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PurposeTo conduct an updated exploratory analysis of overall survival (OS) with a longer median follow-up of 73.3 months and evaluate the prognostic value of molecular analysis by circulating tumor DNA (ctDNA).Patients and methodsPatients with hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) advanced breast cancer (ABC) were randomized 2:1 to receive palbociclib (125 mg orally/day; 3/1 week schedule) and fulvestrant (500 mg intramuscularly) or placebo and fulvestrant. This OS analysis was performed when 75% of enrolled patients died (393 events in 521 randomized patients). ctDNA analysis was performed among patients who provided consent.ResultsAt the data cutoff (August 17, 2020), 258 and 135 deaths occurred in the palbociclib and placebo groups, respectively. The median OS [95% confidence interval (CI)] was 34.8 months (28.8-39.9) in the palbociclib group and 28.0 months (23.5-33.8) in the placebo group (stratified hazard ratio, 0.81; 95% CI, 0.65-0.99). The 6-year OS rate (95% CI) was 19.1% (14.9-23.7) and 12.9% (8.0-19.1) in the palbociclib and placebo groups, respectively. Favorable OS with palbociclib plus fulvestrant compared with placebo plus fulvestrant was observed in most subgroups, particularly in patients with endocrine-sensitive disease, no prior chemotherapy for ABC and low circulating tumor fraction and regardless of ESR1, PIK3CA, or TP53 mutation status. No new safety signals were identified.ConclusionsThe clinically meaningful improvement in OS associated with palbociclib plus fulvestrant was maintained with >6 years of follow-up in patients with HR+/HER2- ABC, supporting palbociclib plus fulvestrant as a standard of care in these patients.

PurposeRibociclib plus endocrine therapy (ET) demonstrated a statistically significant progression-free survival and overall survival (OS) benefit in the phase III MONALEESA-7 trial of pre-/perimenopausal patients with hormone receptor (HR)-positive (HR+), HER2-negative (HER2-) advanced breast cancer (ABC). The median OS was not reached in the ribociclib arm in the protocol-specified final analysis; we hence performed an exploratory OS and additional outcomes analysis with an extended follow-up (median, 53.5 months).Patients and methodsPatients were randomized to receive ET [goserelin plus nonsteroidal aromatase inhibitor (NSAI) or tamoxifen] with ribociclib or placebo. OS was evaluated with a stratified Cox proportional hazard model and summarized with Kaplan-Meier methods.ResultsThe intent-to-treat population included 672 patients. Median OS was 58.7 months with ribociclib versus 48.0 months with placebo [hazard ratio = 0.76; 95% confidence interval (CI), 0.61-0.96]. Kaplan-Meier estimated OS at 48 months was 60% and 50% with ribociclib and placebo, respectively. Subgroup analyses were generally consistent with the OS benefit, including patients who received NSAI and patients aged less than 40 years. Subsequent antineoplastic therapies following discontinuation were balanced between the ribociclib (77%) and placebo (78%) groups. Use of cyclin-dependent kinase 4/6 inhibitors after discontinuation was higher with placebo (26%) versus ribociclib (13%). Time to first chemotherapy was significantly delayed with ribociclib versus placebo. No drug-drug interactions were observed between ribociclib and either NSAI.ConclusionsRibociclib plus ET continued to show significantly longer OS than ET alone in pre-/perimenopausal patients, including patients aged less than 40 years, with HR+/HER2- ABC with 53.5 months of median follow-up (ClinicalTrials.gov, NCT02278120).

