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Zusammenfassung Hintergrund Umfangreiche Daten aus prospektiven klinischen Studien liefern einen hohen Evidenzgrad für den Einsatz von CDK4/6-Hemmern in Kombination mit einer endokrinen Therapie (CDK4/6i + ET) als Standard bei der First-Line-Behandlung von metastatischem HER2-negativen hormonrezeptorpositiven (HER2−/HR+) Brustkrebs. Reale Daten von Patientinnengruppen, die damit in der Praxis behandelt wurden, liefern Erkenntnisse über Veränderungen von Patientenmerkmalen und Prognosen im Laufe der Zeit. Methoden Die Daten wurden dem prospektiven praxisbezogenen PRAEGNANT-Register (NCT02 338 167) entnommen. Die eingeschlossenen Patientinnen hatten fortgeschrittenen primären und metastasierten HER2−/HR+ Brustkrebs. Die gewählten Therapien, das progressionsfreie Überleben und das Gesamtüberleben der jeweiligen Therapie sowie die Zeitspanne, während der die Behandlung erfolgte, werden dargelegt. Ergebnisse Nachdem CDK4/6-Hemmer erstmals im November 2016 eingesetzt wurden, stieg die Häufigkeit ihres Einsatzes schnell an. In den letzten Jahren (2018–2022) wurden ca. 70–80 % aller Patientinnengruppen mit CDK4/6-Hemmern behandelt; eine endokrine Monotherapie wurde rund 10 % und eine Chemotherapie ungefähr 15 % aller Patientinnen verabreicht. Die schlechteste Prognose hatten Patientinnen, die eine Chemotherapie erhielten. Seit Kurzem erhalten hauptsächlich Patientinnen mit guter Prognose eine endokrine Monotherapie; Patientinnen, die eine Chemotherapie erhalten, haben eine ungünstigere Prognose. Das progressionsfreie Überleben und das Gesamtüberleben von mit CDK4/6i + ET behandelten Patientinnen blieb über einen längeren Zeitraum ähnlich, obwohl sich die Patientenmerkmale änderten. Schlussfolgerung Die Behandlung mit CDK4/6i + ET entwickelte sich rasch zum First-Line-Therapiestandard für Patienten mit fortgeschrittenem Mammakarzinom. Seit der Einführung von CDK4/6i + ET wird die endokrine Monotherapie nur bei Patientinnen mit einer sehr günstigen Prognose eingesetzt, während Chemotherapie meist nur an Patientinnen verabreicht wird, die eine eher ungünstige Prognose haben. Veränderungen der Patientenmerkmale scheinen die Prognose von mit CDK4/6i + ET behandelten Patientinnen nicht zu beeinflussen.

ZusammenfassungFür die Behandlung von Patientinnen mit fortgeschrittenem HER2-negativem, hormonrezeptorpositivem Mammakarzinom sind in den letzten Jahren einige Substanzen in die Praxis eingeführt worden. Zusätzlich sind weitere Medikamente in der Entwicklung. Im letzten Jahr sind einige Studien veröffentlicht worden, die entweder einen Vorteil für das progressionsfreie Überleben oder aber auch für das Gesamtüberleben gezeigt haben. Diese Übersichtsarbeit fasst die neuesten Ergebnisse, welche auf aktuellen Kongressen oder in Fachzeitschriften veröffentlicht wurden, zusammen und ordnet sie in den klinischen Behandlungskontext ein. Insbesondere wird auf den Stellenwert einer Therapie mit CDK4/6 Inhibitoren, Trastuzumab-Deruxtecan, Sacituzumab-Govitecan und Capivasertib eingegangen. Für Trastuzumab-Deruxtecan wurde in der Destiny-Breast-04-Studie ein Gesamtüberlebensvorteil bei HER2-negativem Mammakarzinom mit einer niedrigen HER2-Expression (HER2-low expression) berichtet. Ebenso konnte ein Gesamtüberlebensvorteil in der FAKTION-Studie mit Capivasertib verzeichnet werden. Nach dem fehlenden Gesamtüberlebensvorteil für Palbociclib in der 1. Therapielinie stellt sich hier die Frage nach der klinischen Einordnung.

