report the secondary survival end points and biomarker analysis. Patients who received at least one dose of study treatment were analyzed. Survival was analyzed using the Kaplan-Meier method, two-sided log-rank statistics, and Cox regression models stratified for nodal and menopausal status. P values < .05 were considered statistically significant. RESULTS: T-DM1, T-DM1 + ET, and trastuzumab + ET induced similar 5-year invasive disease-free survival (iDFS; 88.9%, 85.3%, 84.6%; Plog-rank = .608) and overall survival rates (97.2%, 96.4%, 96.3%; Plog-rank = .534). Patients with pCR versus non-pCR had improved 5-year iDFS rates (92.7% v 82.7%; hazard ratio, 0.40 [95% CI, 0.18 to 0.85]). Among the 117 patients with pCR, 41 did not receive ACT; 5-year iDFS rates were similar in those with (93.0% [95% CI, 84.0 to 97.0]) and without ACT (92.1% [95% CI, 77.5 to 97.4]; Plog-rank = .848). Translational research revealed that tumors with PIK3CA wild type, high immune marker expression, and luminal-A tumors (by PAM50) had an excellent prognosis with de-escalated anti-HER2 therapy. CONCLUSION: The WSG-ADAPT-TP trial demonstrated that pCR after 12 weeks of chemotherapy-free de-escalated neoadjuvant therapy was associated with excellent survival in HR+/HER2+ EBC without further ACT. Despite higher pCR rates for T-DM1 ± ET versus trastuzumab + ET, all trial arms had similar outcomes because of mandatory standard chemotherapy after non-pCR. WSG-ADAPT-TP demonstrated that such de-escalation trials in HER2+ EBC are feasible and safe for patients. Patient selection on the basis of biomarkers or molecular subtypes may increase the efficacy of systemic chemotherapy-free HER2-targeted approaches.

Impact of RNA Signatures on pCR and Survival after 12-Week Neoadjuvant Pertuzumab plus Trastuzumab with or without Paclitaxel in the WSG-ADAPT HER2+/HR- Trial.

PURPOSE: To identify associations of biological signatures and stromal tumor-infiltrating lymphocytes (sTIL) with pathological complete response (pCR; ypT0 ypN0) and survival in the Phase II WSG-ADAPT HER2+/HR- trial (NCT01817452). EXPERIMENTAL DESIGN: Patients with cT1-cT4c, cN0-3 HER2+/HR- early breast cancer (EBC) were randomized to pertuzumab+trastuzumab (P+T, n = 92) or P+T+paclitaxel (n = 42). Gene expression signatures were analyzed in baseline biopsies using NanoString Breast Cancer 360 panel (n = 117); baseline and on-treatment (week 3) sTIL levels were available in 119 and 76 patients, respectively. Impacts of standardized gene expression signatures on pCR and invasive disease-free survival (iDFS) were estimated by logistic and Cox regression. RESULTS: In all patients, ERBB2 [OR, 1.70; 95% confidence interval (CI), 1.08-2.67] and estrogen receptor (ER) signaling (OR, 1.72; 95% CI, 1.13-2.61) were favorable, whereas PTEN (OR, 0.57; 95% CI, 0.38-0.87) was unfavorable for pCR. After 60 months median follow-up, 13 invasive events occurred (P+T: n = 11, P+T+paclitaxel: n = 2), none following pCR. Gene signatures related to immune response (IR) and ER signaling were favorable for iDFS, all with similar HR about 0.43-0.55. These patterns were even more prominent in the neoadjuvant chemotherapy-free group, where additionally BRCAness signature was unfavorable (HR, 2.00; 95% CI, 1.04-3.84). IR signatures were strongly intercorrelated. sTILs (baseline/week 3/change) were not associated with pCR or iDFS, though baseline sTILs correlated positively with IR signatures. CONCLUSIONS: Distinct gene signatures were associated with pCR versus iDFS in HER2+/HR- EBC. The potential role of IR in preventing recurrence suggests that patients with upregulated IR signatures could be candidates for de-escalation concepts in HER2+ EBC.

Lessons learned: the first consecutive 1000 patients of the CCCMunichLMU Molecular Tumor Board.

PURPOSE: In 2016, the University of Munich Molecular Tumor Board (MTB) was implemented to initiate a precision oncology program. This review of cases was conducted to assess clinical implications and functionality of the program, to identify current limitations and to inform future directions of these efforts. METHODS: Charts, molecular profiles, and tumor board decisions of the first 1000 consecutive cases (01/2016-03/2020) were reviewed. Descriptive statistics were applied to describe relevant findings. RESULTS: Of the first 1000 patients presented to the MTB; 914 patients received comprehensive genomic profiling. Median age of patients was 56 years and 58% were female. The most prevalent diagnoses were breast (16%) and colorectal cancer (10%). Different types of targeted or genome-wide sequencing assays were used; most of them offered by the local department of pathology. Testing was technically successful in 88%. In 41% of cases, a genomic alteration triggered a therapeutic recommendation. The fraction of patients receiving a tumor board recommendation differed significantly between malignancies ranging from over 50% in breast or biliary tract to less than 30% in pancreatic cancers. Based on a retrospective chart review, 17% of patients with an MTB recommendation received appropriate treatment. CONCLUSION: Based on these retrospective analyses, patients with certain malignancies (breast and biliary tract cancer) tend to be more likely to have actionable variants. The low rate of therapeutic implementation (17% of patients receiving a tumor board recommendation) underscores the importance of meticulous follow-up for these patients and ensuring broad access to innovative therapies for patients receiving molecular tumor profiling.

Implementation of CDK4/6 Inhibitors and its Influence on the Treatment Landscape of Advanced Breast Cancer Patients - Data from the Real-World Registry PRAEGNANT.

Background Comprehensive data from prospective clinical trials have led to a high level of evidence establishing CDK4/6 inhibitors in combination with endocrine treatment (CDK4/6i + ET) as a standard for the treatment of HER2-negative, hormone receptor-positive (HER2- HR+) breast cancer patients in the first-line advanced therapy setting. Data on patient populations that have been treated in the real-world setting may provide an insight into changes of patient characteristics and prognosis over time. Methods The data were extracted from the prospective real-world registry PRAEGNANT (NCT02338167). Patients had to have HER2- HR+ advanced breast cancer in the first-line metastatic setting. The chosen therapies were described as well as progression-free survival (PFS) and overall survival (OS) in relation to the given therapies and time periods during which they were indicated. Results CDK4/6 inhibitors have been rapidly implemented since their introduction in November 2016. In recent years (2018 - 2022), about 70 - 80% of the patient population have been treated with CDK4/6 inhibitors, while endocrine monotherapy was given to about 10% and chemotherapy to about 15% of all patients. The prognosis was worst in patients treated with chemotherapy. Recently, mainly patients with a good prognosis are being treated with endocrine monotherapy, and patients who are treated with chemotherapy have an unfavorable prognosis. The PFS and OS of patients treated with CDK4/6i + ET have remained similar over time despite changes in patient characteristics. Conclusion A treatment with CDK4/6i + ET has rapidly become the therapy standard for patients in the first-line advanced breast cancer setting. After the implementation of CDK4/6i + ET, endocrine monotherapy is only given to patients with a very favorable prognosis, while chemotherapy is provided to patients with a rather unfavorable prognosis. These changes in patient characteristics did not seem to influence the prognosis of patients treated with CDK4/6i + ET.