PurposeThis analysis evaluated the genomic landscape of premenopausal patients with hormone receptor-positive and human epidermal growth factor receptor 2-negative advanced breast cancer and the association of genetic alterations with response to ribociclib in the phase III MONALEESA-7 trial.MethodsPremenopausal patients were randomly assigned 1:1 to receive endocrine therapy plus ribociclib or placebo. Plasma collected at baseline was sequenced using targeted next-generation sequencing for approximately 600 relevant cancer genes. The association of circulating tumor DNA alterations with progression-free survival (PFS) was evaluated to identify biomarkers of response and resistance to ribociclib.ResultsBaseline circulating tumor DNA was sequenced in 565 patients; 489 had evidence of ≥ 1 alteration. The most frequent alterations included PIK3CA (28%), TP53 (19%), CCND1 (10%), MYC (8%), GATA3 (8%), receptor tyrosine kinases (17%), and the Chr8p11.23 locus (12%). A treatment benefit of ribociclib was seen with wild-type (hazard ratio [HR] 0.45 [95% CI, 0.33 to 0.62]) and altered (HR 0.57 [95% CI, 0.36 to 0.9]) PIK3CA. Overall, patients with altered CCND1 had shorter PFS regardless of treatment, suggesting CCND1 as a potential prognostic biomarker. Benefit with ribociclib was seen in patients with altered (HR 0.21 [95% CI, 0.08 to 0.54]) or wild-type (HR 0.52 [95% CI, 0.39 to 0.68]) CCND1, but greater benefit was observed with altered, suggesting predictive potential of CCND1. Alterations in TP53, MYC, Chr8p11.23 locus, and receptor tyrosine kinases were associated with worse PFS, but ribociclib benefit was independent of alteration status.ConclusionIn this study-to our knowledge, the first large study of premenopausal patients with hormone receptor-positive and human epidermal growth factor receptor 2-negative advanced breast cancer-multiple genomic alterations were associated with poor outcome. A PFS benefit of ribociclib was observed regardless of gene alteration status, although in this exploratory analysis, a magnitude of benefits varied by alteration.

BackgroundThis analysis investigated whether baseline characteristics affect the survival benefit derived from palbociclib-fulvestrant and the optimal timing of cyclin-dependent kinase 4/6 inhibitor therapy for advanced breast cancer (ABC) in patients from PALOMA-3.Patients and methodsIn total, 521 patients were randomized 2:1 to receive palbociclib (125 mg/day, 3/1 schedule)-fulvestrant (500 mg, intramuscular injection, on days 1 and 15 of cycle 1, and then day 1 of each subsequent cycle) or matching placebo-fulvestrant. Median overall survival (OS) and progression-free survival were estimated using the Kaplan-Meier method.ResultsMultivariable analysis identified endocrine sensitivity, nonvisceral disease, no prior chemotherapy for ABC, and Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 as significant prognostic factors for OS. Patients without chemotherapy for ABC had fewer prior lines of treatment in any setting and in the ABC setting versus patients with prior chemotherapy for ABC (two or fewer prior systemic therapies: 69% vs. 42%; no more than one prior line for ABC: 82% vs. 33%, respectively). Median OS was prolonged with palbociclib-fulvestrant in patients without prior chemotherapy for ABC (39.7 vs. 29.5 months; hazard ratio, 0.75; 95% confidence interval [CI]: 0.56-1.01) and was similar in patients with prior chemotherapy for ABC (25.6 vs. 26.2 months; hazard ratio, 0.91 [95% CI: 0.63-1.32]) versus placebo-fulvestrant.ConclusionPrognostic factors for OS included endocrine sensitivity, nonvisceral disease, ECOG PS of 0, and no prior chemotherapy for ABC. Exploratory analyses suggest improved OS with palbociclib-fulvestrant versus placebo-fulvestrant in patients with no prior chemotherapy for ABC, prior endocrine sensitivity, and fewer prior regimens of systemic therapy. (Clinical trial identification number: NCT01942135).Implications for practicePrognostic factors for overall survival in HR+/HER2- advanced breast cancer (ABC) include the absence of prior chemotherapy in the advanced setting, endocrine sensitivity, nonvisceral disease, and an ECOG performance status of 0. Improved overall survival benefit was observed with palbociclib-fulvestrant versus placebo-fulvestrant in patients (regardless of menopausal status or visceral involvement) with no prior chemotherapy for ABC, with prior endocrine sensitivity, and fewer prior regimens of systemic therapy. Progression-free survival was prolonged with palbociclib across subgroups (regardless of chemotherapy exposure in ABC). These exploratory findings suggest that patients may receive greater clinical benefit from palbociclib-fulvestrant if they receive the combination before chemotherapy in the advanced setting.