ZusammenfassungIn dieser Übersichtsarbeit werden neueste Entwicklungen in der Prävention von Brustkrebs und Behandlung von Patientinnen mit frühen Krankheitsstadien mit Mammakarzinom zusammengefasst. Die Ermittlung von individuellen Erkrankungsrisiken nach molekularen Subtypen wurde in einer großen epidemiologischen Studie untersucht. Im Bereich der Behandlung gibt es neue Daten zur Langzeitnachbeobachtung der Aphinity-Studie ebenso wie neue Daten zur neoadjuvanten Therapie von HER2-positiven Patientinnen mit Atezolizumab. Biomarker wie Residual Cancer Burden wurden im Zusammenhang mit einer Pembrolizumab-Therapie untersucht. Eine Untersuchung des Genomic-Grade-Indexes bei älteren Patientinnen reiht sich ein in die Gruppe von Studien, die versucht, durch moderne Multigentests Patientinnen zu identifizieren, bei denen eine Chemotherapie vermieden werden kann, weil diese eine exzellente Prognose haben. Diese und weitere Aspekte der neuesten Entwicklungen bei der Diagnostik und Therapie des Mammakarzinoms werden in dieser Übersichtsarbeit beschrieben.

ZusammenfassungFür Patientinnen mit einem fortgeschrittenen Mammakarzinom sind in den letzten Jahren mit den CDK4/6‑Inhibitoren, den Immuncheckpoint-Inhibitoren, den PARP-Inhibitoren, dem Alpelisib, Tucatinib und Trastuzumab-Deruxtecan sowie Sacituzumab-Govitecan einige Therapien neu etabliert worden, welche die Therapielandschaft von Patientinnen mit einem fortgeschrittenen Mammakarzinom deutlich verändert bzw. erweitert haben. Einige dieser Substanzen sind mittlerweile auch bei frühen Krankheitsstadien zugelassen bzw. eine Zulassung ist in naher Zukunft wahrscheinlich, sodass sich die Therapielandschaft abermals ändern wird. Die Einführung neuer Substanzen und das Verständnis der Progressions- und Effektivitätsmechanismen für diese Substanzen steht deswegen im Fokus der aktuellen wissenschaftlichen Bemühungen. In dieser Übersichtsarbeit werden die neuen Entwicklungen basierend auf aktuellen Publikationen und Kongressen zusammengefasst. Erkenntnisse zur Behandlung von Patientinnen mit einem HER2-positiven Mammakarzinom und Hirnmetastasen werden ebenso dargestellt wie eine Reihe von Studien, die sich mit Biomarkern bei Patientinnen mit HER2-negativem, hormonrezeptorpositivem Mammakarzinom beschäftigen. Insbesondere die Einführung der oralen, selektiven Östrogenrezeptor-Degradierer birgt neue Chancen, eine biomarkerbasierte Therapie zu etablieren. Die molekulare Diagnostik etabliert sich als diagnostischer Marker und Verlaufsparameter.

