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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.

In patients with existing ovarian function, there are some special aspects to adjuvant endocrine therapy in premenopausal patients with hormone receptor-positive, HER2-negative (HR pos./HER2 neg.) breast cancer. Treatment options include tamoxifen with or without a GnRH analog, and aromatase inhibitors with a GnRH analog. Furthermore, ovarian function is affected by previous chemotherapy. Both aromatase inhibitors (+GnRH analogs) and GnRH analogs in combination with tamoxifen are supposed to be indicated for patients at increased risk of recurrence.However, national and international guidelines and therapy recommendations do not provide a clear definition of intermediate or high risk; as a result, therapy decisions are often made for each patient on an individual basis. This is also reflected in the considerable variability at national and international levels, e.g., with regard to the use of aromatase inhibitors + GnRH analogs.This review summarizes the data on completed studies (e.g., SOFT, TEXT, EBCTCG meta-analyses) and the current multigene testing studies (TailorX, RxPonder, ADAPT), discusses the rationale for current studies (e.g., CLEAR-B), and looks ahead to future questions.

Disseminated tumor cells (DTCs) in the bone marrow (BM) are known to be of prognostic value for patients with early breast cancer (EBC). In addition to histopathological features, multigene expression assays, such as the commercially available 21-gene Breast Recurrence Score® assay, have been validated for evaluating prognosis and making decisions concerning adjuvant treatment in EBC. In a previous retrospective study from our group, the 21-gene assay was shown to be associated with DTC-detection. A key endpoint of the prospective IRMA trial was to evaluate the association between Recurrence Score® (RS) result and tumor cell dissemination in patients with EBC. DTC-status and RS result were assessed in patients with ER-positive/HER2-negative EBC with 0–3 pathologic lymph nodes who underwent primary surgical treatment at the Department for Women’s Health of Tuebingen University, Germany. Patients with a high RS result (≥ 26) were more frequently DTC-positive (22.6%) than patients with a low RS result (8.6%, p=0.034). The odds for DTC-positivity increased with rising RS values (p= 0.047). We therefore confirm that a high genomic risk is associated with tumor cell dissemination into the BM. Further trials are needed to investigate whether therapeutic decisions could be further individualized by combining DTC-status and prognostic gene signature testing.

Table S1: Clinical attributes of primary ovarian cancer patients used in this study. Table S3: Proteins and protein modifications detected in differential amounts in responsive and non-responsive ovarian cancers. Wilcoxon-Mann-Whitney Test; W = rank sum; RESP = responsive (DFS > 12 months); NRESP = non-responsive (DFS {less than or equal to} 12 months). Table S4: Gene variants (Variant), amino acid change (AA change) and allele frequencies of sequenced tumors from 17 patients (SXXX). Tumor content of tissues is listed at the end of the table. Figure S1: Screening of eight non-responsive and nine responsive tumor samples from ovarian cancer patients using DigiWest protein array analysis with 279 antibodies against proteins and their modifications (Wilcoxon-Mann-Whitney, p{less than or equal to}0.05). Figure S2: ATM/EZH2 protein ratios in 17 tumor samples with non-responders and responders quantified in the DigiWest analysis. Figure S3: Controls of immunohistochemistry staining. Figure S4: Correlation analysis of mean immunoreactive scores from stainings of EZH2 and ATM (left or phospho-Rb (Ser807/811) (right) in 34 ovarian cancer patients. n=2 per tumor sample Figure S5: A: Representative image of PLA analysis on tissue microarray spots. DAPI: staining of cell nuclei. FITC: Autofluorescence of tissue in FITC channel and determination of area for analysis (830 µm diameter). Cy5: Channel for PLA measurement after subtracting background signals of FITC channels. Analyzed: Automated counted spots of interactions. Bars represent 200 µm. B: Representative control (rabbit isotype) for PLA analysis on tissue microarray spots. C: Quantification of PLA interactions in an ovarian cancer tissue. Positive control: original PLA protocol using EZH2 and phospho-ATM (S1981) antibodies. Negative control: Staining procedure without primary antibodies. Isotype control rabbit: PLA protocol using rabbit isotype antibodies instead of antibodies against EZH2. Isotype control mouse: PLA protocol using mouse isotype antibodies instead of antibodies against phospho-ATM (S1981). n = 5. Figure S6: Correlation analysis of the mean IRS scores from stainings of ATM and mean PLA signals of EZH2 and ATM pS1981 in 34 samples on tissue microarrays; Spearman correlation; n=2 per tumor sample. Figure S7: Correlation analysis of mean IC50 values calculated in cell line cells. Values of paclitaxel mono-treatment were compared to the values of combinational treatment (CP scale). Figure S8: EZH2 protein levels in lysates of untreated cell lines analyzed with Spearman correlation against mean logIC50 values for CP (left) and TX (right); n=3. Grid line=linear regression line. Figure S9: ATM protein levels in lysates of untreated cell lines analyzed with Spearman correlation against mean logIC50 values for CP (left) and TX (right); n=3. Grid line=linear regression line. Figure S10: Hierarchical clustering of quantified total protein and protein modifications of cell cycle proteins measured with DigiWest technology. Figure S11: Proximity ligation assay on A2780 cells during treatment with CPTX using standard protocol (EZH2 + pATM) as positive control or isotype controls with mouse antibodies instead of pATM (mIgG1) or rabbit antibodies instead of EZH2 antibodies. Figure S12: Scheme suggesting a putative interaction of EZH2 and ATM during treatment with CPTX.