BackgroundPALOMA-2 confirmed that first-line palbociclib + letrozole improved progression-free survival (hazard ratio, 0.58; 95% confidence interval, 0.46-0.72) in postmenopausal women with estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC). This analysis evaluated palbociclib-associated hematologic adverse events (AEs) and provides insight on managing these AEs.Materials and methodsPostmenopausal women with ER+/HER2- ABC were randomly assigned 2:1 to letrozole (2.5 mg daily continuously) plus oral palbociclib (125 mg daily; 3 weeks on/1 week off) or placebo. Safety assessments were performed at baseline, days 1 and 15 (first two cycles) and day 1 of subsequent cycles, and included white blood cell, platelet, and absolute neutrophil count (ANC).ResultsPALOMA-2 randomized 666 women to palbociclib + letrozole (n = 444) or placebo + letrozole (n = 222). Neutropenia was the most common AE (95.3%) with palbociclib (grade 3, 55.6%; grade 4, 11.5%) and was managed by dose modifications; progression-free survival was similar between patients who experienced grade ≥ 3 neutropenia versus those who did not. Median (range) time to onset of neutropenia with palbociclib + letrozole was 15 (12-700) days (grade ≥ 3, 28.0 [12-854] days); median duration of each neutropenia episode grade ≥ 3 was 7.0 days. Asian ethnicity and low baseline ANC were associated with increased risk of grade 3/4 neutropenia with palbociclib (p < .001).ConclusionPalbociclib + letrozole was generally well tolerated. Neutropenia, the most frequently reported AE in women with ER+/HER2- ABC, was mostly transient and manageable by dose modifications in patients who experienced grade ≥ 3 neutropenia, without appearing to compromise efficacy. (Pfizer; NCT01740427) IMPLICATIONS FOR PRACTICE: Palbociclib demonstrated an acceptable safety profile in PALOMA-2 in women with estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC) receiving first-line palbociclib + letrozole. Although hematologic adverse events (AEs) are typically expected with anticancer therapies and are often clinically significant, palbociclib-related hematologic AEs, particularly neutropenia (most frequent AE), were transient/manageable by dose reduction, interruption, or cycle delay, which is in contrast to the more profound neutropenia associated with chemotherapy. Palbociclib dose adjustments decreased hematologic AE severity without appearing to compromise efficacy, supporting palbociclib + letrozole as a first-line treatment for ER+/HER2- ABC.

PurposeThe KRISTINE study compared neoadjuvant trastuzumab emtansine plus pertuzumab (T-DM1+P) with docetaxel, carboplatin, trastuzumab plus P (TCH+P) for the treatment human epidermal growth factor receptor 2-positive stage II to III breast cancer. T-DM1+P led to a lower pathologic complete response rate (44.4% v 55.7%; P = .016), but fewer grade 3 or greater and serious adverse events (AEs). Here, we present 3-year outcomes from KRISTINE.MethodsPatients were randomly assigned to neoadjuvant T-DM1+P or TCH+P every 3 weeks for six cycles. Patients who received T-DM1+P continued adjuvant T-DM1+P, and patients who received TCH+P received adjuvant trastuzumab plus pertuzumab. Secondary end points included event-free survival (EFS), overall survival, patient-reported outcomes (measured from random assignment), and invasive disease-free survival (IDFS; measured from surgery).ResultsOf patients, 444 were randomly assigned (T-DM1+P, n = 223; TCH+P, n = 221). Median follow-up was 37 months. Risk of an EFS event was higher with TDM-1+P (hazard ratio [HR], 2.61 [95% CI, 1.36 to 4.98]) with more locoregional progression events before surgery (15 [6.7%] v 0). Risk of an IDFS event after surgery was similar between arms (HR, 1.11 [95% CI, 0.52 to 2.40]). Pathologic complete response was associated with a reduced risk of an IDFS event (HR, 0.24 [95% CI, 0.09 to 0.60]) regardless of treatment arm. Overall, grade 3 or greater AEs (31.8% v 67.7%) were less common with T-DM1+P. During adjuvant treatment, grade 3 or greater AEs (24.5% v 9.9%) and AEs leading to treatment discontinuation (18.4% v 3.8%) were more common with T-DM1+P. Patient-reported outcomes favored T-DM1+P during neoadjuvant treatment and were similar to trastuzumab plus pertuzumab during adjuvant treatment.ConclusionCompared with TCH+P, T-DM1+P resulted in a higher risk of an EFS event owing to locoregional progression events before surgery, a similar risk of an IDFS event, fewer grade 3 or greater AEs during neoadjuvant treatment, and more AEs leading to treatment discontinuation during adjuvant treatment.