ZusammenfassungDie Erkenntnisse über die Behandlung von Mammakarzinompatientinnen mit frühen Krankheitsstadien haben im letzten Jahr deutlich zugenommen. Abemaciclib, Olaparib und Pembrolizumab sind neue Medikamente mit einer guten Wirksamkeit bei den entsprechenden Patientinnengruppen. Jedoch sind einige Fragestellungen nach wie vor unbeantwortet. Insbesondere welchen Patientinnen unnötige Therapien erspart werden können, ist bei prämenopausalen Patientinnen mit einem hormonrezeptorpositiven Mammakarzinom weiterhin unklar. Die Frage, inwieweit eine Chemotherapie einen direkten zytotoxischen Effekt auf den Tumor hat oder eher dadurch wirkt, dass die Ovarfunktion durch die Chemotherapie reduziert wird, könnte wegweisend sein. Dieser Patientinnengruppe kann möglicherweise eine Chemotherapie erspart bleiben. Neue, bislang experimentelle Biomarker-Analysemethoden, wie die räumliche Analyse der Genexpression (spatial transcriptomics), halten nach und nach Einzug in die großen randomisierten Phase-III-Studien, wie die NeoTRIPStudie. Dies führt wiederum zum besseren Verständnis der prädiktiven Faktoren neuer Therapien, zum Beispiel der Immuntherapie. Diese Übersichtsarbeit fasst die wissenschaftlichen Neuerungen der aktuellen Kongresse wie dem San Antonio Breast Cancer Symposium 2021, aber auch von kürzlich veröffentlichten Publikationen zusammen.

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.

ZusammenfassungIm vergangenen Jahr wurden für viele Patientinnen mit Mammakarzinom in frühem Krankheitsstadium neue und effektive Optionen für eine weitere Verbesserung der Behandlungsergebnisse gezeigt. Für Patientinnen mit hormonrezeptorpositiver Erkrankung zeigte sich ein signifikanter Zusatzeffekt durch den Einsatz des CDK4/6-Inhibitors Abemaciclib zusätzlich zur endokrinen adjuvanten Therapie. Bei triple-negativer Erkrankung wurden Daten für 2 Therapieprinzipien gezeigt. Patientinnen mit fortgeschrittener Erkrankung (Stadium 2 und 3) profitieren von dem neoadjuvanten Einsatz des Immuncheckpoint-Inhibitors Pembrolizumab unabhängig von der PD‑L1-Expression in Kombination mit einer Standardchemotherapie. Bei BRCA1- oder BRCA2-Mutation wurde ein eindrucksvoller Benefit durch den Einsatz des PARP-Inhibitors Olaparib gezeigt, wenn die neoadjuvante Therapie nicht zur gewünschten Remission geführt hat. Weitere Daten betreffen translationale Fragestellungen beim HER2-positiven Mammakarzinom sowie neoadjuvante Therapieansätze mit dem oralen SERD Giredestrant und dem PARP-Inhibitor Talazoparib. In dieser Übersichtsarbeit werden die Ergebnisse der wichtigsten Studienergebnisse dieses Jahres vorgestellt und bewertet.

Changes of CTC numbers in the total study cohort or in any of the different subgroups were not related to DFS.

Purpose:To identify molecular predictors of grade 3/4 neutropenic or leukopenic events (NLE) after chemotherapy using a genome-wide association study (GWAS).Experimental Design:A GWAS was performed on patients in the phase III chemotherapy study SUCCESS-A (n = 3,322). Genotyping was done using the Illumina HumanOmniExpress-12v1 array. Findings were functionally validated with cell culture models and the genotypes and gene expression of possible causative genes were correlated with clinical treatment response and prognostic outcomes.Results:One locus on chromosome 16 (rs4784750; NLRC5; P = 1.56E-8) and another locus on chromosome 13 (rs16972207; TNFSF13B; P = 3.42E-8) were identified at a genome-wide significance level. Functional validation revealed that expression of these two genes is altered by genotype-dependent and chemotherapy-dependent activity of two transcription factors. Genotypes also showed an association with disease-free survival in patients with an NLE.Conclusions:Two loci in NLRC5 and TNFSF13B are associated with NLEs. The involvement of the MHC I regulator NLRC5 implies the possible involvement of immuno-oncological pathways.