Table S2.

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.

Background Circulating tumour cells (CTCs) are mainly enriched based on the epithelial cell adhesion molecule (EpCAM). Although it was shown that an EpCAM low-expressing CTC fraction is not captured by such approaches, knowledge about its prognostic and predictive relevance and its relation to EpCAM-positive CTCs is lacking. Methods We developed an immunomagnetic assay to enrich CTCs from metastatic breast cancer patients EpCAM independently using antibodies against Trop-2 and CD-49f and characterised their EpCAM expression. DNA of single EpCAM high expressing and low expressing CTCs was analyzed regarding chromosomal aberrations and predictive mutations. Additionally, we compared CTC-enrichment on the CellSearch system using this antibody mix and the EpCAM based enrichment. Results Both antibodies acted synergistically in capturing CTCs. Patients with EpCAM high-expressing CTCs had a worse overall and progression-free survival. EpCAM high- and low-expressing CTCs presented similar chromosomal aberrations and mutations indicating a close evolutionary relationship. A sequential enrichment of CTCs from the EpCAM-depleted fraction yielded a population of CTCs not captured EpCAM dependently but harbouring predictive information. Conclusions Our data indicate that EpCAM low-expressing CTCs could be used as a valuable tumour surrogate material—although they may be prognostically less relevant than EpCAM high-expressing CTCs—and have particular benefit if no CTCs are detected using EpCAM-dependent technologies.

PURPOSE To compare standard versus extended duration of bevacizumab treatment in combination with front-line chemotherapy in women with newly diagnosed stage IIB-IV ovarian cancer. METHODS In this multicenter, open-label, randomized phase III trial (ClinicalTrials.gov identifier: NCT01462890 ), patients with newly diagnosed International Federation of Gynecology and Obstetrics stage IIB-IV epithelial ovarian, fallopian tube, or peritoneal cancer underwent primary cytoreductive surgery followed by six cycles of chemotherapy (paclitaxel 175 mg/m2 plus carboplatin area under the curve 5 once every 3 weeks) and bevacizumab (15 mg/kg once every 3 weeks). Patients were randomly assigned 1:1 to receive bevacizumab for either 15 or 30 months, stratified by International Federation of Gynecology and Obstetrics stage/residual tumor. The primary end point was investigator-assessed progression-free survival (PFS) according to RECIST version 1.1. Secondary end points included overall survival (OS), safety, and tolerability. RESULTS Between November 11, 2011, and August 6, 2013, 927 women were randomly assigned. There was no difference in PFS between treatment arms (hazard ratio, 0.99; 95% CI, 0.85 to 1.15; unstratified log-rank P = .90). Median PFS was 24.2 versus 26.0 months with standard versus extended duration of bevacizumab, respectively; restricted mean PFS was 39.5 versus 39.3 months, respectively. There was no OS difference between treatment arms (hazard ratio, 1.04; 95% CI, 0.87 to 1.23; P = .68). Serious/nonserious adverse events of special interest occurred in 29% versus 34% of patients in the standard versus experimental arms, respectively, and were consistent with the known safety profile of standard bevacizumab. CONCLUSION Longer treatment duration with bevacizumab for up to 30 months did not improve PFS or OS in patients with primary epithelial ovarian, fallopian tube, or peritoneal cancer. A bevacizumab treatment duration of 15 months remains the standard of care.