Introduction: Breast cancer patients (BCP) experience considerable side effects during and after treatment. Several studies have shown positive effects of exercise on therapy-related side-effects such as loss of muscle strength, loss of bone mineral density, lymphedema, and several elements of quality of life (QoL). Resistance exercise has proven effective and beneficial for BCP; however, optimal individual training parameters remain to be determined. Methods: The aim of our study was to implement an adaptive, progressive, supervised resistance protocol for BCPs during chemotherapy, improving muscle strength, physical condition, and overall QoL while reducing therapy-induced side-effects. Forty patients receiving adjuvant chemotherapy were included 6–12 weeks post-OP. Twenty patients underwent high intensity resistance-training twice a week for 12 weeks, and the control group received usual care. Results: Strength parameters improved significantly in the intervention group and in different scales of QoL. We documented a cyclic performance level dependent on the number of days after treatment. Conclusion: Adaptive resistance training with simple training control mechanisms proved to be effective regarding optimal intensity in each training session and needs to be implemented in further studies in order to guarantee adequate loads in accordance to the training protocols. [ABSTRACT FROM AUTHOR]

Background: The management of early breast cancer (BC) has witnessed an uprise in the use of neoadjuvant therapy and a remarkable reshaping of the systemic therapy postneoadjuvant treatment in the last few years, with the evolution of many controversial clinical situations that require consensus. Methods: During the 14th Breast‐Gynecological and Immuno‐Oncology International Cancer Conference held in Egypt in 2022, a panel of 44 BC experts from 13 countries voted on statements concerning debatable challenges in the neo/adjuvant treatment setting. The recommendations were subsequently updated based on the most recent data emerging. A modified Delphi approach was used to develop this consensus. A consensus was achieved when ≥75% of voters selected an answer. Results and Conclusions: The consensus recommendations addressed different escalation and de‐escalation strategies in the setting of neoadjuvant therapy for early BC. The recommendations recapitulate the available clinical evidence and expert opinion to individualize patient management and optimize therapy outcomes. Consensus was reached in 63% of the statements (52/83), and the rationale behind each statement was clarified. Consensus recommendations of the 14th Breast‐Gynecological and Immuno‐Oncology International Cancer Conference recapitulate the available clinical evidence and expert opinion to individualize and optimize the neoadjuvant therapy of breast cancer. [ABSTRACT FROM AUTHOR]

BackgroundPalbociclib enhances endocrine therapy and improves clinical outcomes in hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC). Because this is a new target, it is clinically important to understand palbociclib's safety profile to effectively manage toxicity and optimize clinical benefit.Materials and methodsPatients with endocrine-resistant, HR-positive/HER2-negative MBC (n = 521) were randomly assigned 2:1 to receive fulvestrant (500 mg intramuscular injection) with or without goserelin with oral palbociclib (125 mg daily; 3 weeks on/1 week off) or placebo. Safety assessments at baseline and day 1 of each cycle included blood counts on day 15 for the first 2 cycles. Hematologic toxicity was assessed by using laboratory data.ResultsA total of 517 patients were treated (palbociclib, n = 345; placebo, n = 172); median follow-up was 8.9 months. With palbociclib, neutropenia was the most common grade 3 (55%) and 4 (10%) adverse event; median times to onset and duration of grade ≥3 episodes were 16 and 7 days, respectively. Asian ethnicity and below-median neutrophil counts at baseline were significantly associated with an increased chance of developing grade 3-4 neutropenia with palbociclib. Dose modifications for grade 3-4 neutropenia had no adverse effect on progression-free survival. In the palbociclib arm, febrile neutropenia occurred in 3 (