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Correlation of TILs and clinicopathological parameters

Supplementary Data from Identification of Two Genetic Loci Associated with Leukopenia after Chemotherapy in Patients with Breast Cancer

Supplementary Data from Detection and HER2 Expression of Circulating Tumor Cells: Prospective Monitoring in Breast Cancer Patients Treated in the Neoadjuvant GeparQuattro Trial

Purpose: We elucidated the value of tumor-infiltrating lymphocytes (TIL) as an independent predictor for pathologic complete response (pCR) rate and as a prognostic marker for disease-free survival (DFS) in patients with HER2-positive breast cancer in the neoadjuvant setting.Experimental Design: We evaluated stromal TILs in 498 HER2-positive breast cancer samples of the neoadjuvant GeparQuattro (G4) and GeparQuinto (G5) trials. Levels of TILs were determined as a continuous parameter per 10% increase and as lymphocyte-predominant breast cancer (LPBC; ≥ 60% TILs), and correlated with pCR rate and DFS.Results: In the complete cohort, HER2-positive LPBC cases had a significantly increased pCR rates compared with non-LPBC types. They were significant predictors for pCR in univariate (10% TILs: OR 1.12, P = 0.002; LPBC: OR 2.02, P = 0.002) and multivariate analyses (10% TILs: OR 1.1, P = 0.014; LPBC: OR 1.87, P = 0.009). This effect was also detectable in the trastuzumab-treated (10% TILs: OR 1.12, P = 0.018; LPBC: OR 2.08, P = 0.013) but not in the lapatinib-treated subgroup. We identified a low-risk (pCR/LPBC) and a high-risk group (no pCR/no LPBC) regarding DFS. In triple-positive breast cancer, TILs are of more prognostic relevance than pCR.Conclusions: We could demonstrate the predictive and prognostic impact of TILs in HER2-positive breast cancer in the neoadjuvant setting. In combination with pCR rate, TILs may help to stratify prognostic subgroups, thereby guiding future therapy decisions. Clin Cancer Res; 22(23); 5747–54. ©2016 AACR.

Baseline characteristics

Purpose: This study aimed to evaluate the prognostic impact of circulating tumor cells (CTC) detected in patients with operable or locally advanced breast cancer before and after neoadjuvant therapy (NT) within the clinical trial GeparQuattro.Experimental Design: Data on CTCs enumerated with the CellSearch system were available for 213 and 207 patients before and after NT, respectively. Associations of CTCs with disease-free survival (DFS) and overall survival (OS) were analyzed by nonparametric Kaplan–Meier estimates and parametric Cox regression.Results: After a median follow-up of 67.1 months, the detection of ≥1 CTC/7.5 mL and ≥2 CTCs/7.5 mL before NT was associated with reduced DFS (P = 0.031 and P < 0.0001, respectively) and OS (P = 0.0057 and P < 0.0001, respectively), whereas CTCs detected after NT did not correlate with DFS or OS. In parametric univariate and multivariate Cox models, ≥1 CTC/7.5 mL, ≥2 CTCs/7.5 mL, and absolute CTC numbers before NT revealed to be independent prognostic parameters of DFS and OS. CTC-negative patients with pathologic complete response (pCR) exhibited the best prognosis, whereas those with CTCs and less tumor response were at high risk of tumor relapse. In HER2 (ERBB2)-positive and triple-negative patients, ≥2 CTCs/7.5 mL detected before NT also were significantly associated with worse DFS and OS.Conclusions: Detection of CTCs before NT is an independent prognostic factor of impaired clinical outcome, and combined with pCR, it could be helpful to stratify breast cancer patients for therapeutic interventions. Clin Cancer Res; 23(18); 5384–93. ©2017 AACR.

Changes of CTC numbers in the total study cohort or in any of the different subgroups were not related to OS.

PDF file, 66K, Subpopulation Treatment Effect Pattern Plot (STEPP) analysis of the treatment effect of conventional versus response-guided neoadjuvant chemotherapy as measured by mean disease-free survival according to overlapping subpopulations defined by percentages of Ki67 at surgery in patients with hormone-receptor-positive (A) and hormone-receptor-negative (B) disease.

