Prognostic impact of selection criteria of current adjuvant endocrine therapy trials NATALEE and monarchE in postmenopausal HRpos/HER2neg breast cancer patients treated with upfront letrozole.

BACKGROUND: The monarchE and NATALEE trials demonstrated the benefit of CDK4/6 inhibitor (CDK4/6i) therapy in adjuvant breast cancer (BC) treatment. Patient selection, based on clinical characteristics, delineated those at high (monarchE) and high/intermediate recurrence risk (NATALEE). This study employed a historical patient cohort to describe the proportion and prognosis of patients eligible for adjuvant CDK4/6i trials. METHODS: Between 2009 and 2011, 3529 patients were enrolled in the adjuvant PreFace clinical trial (NCT01908556). Eligibility criteria included postmenopausal patients with hormone receptor-positive (HRpos) BC for whom a five-year upfront therapy with letrozole was indicated. Patients were categorized into prognostic groups according to monarchE and NATALEE inclusion criteria, and their invasive disease-free survival (iDFS) and overall survival (OS) were assessed. RESULTS: Among 2891 HRpos patients, 384 (13.3 %) met the primary monarchE inclusion criteria. The majority (n = 261) qualified due to having ≥ 4 positive lymph nodes. For NATALEE, 915 out of 2886 patients (31.7 %) met the eligibility criteria, with 126 patients (13.7 %) being node-negative. Patients from monarchE with ≥ 4 positive lymph nodes and NATALEE with stage III BC exhibited the poorest prognosis (3-year iDFS rate 0.87). Patients ineligible for the trials demonstrated prognoses similar to the most favorable patient groups within the eligibility criteria. CONCLUSION: Patient populations eligible for monarchE and NATALEE trials differed. Nearly a third of the postmenopausal HRpos population, previously under upfront letrozole treatment, met the NATALEE prognostic eligibility criteria. As certain eligible groups had a prognosis similar to non-eligible patients, it might be interesting to explore additional patient groups for CDK4/6i therapy.

Arbeitsgemeinschaft Gynäkologische Onkologie Recommendations for the Diagnosis and Treatment of Patients with Early Breast Cancer: Update 2024.

Introduction: Each year the interdisciplinary AGO (Arbeitsgemeinschaft Gynäkologische Onkologie, 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. Methods: The updated evidence-based treatment recommendations for early and metastatic breast cancer have been released in March 2024. Results and Conclusion: This paper concisely captures the updated recommendations for early breast cancer chapter by chapter.

Arbeitsgemeinschaft Gynäkologische Onkologie Recommendations for the Diagnosis and Treatment of Patients with Locally Advanced and Metastatic Breast Cancer: Update 2024.

The Breast Committee of the Arbeitsgemeinschaft Gynäkologische Onkologie (German Gynecological Oncology Group, AGO) presents the 2024 update of the evidence-based recommendations for the diagnosis and treatment of patients with locally advanced and metastatic breast cancer.

Update Breast Cancer 2024 Part 1 - Expert Opinion on Advanced Breast Cancer.

Clinical evidence is interpreted based on clinical studies and personal experience which can lead to different interpretations of data. This makes the opinions issued by panels of experts such as the Advanced Breast Cancer Panel which convened in November 2023 for the seventh time (ABC7) particularly important. At the conference, current issues around advanced breast cancer were evaluated by an international team of experts. In 2023 the data on CDK4/6 inhibitors was so extensive that the answers to questions about the sequencing of therapy and the potential use of chemotherapy as an alternative therapy were relatively clear. Moreover, data on antibody drug conjugates which provides a good overview of their uses is available for all molecular subtypes. Some therapeutic settings, including patients with brain metastases or leptomeningeal disease, older patients, locally advanced breast cancer and visceral crises, continue to be particularly important and were discussed in structured sessions. The scientific context of some of the topics discussed at ABC7 is presented and assessed here.

Discussion of ABC7 Consensus and German Recommendations.

The rationale behind the "International Consensus Conference for Advanced Breast Cancer" (ABC) is to standardize the treatment of patients with advanced or metastatic breast cancer worldwide using an evidence-based approach. The aim is also to ensure that patients in all countries receive adequate treatment based on current treatment recommendations and standards. The 7th International Consensus Conference on Advanced Breast Cancer (ABC7) took place from November 9 to 12, 2023 in Lisbon/Portugal. ABC7 focused on metastatic disease as well as on locally advanced and inflammatory breast cancer. Special topics included the treatment of oligometastatic patients, leptomeningeal disease, treatment of brain metastases, and pregnant women with ABC. As in previous years, patient advocates from all over the world participated in the consensus conference and were involved in decision making.