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 andmolecular 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 awaiting-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). [ABSTRACT FROM AUTHOR]

Invasive lobular carcinomas (ILC) show better clinical behaviour compared with other histological types, but significantly lower pathological complete response (pCR) rates after neoadjuvant chemotherapy (NACT). We investigated whether factors influencing pCR rate in ILC after NACT can be identified and whether clinical outcome is different. 9,020 breast cancer patients from nine German neoadjuvant trials with known histological type were pooled. 11.7 % of tumours were ILC. Endpoints were: pCR rate, surgery type and survival. ILC was associated with older age, larger tumour size, lymph node negativity, lower grade and positive hormone-receptor-status (HR). Patients with ILC achieved a significantly lower pCR rate compared with non-ILC patients (6.2 vs. 17.4 %, P < 0.001). The pCR rate was 4.2 % in ILC/HR+/G1-2, 7.0 % in ILC with either HR- or G3, and 17.8 % in ILC/HR-/G3. Mastectomy rate was higher in ILC compared with non-ILC patients irrespective of response to NACT (pCR: 27.4 vs. 16.6 %, P = 0.037 and non-pCR: 41.8 % vs. 31.5 %, P < 0.0001). Age and HR independently predicted pCR in ILC. In ILC patients, pCR did not predict distant disease free (DDFS) and loco-regional disease free survival (LRFS), but overall survival (OS). Non-pCR patients with ILC had significantly better DDFS (P = 0.018), LRFS (P < 0.0001) and OS (P = 0.044) compared with non-ILC patients. Patients with ILC had a low chance of obtaining a pCR and this is not well correlated with further outcome. The mastectomy rate was considerably high in ILC patients even after obtaining a pCR. We, therefore, suggest to offer NACT mainly to ILC patients with HR-negative tumours.

Simple Summary: The presented data provides intriguing insights into the users of the PINK! Coach app and the impact of this usage in regards to body mass index (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. 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Taselisib is a potent β‐sparing phosphatidylinositol 3‐kinase (PI3K) inhibitor that, with endocrine therapy, improves outcomes in phosphatidylinositol‐4,5‐bisphosphate 3‐kinase catalytic subunit alpha (PIK3CA)‐mutated (PIK3CAmut) advanced breast cancer. To understand alterations associated with response to PI3K inhibition, we analysed circulating tumour DNA (ctDNA) from participants enrolled in the SANDPIPER trial. Participants were designated as either PIK3CAmut or PIK3CA no mutation was detected (NMD) per baseline ctDNA. The top mutated genes and tumour fraction estimates identified were analysed for their association with outcomes. In participants with PIK3CAmut ctDNA treated with taselisib + fulvestrant, tumour protein p53 (TP53; encoding p53) and fibroblast growth factor receptor 1 (FGFR1) alterations were associated with shorter progression‐free survival (PFS) compared to participants with NMD in these genes. Conversely, participants with PIK3CAmut ctDNA harbouring a neurofibromin 1 (NF1) alteration or high baseline tumour fraction estimate experienced improved PFS upon treatment with taselisib + fulvestrant compared to placebo + fulvestrant. Broadly, alterations in oestrogen receptor (ER), PI3K and p53 pathway genes were associated with resistance to taselisib + fulvestrant in participants with PIK3CAmut ctDNA. Altogether, we demonstrated the impact of genomic (co‐)alterations on outcomes with one of the largest clinico‐genomic datasets of ER+, HER2−, PIK3CAmut breast cancer patients treated with a PI3K inhibitor. [ABSTRACT FROM AUTHOR]