Purpose: The value of Ki67 measured on residual disease after neoadjuvant chemotherapy is not sufficiently described.Experimental Design: Participants of the GeparTrio study with primary breast cancer randomly received neoadjuvant response-guided [8 cycles TAC (docetaxel/doxorubicin/cyclophosphamide) in responding and TAC-NX (vinorelbine/capecitabine) in nonresponding patients] or conventional (6 cycles TAC) chemotherapy according to interim response assessment. Ki-67 levels were centrally measured immunohistochemically after neoadjuvant treatment if tumor tissue was available. Here, we analyze 1,151 patients having a pathologic complete response (pCR; n, 484), or residual disease with low (0–15%), intermediate (15.1–35%), or high (35.1–100%) posttreatment Ki67 levels in 488, 77, and 102 patients, respectively.Results: Patients with high posttreatment Ki67 levels showed higher risk for disease relapse (P < 0.0001) and death (P < 0.0001) compared with patients with low or intermediate Ki67 levels. Patients with low Ki67 levels showed a comparable outcome to patients with a pCR (P = 0.211 for disease-free and P = 0.779 for overall survival). Posttreatment Ki67 levels provided more prognostic information than pretreatment Ki67 levels or changes of Ki67 from pre- to posttreatment. Information on pCR plus posttreatment Ki67 levels surmount the prognostic information of pCR alone in hormone–receptor-positive disease [hazard ratios (HR), 1.82–5.88] but not in hormone–receptor-negative disease (HR: 0.61–1.73). Patients with conventional and response-guided treatment did not show a different distribution of posttreatment Ki67 (P = 0.965).Conclusions: Posttreatment Ki67 levels provide prognostic information for patients with hormone–receptor-positive breast cancer and residual disease after neoadjuvant chemotherapy. Levels were not prognostic for outcome after response-guided chemotherapy. High posttreatment Ki67 indicates the need for innovative postneoadjuvant treatments. Clin Cancer Res; 19(16); 4521–31. ©2013 AACR.

Supplementary Figure S2: Kaplan Meier plots by pathologic complete response (pCR) and CTCs detected after NT. (A, B) DFS, analysis of the whole patient cohort at cut-off {greater than or equal to}1 (A) CTC/7.5 mL and {greater than or equal to}2 (B) CTCs/7.5 mL blood, (C, D) OS, analysis of the whole patient cohort at cut-off {greater than or equal to}1 (C) CTC/7.5 mL and {greater than or equal to}2 (D) CTCs/7.5 mL blood.

Purpose: This study was aimed at detecting and characterizing circulating tumor cells (CTC) before and after neoadjuvant therapy (NT) in the peripheral blood of patients with breast cancer.Experimental Design: The clinical trial GeparQuattro incorporated NT approaches (epirubicin/cyclophosphamide prior to randomization to docetaxel alone, docetaxel in combination with capecitabine, or docetaxel followed by capecitabine) and additional trastuzumab treatment for patients with HER2-positive tumors. We used the Food and Drug Administration–approved CellSearch system for CTC detection and evaluation of HER2 expression and developed HER2 immunoscoring for CTC.Results: We detected ≥1 CTC/7.5 mL in 46 of 213 patients (21.6%) before NT and in 22 of 207 patients (10.6%) after NT (P = 0.002). Twenty (15.0%) initially CTC-positive cases were CTC-negative after NT, whereas 11 (8.3%) cases were CTC-positive after NT, although no CTC could be found before NT. CTC detection did not correlate with primary tumor characteristics. Furthermore, there was no association between tumor response to NT and CTC detection. HER2-overexpressing CTC were observed in 14 of 58 CTC-positive patients (24.1%), including 8 patients with HER2-negative primary tumors and 3 patients after trastuzumab treatment. CTC scored HER2-negative or weakly HER2-positive before or after NT were present in 11 of 21 patients with HER2-positive primary tumors. HER2 overexpression on CTC was restricted to ductal carcinomas and associated with high tumor stage (P = 0.002).Conclusion: CTC number was low in patients with primary breast cancer. The decrease in CTC incidence during treatment was not correlated with standard clinical characteristics and primary tumor response. Information on the HER2 status of CTC might be helpful for stratification and monitoring of HER2-directed therapies. Clin Cancer Res; 16(9); 2634–45. ©2010 AACR.