Impact of Electronic Patient-Reported Outcomes on Unplanned Consultations and Hospitalizations in Patients With Cancer Undergoing Systemic Therapy: Results of a Patient-Reported Outcome Study Compared With Matched Retrospective Data.

BACKGROUND: The evaluation of electronic patient-reported outcomes (ePROs) is increasingly being used in clinical studies of patients with cancer and enables structured and standardized data collection in patients' everyday lives. So far, few studies or analyses have focused on the medical benefit of ePROs for patients. OBJECTIVE: The current exploratory analysis aimed to obtain an initial indication of whether the use of the Consilium Care app (recently renamed medidux; mobile Health AG) for structured and regular self-assessment of side effects by ePROs had a recognizable effect on incidences of unplanned consultations and hospitalizations of patients with cancer compared to a control group in a real-world care setting without app use. To analyze this, the incidences of unplanned consultations and hospitalizations of patients with cancer using the Consilium Care app that were recorded by the treating physicians as part of the patient reported outcome (PRO) study were compared retrospectively to corresponding data from a comparable population of patients with cancer collected at 2 Swiss oncology centers during standard-of-care treatment. METHODS: Patients with cancer in the PRO study (178 included in this analysis) receiving systemic therapy in a neoadjuvant or noncurative setting performed a self-assessment of side effects via the Consilium Care app over an observational period of 90 days. In this period, unplanned (emergency) consultations and hospitalizations were documented by the participating physicians. The incidence of these events was compared with retrospective data obtained from 2 Swiss tumor centers for a matched cohort of patients with cancer. RESULTS: Both patient groups were comparable in terms of age and gender ratio, as well as the distribution of cancer entities and Joint Committee on Cancer stages. In total, 139 patients from each group were treated with chemotherapy and 39 with other therapies. Looking at all patients, no significant difference in events per patient was found between the Consilium group and the control group (odds ratio 0.742, 90% CI 0.455-1.206). However, a multivariate regression model revealed that the interaction term between the Consilium group and the factor "chemotherapy" was significant at the 5% level (P=.048). This motivated a corresponding subgroup analysis that indicated a relevant reduction of the risk for the intervention group in the subgroup of patients who underwent chemotherapy. The corresponding odds ratio of 0.53, 90% CI 0.288-0.957 is equivalent to a halving of the risk for patients in the Consilium group and suggests a clinically relevant effect that is significant at a 2-sided 10% level (P=.08, Fisher exact test). CONCLUSIONS: A comparison of unplanned consultations and hospitalizations from the PRO study with retrospective data from a comparable cohort of patients with cancer suggests a positive effect of regular app-based ePROs for patients receiving chemotherapy. These data are to be verified in the ongoing randomized PRO2 study (registered on ClinicalTrials.gov; NCT05425550). TRIAL REGISTRATION: ClinicalTrials.gov NCT03578731; https://www.clinicaltrials.gov/ct2/show/NCT03578731. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.2196/29271.

Correction: Long-term Follow-up and Safety of Patients after an Upfront Therapy with Letrozole for Early Breast Cancer in Routine Clinical Care - The PreFace Study.

[This corrects the article DOI: 10.1055/a-2238-3153.].

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).

Long-term Follow-up and Safety of Patients after an Upfront Therapy with Letrozole for Early Breast Cancer in Routine Clinical Care - The PreFace Study.

Introduction: Adjuvant treatment of patients with early-stage breast cancer (BC) should include an aromatase inhibitor (AI). Especially patients with a high recurrence risk might benefit from an upfront therapy with an AI for a minimum of five years. Nevertheless, not much is known about the patient selection for this population in clinical practice. Therefore, this study analyzed the prognosis and patient characteristics of postmenopausal patients selected for a five-year upfront letrozole therapy. Patients and Methods: From 2009 to 2011, 3529 patients were enrolled into the adjuvant phase IV PreFace clinical trial (NCT01908556). Postmenopausal hormone receptor-positive BC patients, for whom an upfront five-year therapy with letrozole (2.5 mg/day) was indicated, were eligible. Disease-free survival (DFS), overall survival (OS) and safety in relation to patient and tumor characteristics were assessed. Results: 3297 patients started letrozole therapy. The majority of patients (n = 1639, 57%) completed the five-year treatment. 34.5% of patients continued with endocrine therapy after the mandated five-year endocrine treatment. Five-year DFS rates were 89% (95% CI: 88-90%) and five-year OS rates were 95% (95% CI: 94-96%). In subgroup analyses, DFS rates were 83%, 84% and 78% for patients with node-positive disease, G3 tumor grading, and pT3 tumors respectively. The main adverse events (any grade) were pain and hot flushes (66.8% and 18.3% of patients). Conclusions: The risk profile of postmenopausal BC patients selected for a five-year upfront letrozole therapy showed a moderate recurrence and death risk. However, in subgroups with unfavorable risk factors, prognosis warrants an improvement, which might be achieved with novel targeted therapies.