To individualise breast cancer (BC) prevention, markers to follow a person's changing environment and health extending beyond static genetic risk scores are required. Here, we analysed cervical and breast DNA methylation (n = 1848) and single nucleotide polymorphisms (n = 1442) and demonstrate that a linear combination of methylation levels at 104 BC-associated methylation quantitative trait loci (mQTL) CpGs, termed the WID™-qtBC index, can identify women with breast cancer in hormone-sensitive tissues (AUC = 0.71 [95% CI: 0.65–0.77] in cervical samples). Women in the highest combined risk group (high polygenic risk score and WID™-qtBC) had a 9.6-fold increased risk for BC [95% CI: 4.7–21] compared to the low-risk group and tended to present at more advanced stages. Importantly, the WID™-qtBC is influenced by non-genetic BC risk factors, including age and body mass index, and can be modified by a preventive pharmacological intervention, indicating an interaction between genome and environment recorded at the level of the epigenome. Our findings indicate that methylation levels at mQTLs in relevant surrogate tissues could enable integration of heritable and non-heritable factors for improved disease risk stratification. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Introduction: [18F]Fluoroestradiol ([18F]FES) PET/CT has been proposed as a tool for detecting the oestrogen receptor density in patients with metastatic breast cancer (BC) non-invasively across all disease localizations. However, its diagnostic potential in terms of the detection rate (DR) of metastases is unclear. In this study, we pitted this method against [18F]FDG PET/CT and tried to identify predictors of the diagnostic superiority of the [18F] FES-based method. Materials and methods: From a multicentre database, we enrolled all patients with metastatic BC who had undergone both [18F]FES PET/CT and [18F]FDG PET/CT. Two readers assessed both images independently and used a patient-based (PBA) and lesion-based analysis (LBA) to calculate the DR. Pathology-related and clinical factors were tested as predictors of [18F]FES PET/CT superiority using a multivariate model. Results: 92 patients, bearing a total of 2678 metastases, were enrolled. On PBA, the DR of [18F]FDG and [18F]FES PET/CT was 97% and 86%, respectively (p = 0.018). On LBA, the [18F]FES method proved more sensitive than [18F]FDG PET/CT in lymph nodes, bone, lung and soft tissue (p < 0.01). This greater sensitivity was associated with lobular histology, both on PBA (Odds Ratio (OR) 3.4, 95%CI 1.0–12.3) and on LBA (OR 4.4, 95%CI 1.2–16.1 for lymph node metastases and OR 3.29, 95%CI 1.1–10.2 for bone localizations). Conclusions: The overall DR of [18F]FES PET/CT appears to be lower than that of [18F]FDG PET/CT on PBA. However, the [18F]FES method, if positive, can identify more lesions than [18F]FDG at most sites. The higher sensitivity of [18F]FES PET/CT was associated with lobular histology. [ABSTRACT FROM AUTHOR]

Simple Summary: The treatment of elderly patients with breast cancer often deviates from guideline recommendations due to comorbidities, expected side effects, and patient preference. We investigated the standard of care of postoperative radiotherapy after breast-conserving surgery in elderly patients (≥65 years) treated outside of clinical trials, potential factors related to the omission of radiotherapy, and the interaction with endocrine therapy. Overall, three thousand one hundred seventy-one women treated at two major breast centers were evaluated. Postoperative radiotherapy was performed in 82% of these cases. The irradiated patients were younger and more likely to receive additional endocrine therapy and chemotherapy. Patients who did not receive radiotherapy were significantly more likely to have non-invasive DCIS tumors and did not undergo axillary surgery. Radiotherapy was associated with improved locoregional tumor control, even in patients receiving endocrine therapy. Patients treated with radiotherapy alone had significantly better locoregional control than with endocrine therapy alone. In conclusion, the present work confirms the efficacy of postoperative radiotherapy in the elderly, even in patients receiving endocrine therapy. We aimed to evaluate the standard of care of adjuvant radiotherapy (RT) after breast-conserving surgery (BCS) in elderly female patients (≥65 years) treated outside of clinical trials and to identify potential factors related to the omission of RT and the interaction with endocrine therapy (ET). All women treated with BCS at two major breast centers between 1998 and 2014 were evaluated. Data were provided by the Tumor Registry Munich. Survival analyses were conducted using the Kaplan–Meier method. Prognostic factors were identified using multivariate Cox regression analysis. The median follow-up was 88.4 months. Adjuvant RT was performed in 82% (2599/3171) of patients. Irradiated patients were younger (70.9 vs. 76.5 years, p < 0.001) and were more likely to receive additional chemotherapy (p < 0.001) and ET (p = 0.014). Non-irradiated patients more often had non-invasive DCIS tumors (pTis: 20.3% vs. 6.8%, p < 0.001) and did not undergo axillary surgery (no axillary surgery: 50.5% vs. 9.5%, p < 0.001). Adjuvant RT was associated with improved locoregional tumor control after BCS in invasive tumors (10-year local recurrence-free survival (LRFS): 94.0% vs. 75.1%, p < 0.001, 10-year lymph node recurrence-free survival (LNRFS): 98.1% vs. 93.1%, p < 0.001). Multivariate analysis confirmed significant benefits for local control with postoperative RT. Furthermore, RT led to increased locoregional control even in patients who received ET (10-year LRFS 94.8% with ET + RT vs. 78.1% with ET alone, p < 0.001 and 10-year LNRFS: 98.2% vs. 95.0%, p = 0.003). Similarly, RT alone had significantly better locoregional control rates compared to ET alone (10-year LRFS 92.6% with RT alone vs. 78.1% with ET alone, p < 0.001 and 10-year LNRFS: 98.0% vs. 95.0%, p = 0.014). The present work confirms the efficacy of postoperative RT for breast carcinoma in elderly patients (≥65 years) treated in a modern clinical setting outside of clinical trials, even in patients who receive ET. [ABSTRACT FROM AUTHOR]