Supplementary Figure from Identification of Two Genetic Loci Associated with Leukopenia after Chemotherapy in Patients with Breast Cancer

Detection of CTCs associated with patient and tumor characteristics for both time points in patients with measurements at both time points is listed. There was no significant correlation of {greater than or equal to}1CTC or {greater than or equal to}2CTCs to any of these parameters.

Purpose The WHO 2016 re-classification of myeloproliferative neoplasms resulted in a separation of essential thrombocythemia (ET) from the pre-fibrotic and fibrotic (overt) phases of primary myelofibrosis (MF). This study reports on a chart review conducted to evaluate the real life approach regarding clinical characteristics, diagnostic assessment, risk stratification and treatment decisions for MPN patients classified as ET or MF after implementation of the WHO 2016 classification. Methods In this retrospective chart review, 31 office-based hematologists/oncologists and primary care centers in Germany participated between April 2021 and May 2022. Physicians reported available data obtained from patient charts via paper–pencil based survey (secondary use of data). Patient features were evaluated using descriptive analysis, also including diagnostic assessment, therapeutic strategies and risk stratification. Results Data of 960 MPN patients diagnosed with essential thrombocythemia (ET) (n = 495) or myelofibrosis (MF) (n = 465) after implementation of the revised 2016 WHO classification of myeloid neoplasms was collected from the patient charts. While they met at least one minor WHO-criteria for primary myelofibrosis, 39.8% of those diagnosed with ET did not have histological BM testing at diagnosis. 63.4% of patients who were classified as having MF, however, did not obtain an early prognostic risk assessment. More than 50% of MF patients showed characteristics consistent with the pre-fibrotic phase, which was emphasized by the frequent use of cytoreductive therapy. Hydroxyurea was the most frequently used cytoreductive medication in 84.7% of ET and 53.1% of MF patients. While both ET and MF cohorts showed cardiovascular risk factors in more than 2/3 of the cases, the use of platelet inhibitors or anticoagulants varied between 56.8% in ET and 38.1% in MF patients. Conclusions Improved histopathologic diagnostics, dynamic risk stratification including genetic risk factors for cases of suspected ET and MF are recommended for precise risk assessment and therapeutic stratification according to WHO criteria.

Introduction: Treatment-free remission (TFR) is increasingly considered as treatment goal for patients with chronic myeloid leukemia (CML), but information on the disposition and outcome of TFR in clinical practice is scarce. Here, we report the characteristics of patients with CML in deep molecular remission (DMR) and/or after an attempt of TFR reported by 33 German hematologists. Methods: Data were collected retrospectively by means of a questionnaire. Patients were eligible if they had either discontinued tyrosine kinase inhibitor (TKI) therapy or had achieved DMR of at least MR4 (BCR-ABL ≤0.01%) prior to the time-point of data collection. Results: 797 patients were included in the analysis, out of which 281 patients had been discontinued from TKI treatment. TKI discontinuation rates among practices were variable, ranging from 0 to 36 patients. Mean time from TKI initiation to discontinuation was 7.2 years; mean duration of MR4 before TFR was 3.5 years. At the time of entering TFR, most patients (90.8%) had achieved a deep molecular response (≥MR4). BCR-ABL monitoring during TFR was performed heterogeneously: Within the first 6 months of TFR, 58.6% of the practices reported mean monitoring intervals of 8 weeks. After entering TFR, 53.2% of patients remained in MR4 or better. TKI treatment was reinitiated in 108 patients, mainly for loss of major molecular remission. Conclusions: These clinical data from a German real-life population show that TKI discontinuation is feasible in clinical practice. Outcomes appear to be comparable to those reported in clinical trials, but molecular monitoring in TFR is rather variable.