GRB2 is a BECN1 interacting protein that regulates autophagy.

GRB2 is an adaptor protein of HER2 (and several other tyrosine kinases), which we identified as a novel BECN1 (Beclin 1) interacting partner. GRB2 co-immunoprecipitated with BECN1 in several breast cancer cell lines and regulates autophagy through a mechanism involving the modulation of the class III PI3Kinase VPS34 activity. In ovo studies in a CAM (Chicken Chorioallantoic Membrane) model indicated that GRB2 knockdown, as well as overexpression of GRB2 loss-of-function mutants (Y52A and S86A-R88A) compromised tumor growth. These differences in tumor growth correlated with differential autophagy activity, indicating that autophagy effects might be related to the effects on tumorigenesis. Our data highlight a novel function of GRB2 as a BECN1 binding protein and a regulator of autophagy.

Update Breast Cancer 2023 Part 1 - Early Stage Breast Cancer.

With abemaciclib (monarchE study) and olaparib (OlympiA study) gaining approval in the adjuvant treatment setting, a significant change in the standard of care for patients with early stage breast cancer has been established for some time now. Accordingly, some diverse developments are slowly being transferred from the metastatic to the adjuvant treatment setting. Recently, there have also been positive reports of the NATALEE study. Other clinical studies are currently investigating substances that are already established in the metastatic setting. These include, for example, the DESTINY Breast05 study with trastuzumab deruxtecan and the SASCIA study with sacituzumab govitecan. In this review paper, we summarize and place in context the latest developments over the past months.

Update Breast Cancer 2023 Part 2 - Advanced-Stage Breast Cancer.

In recent years, a number of new therapies have led to advances in the treatment of patients with advanced breast carcinoma. These substances are mainly CDK4/6 inhibitors and other substances that can overcome endocrine resistance, oral selective estrogen receptor degraders, antibody drug conjugates (ADCs), and PARP inhibitors. This review summarizes and evaluates the latest study results that have been published in recent months. This includes the overall survival data of the Destiny-Breast03 study, the first analysis of the CAPItello-291 study, the comparison of CDK4/6 inhibitor treatment with chemotherapy in the first line of therapy (RIGHT Choice study), the first analysis of the Destiny-Breast02 study in the treatment setting after T-DM1 treatment, and the first analysis of the Serena-2 study. Most of these studies have the potential to significantly change the therapeutic landscape for patients with advanced breast carcinoma and show that the continued rapid development of new therapies is always producing new results.

AGO Recommendations for the Diagnosis and Treatment of Patients with Locally Advanced and Metastatic Breast Cancer: Update 2023.

The Breast Committee of the Arbeitsgemeinschaft Gynäkologische Onkologie (German Gynecological Oncology Group, AGO) presents the 2023 update of the evidence-based recommendations for the diagnosis and treatment of patients with locally advanced and metastatic breast cancer (mBC).

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.

Update Breast Cancer 2023 Part 3 - Expert Opinions of Early Stage Breast Cancer Therapies.

The St. Gallen (SG) International Breast Cancer Conference is held every two years, previously in St. Gallen and now in Vienna. This year (2023) marks the eighteenth edition of this conference, which focuses on the treatment of patients with early-stage breast carcinoma. A panel discussion will be held at the end of this four-day event, during which a panel of experts will give their opinions on current controversial issues relating to the treatment of early-stage breast cancer patients. To this end, questions are generally formulated in such a way that clinically realistic cases are presented - often including poignant hypothetical modifications. This review reports on the outcome of these discussions and summarises the data associated with individual questions raised.

Impact of BMI in Patients With Early Hormone Receptor-Positive Breast Cancer Receiving Endocrine Therapy With or Without Palbociclib in the PALLAS Trial.