Ki67 represents an immunohistochemical nuclear localized marker that is widely used in surgical pathology. Nuclear immunoreactivity for Ki67 indicates that cells are cycling and are in G1- to S-phase. The percentage of Ki67-positive tumor cells (Ki67 index) therefore provides an estimate of the growth fraction in tumor specimens. In breast cancer (BC), tumor cell proliferation rate is one of the most relevant prognostic markers and Ki67 is consequently helpful in prognostication similar to histological grading and mRNA profiling-based BC risk stratification. In BCs treated with short-term preoperative endocrine therapy, Ki67 dynamics enable distinguishing between endocrine sensitive and resistant tumors. Despite its nearly universal use in pathology laboratories worldwide, no internationally accepted consensus has yet been achieved for some methodological details related to Ki67 immunohistochemistry (IHC). Controversial issues refer to choice of IHC antibody clones, scoring methods, inter-laboratory reproducibility, and the potential value of computer-assisted imaging analysis and/or artificial intelligence for Ki67 assessment. Prospective clinical trials focusing on BC treatment have proven that Ki67, as determined by standardized central pathology assessment, is of clinical validity. Clinical utility has been demonstrated in huge observational studies. [ABSTRACT FROM AUTHOR]

Introduction: This project aimed to identify the frequency of a switch of hormone receptor (HR) and/or HER2 status after neoadjuvant chemotherapy (NAC) for early breast cancer. Methods: Tumor samples from patients without pathological complete response (non-pCR) were evaluated. Pathological complete response (pCR) was defined as no invasive tumor in breast and lymph nodes (ypT0/is ypN0). HR and HER2 status determined before NAC was compared with the corresponding receptor status determined in the surgical specimen after NAC. Results: 245 consecutive patients with primary invasive breast cancer, treated with NAC with/without targeted therapy between January 1, 2016 and December 31, 2019, at the LMU Breast Center, Munich, Germany, were identified. In 128 patients (52%), surgery revealed non-pCR after completed NAC. In 35 cases (27%), a switch of either HR and/or HER2 status between the initial biopsy and the surgical specimen was detected. Twenty cases had a switch in HR status, while 15 cases had a switch in HER2 status. Conclusion: In a substantial number (27%) of non-pCR cases, a switch in biomarker status after completed neoadjuvant treatment was detected. These results are consistent with prior evidence. Yet, routine reevaluation of HR and HER2 status is not recommended in guidelines so far. Future research needs to address the impact of HR and HER2 status switch on therapy adaptation and on subsequent patient outcome. Particularly, in view of the recent therapy advances, it will be critical to evaluate whether individualization of treatment concepts based on the biology of the non-pCR specimens is preferable to the initial therapy concept based on the pathology at primary diagnosis. [ABSTRACT FROM AUTHOR]