The treatment of patients with early stage breast cancer has changed in recent years due to the introduction of pembrolizumab, olaparib, and abemaciclib. These and other drugs with the same class of active ingredient are currently in trial for various indications. This review article summarizes the latest results that have either been presented at major conferences such as the ESMO 2022 or published recently in international journals. This includes reports on newly discovered breast cancer genes, atezolizumab in neoadjuvant therapy in HER2-positive patients, long-term data from the APHINITY study, and on how preoperative peritumoral application of local anesthetics can influence the prognosis. We also present solid data on dynamic Ki-67 from the ADAPT studies.

Large-scale study programs on CDK4/6 inhibitors, targeted therapies, and antibody–drug conjugates launched in recent years have yielded results from current studies which are now being published in journals and presented at international conferences. In this context, new results are available from the major CDK4/6 inhibitor studies. Also, an increasing amount of data is being published from large-scale genomic studies on efficacy and resistance mechanisms in patients treated with CDK4/6 inhibitors. These results now form the basis for further research plans to investigate combination therapies and treatment sequencing. Based on the latest published results, sacituzumab govitecan is now available as a second antibody–drug conjugate; this brings an advantage in terms of overall survival for patients with hormone receptor-positive (HRpos)/HER2-negative (HER2neg) breast cancer. In this review article, we summarize the latest developments and place them in context according to the current status of research.

ZusammenfassungIn dieser Übersichtsarbeit werden nicht nur die neuesten Erkenntnisse zur Prävention, sondern auch die aktuellen Arbeiten zur Behandlung von Mammakarzinompatientinnen im frühen Krankheitsstadium zusammengefasst. In den letzten Jahren haben sich die Hinweise über hoch-penetrante und mittelgradig penetrante Risikogene für ein Mammakarzinom verdichtet. Nun konnte in einem großen internationalen Konsortium die Antwort auf die Frage nach der Wertigkeit der sogenannten Panelgene weiterentwickelt werden. Des weiteren sind auch die Daten zur Therapieselektion in Bezug auf endokrine Wirksamkeit und die Entscheidung für oder gegen eine Chemotherapie deutlich weiterentwickelt worden. Ebenso gibt es neue Daten zum adjuvanten Einsatz von CDK4/6-(Cyclin-dependent-kinase-4/6-)Inhibitoren, die in der 1. Therapielinie für Patientinnen mit metastasiertem HER2-negativem, hormonrezeptorpositiven (HR+) Mammakarzinom zum Therapiestandard gehören. Bei anderen Therapien wie den Immuncheckpoint-Inhibitoren, welche erfolgreich in der neoadjuvanten Therapiesituation bei Patientinnen mit einem triple-negativen Mammakarzinom (TNBC) die Rate an pathologischen Komplettremissionen (pCR) verbessern konnten, wächst das Verständnis für Lebensqualität und Nebenwirkungen. Dies ist von besonderer Bedeutung in einer Situation, in der Patientinnen potenziell auch ohne eine solche Therapie geheilt werden könnten.