PURPOSE: BMI affects breast cancer risk and prognosis. In contrast to cytotoxic chemotherapy, CDK4/6 inhibitors are given at a fixed dose, irrespective of BMI or weight. This preplanned analysis of the global randomized PALLAS trial investigates the impact of BMI on the side-effect profile, treatment adherence, and efficacy of palbociclib. METHODS: Patients were categorized at baseline according to WHO BMI categories. Neutropenia rates were assessed with univariable and multivariable logistic regression. Time to early discontinuation of palbociclib was analyzed with Fine and Gray competing risk models. Unstratified Cox models were used to investigate the association between BMI category and time to invasive disease-free survival (iDFS). 95% CIs were derived. RESULTS: Of 5,698 patients included in this analysis, 68 (1.2%) were underweight, 2,082 (36.5%) normal weight, 1,818 (31.9%) overweight, and 1,730 (30.4%) obese at baseline. In the palbociclib arm, higher BMI was associated with a significant decrease in neutropenia (unadjusted odds ratio for 1-unit change, 0.93; 95% CI, 0.91 to 0.94; adjusted for age, race ethnicity, region, chemotherapy use, and Eastern Cooperative Oncology Group at baseline, 0.93; 95% CI, 0.92 to 0.95). This translated into a significant decrease in treatment discontinuation rate with higher BMI (adjusted hazard ratio [HR] for 10-unit change, 0.75; 95% CI, 0.67 to 0.83). There was no significant improvement in iDFS with the addition of palbociclib to ET in any weight category (normal weight HR, 0.84; 95% CI, 0.63 to 1.12; overweight HR, 1.10; 95% CI, 0.82 to 1.49; and obese HR, 0.95; 95% CI, 0.69 to 1.30) in this analysis early in follow-up (31 months). CONCLUSION: This preplanned analysis of the PALLAS trial demonstrates a significant impact of BMI on side effects, dose reductions, early treatment discontinuation, and relative dose intensity. Additional long-term follow-up will further evaluate whether BMI ultimately affects outcome.

St. Gallen/Vienna 2023: Optimization of Treatment for Patients with Primary Breast Cancer - A Brief Summary of the Consensus Discussion.

The St. Gallen Consensus Conference on early breast cancer treatment 2023 was again a live event and took place in Vienna, Austria. After 4 years and one virtual event due to the pandemic, more than 2,800 participants from over 100 countries came together in Vienna, and the 2023 St. Gallen/Vienna conference was a great success. Over 3 days, the global faculty reviewed the most important evidence published during the last 2 years and debated over controversial topics, and finally, the consensus votes aimed to define the impact of the new data on everyday routine practice. Focuses of this year's conference were radiotherapy and local management of the axilla, genetics, and their impact on treatment, as well as the role of the immune system and tumor-infiltrating lymphocytes in pathological reports and treatment decision-making. The traditional panel votes were moderated for the first time by Harold Burstein from Boston, and with questions previously voted on and live voting, the panel managed for the most part to clarify the critical questions. This report by editors of BREAST CARE summarizes the results of the 2023 international panel votes with respect to locoregional and systemic treatment as a brief news update but does not intend to replace the official St. Gallen Consensus publication that not just reports but also interprets the panel votes and will follow shortly in a major oncological journal. The next (19th) St. Gallen International Breast Cancer Conference will again take place in Vienna (save the date: March 12-15, 2025).

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.

Adjuvant Docetaxel in Node-Negative Breast Cancer Patients: A Randomized Trial of AGO-Breast Study Group, German Breast Group, and EORTC-Pathobiology Group.

BACKGROUND: In node-negative breast cancer (NNBC), a high risk of recurrence is determined by clinico-pathological or tumor-biological assessment. Taxanes may improve adjuvant chemotherapy. METHODS: NNBC 3-Europe, the first randomized phase-3 trial in node-negative breast cancer (BC) with tumor-biological risk assessment, recruited 4146 node-negative breast cancer patients from 2002 to 2009 in 153 centers. Risk assessment was performed by clinico-pathological factors (43%) or biomarkers (uPA/PAI-1, urokinase-type plasminogen activator/its inhibitor PAI-1). High-risk patients received six courses 5-fluorouracil (500 mg/m2), epirubicin (100 mg/m2), cyclophosphamide (500 mg/m2) (FEC), or three courses FEC followed by three courses docetaxel 100 mg/m2 (FEC-Doc). Primary endpoint was disease-free survival (DFS). RESULTS: In the intent-to-treat population, 1286 patients had received FEC-Doc, and 1255 received FEC. Median follow-up was 45 months. Tumor characteristics were equally distributed; 90.6% of tested tumors had high uPA/PAI-1-concentrations. Planned courses were given in 84.4% (FEC-Doc) and 91.5% (FEC). Five-year-DFS was 93.2% (95% C.I. 91.1-94.8) with FEC-Doc and 93.7% (91.7-95.3) with FEC. Five-year-overall survival was 97.0% (95.4-98.0) for FEC-Doc and 96.6% % (94.9-97.8) for FEC. CONCLUSIONS: With adequate adjuvant chemotherapy, even high-risk node-negative breast cancer patients have an excellent prognosis. Docetaxel did not further reduce the rate of early recurrences and led to significantly more treatment discontinuations.