Background: Neoadjuvant chemotherapy (NACT) is standard of care for patients with triple-negative breast cancer (TNBC). Treatment response, especially pathologic complete response (pCR), is a strong predictive factor for treatment outcome. In the setting of up-front surgery, retrospective data have suggested improved outcome in patients with early TNBC that received breast-conserving surgery with adjuvant radiotherapy (BCT) as compared to mastectomy. Methods: We identified 2632 patients with early TNBC from the German Breast Group meta-database. Patients with cT1-2 cN0 and ypN0, available surgery and follow-up data were eligible for this project. A total of 1074 patients from 8 prospective NACT trials were analyzed. Endpoints of interest were locoregional recurrence as first site of relapse (LRR, other sites of recurrence were considered competing events), disease-free survival (DFS) and overall survival (OS); analyses were performed using univariate and multivariate Fine-Gray (for LRR) and Cox models including study, age, cT, surgery type and pCR. For the analyses including pCR as covariable, only patients at risk at the landmark time were evaluated. Results: Median age was 48 years, 69.6% of patients had cT2 tumors and 85.3% underwent BCS. Of the 1074 analyzed patients, 48.8% achieved pCR. After a median follow-up of 64 months, there were 94 (8.8%) locoregional events as first site of relapse. Upon univariate analysis, absence of pCR (hazard ratio [HR]=2.28; 95%CI 1.44-3.61; p< 0.001) and ypT-stage (ypT0/is vs. ypT1-3, HR=0.61; 95%CI 0.40-0.95; p=0.028) were significantly associated with LRR, while type of surgery, age and cT-stage were not. Upon multivariate analysis, absence of pCR was the only factor associated with increased risk of LRR (HR=2.22; 95%CI 1.38-3.58; p=0.001). Patients that underwent mastectomy (N=158) were significantly younger (age ≤ 50 years 72.8% vs. 59.9% for BCT [N=916]; p=0.002) DFS and OS was significantly better in patients who underwent BCT compared to mastectomy (DFS: HR=0.47; 95%CI 0.34-0.66; p< 0.001 and OS: HR=0.40; 95%CI 0.26-0.63; p< 0.001). In multivariate analysis, BCT was associated with a significantly better DFS and OS as compared to mastectomy (DFS: HR=0.51; 95%CI 0.36-0.72; p< 0.001; and OS HR=0.43; 95%CI 0.27-0.68; p< 0.001), whereas absence of pCR was associated with significantly worse DFS and OS (DFS: HR=2.43; 95%CI 1.78-3.31; p< 0.001; and OS: HR=3.15; 95%CI 1.94-5.10; p< 0.001). Conclusions: In this retrospective analysis from the GBG meta-database, treatment response, e.g. pCR, was the main determinant of locoregional recurrence in patients with early stage TNBC treated with NACT. BCT was associated with improved DFS and OS compared to mastectomy, which may at least in part reflect favorable patient selection. Citation Format: David Krug, Valentina Vladimirova, Michael Untch, Thorsten Kühn, Andreas Schneeweiss, Carsten Denkert, Beyhan Ataseven, Christine Solbach, Bernd Gerber, Hans Tesch, Michael Golatta, Sabine Seiler, Jörg Heil, Valentina Nekljudova, Sibylle Loibl. PD15-06 Pathologic complete response and breast-conserving surgery are associated with improved prognosis in patients with early-stage triple-negative breast cancer treated with neoadjuvant chemotherapy [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD15-06.

Purpose Assessment of HER2 overexpression using immunohistochemistry (IHC) and/or in situ hybridisation (ISH) for the detection of HER2 amplifications is standard to identify patients for established HER2-directed treatments. Patients with lower HER2 expression levels have recently also become candidates for novel therapies targeting HER2. This study aimed to assess tumour and patient characteristics and prognosis in patients with advanced breast cancer (aBC), relative to low HER2 expression levels. Methods PRAEGNANT is a prospective aBC registry (NCT02338167), focusing on molecular biomarkers. Patients in all therapy lines receiving any kind of treatment are eligible. This analysis includes patients with conventionally HER2-negative aBC. Clinical outcome was compared in the groups with no (IHC score 0) or with low HER2 expression (IHC 1+, or IHC 2+/ISH negative). Results Low HER2 expression levels in triple-negative aBC patients did not influence progression-free survival. Overall survival appeared poorer in patients with IHC 2+ compared with patients with no HER2 expression in the unadjusted analysis (hazard ratio 2.24, 95% confidence interval 0.1.12–4.47). However, this effect was not maintained in the adjusted analysis. In HER2-negative, hormone receptor–positive patients, low HER2 expression appeared to have no effect on prognosis, neither progression-free survival nor overall survival. Conclusions We could not demonstrate that HER2 expression at a low level and assessed in clinical routine can differentiate patients into prognostic groups. However, the prevalence of patients with a low expression makes this population interesting for clinical trials with potentially active treatments using HER2 as a target.