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.

ZusammenfassungBei neuen Therapieansätzen des Mammakarzinoms sind insbesondere bei Patientinnen mit HER2-positivem und HER2-negativem/hormonrezeptorpositivem (HR+) Mammakarzinom in den letzten Jahren deutliche Fortschritte gesehen worden. Bei HER2-positiven Tumoren müssen in dem Zusammenhang Pertuzumab, T‑DM1, Neratinib und bald auch Tucatinib und Trastuzumab-Deruxtecan (beide in Europa noch nicht zugelassen) genannt werden. Bei den Patientinnen mit HER2−/HR+-Mammakarzinom sind insbesondere die CDK4/6-Inhibitoren und der PIK3CA-Inhibitor Alpelisib zu nennen. Weitere, neue Therapien wie Akt-Kinase-Inhibitoren und orale SERDs (selective estrogen receptor down-regulators) werden bereits in laufenden klinischen Studien untersucht. Nicht nur bei den HER2-positiven Tumoren halten die Therapien Einzug in die kurative, (neo-) adjuvante Therapiesituation, sondern es wurde nun eine erste positive Studie mit Abemaciclib in der adjuvanten Situation vorgestellt. Bei Patientinnen mit einem triple-negativen Mammakarzinom ist nach vielen Jahren mit negativen Studienergebnissen mit dem Trop-2-Antikörper-Wirkstoff-Konjugat (antibody drug conjugate, ADC) Sacituzumab-Govitecan eine randomisierte Studie veröffentlicht worden, die einen deutlichen Therapiefortschritt bedeuten kann. Diese Übersichtsarbeit beschreibt die neuesten Entwicklungen beim Mammakarzinom nach dem ESMO-Kongress 2020.

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.

Zusammenfassung Einleitung Multigen-Assays werden zunehmend als Entscheidungshilfe für eine Chemotherapie beim Mammakarzinom verwendet. Wir stellen hier den 21-Gen-Recurrence-Score (RS) von Patientinnen mit Brustkrebs vor, die routinemäßig in Deutschland untersucht wurden. Patientinnen und Methoden 4695 Patientinnen mit hormonrezeptorpositivem und HER2-negativem Brustkrebs im Frühstadium (pT1–3, pN0–1, M0) wurden einer retrospektiven Analyse unterzogen. Bei diesen Patientinnen wurde in Deutschland zwischen November 2015 und Juli 2018 der Genexpressionstest Oncotype DX zur Ermittlung des Recurrence-Scores durchgeführt. Die Klassifikation der RS-Gruppen erfolgte gemäß der TAILORx Studie (RS: 0–10; 11–25; 26–100). Ergebnisse Von diesen Patientinnen wurden 21 % in die niedrige RS-Gruppe, 63 % in die mittlere RS-Gruppe, und 15 % in die hohe RS-Gruppe eingeteilt. 1772 (81 %) von 2175 Patientinnen im Alter von über 50 Jahren und ohne Lymphknotenbefall wurden entweder in die niedrige oder die mittlere RS-Gruppe eingeteilt. Der Prozentsatz an Patientinnen mit einem niedrigen oder mittleren RS betrug 90 % bei Patientinnen ohne Lymphknotenbefall (1284 von 1432 Patientinnen), 79 % bei Patientinnen mit einem hohen (≥ 20 %) Ki-67-Wert (1829 von 2310 Patientinnen), 86 % bzw. 70 % bei Patientinnen mit G2- bzw. G3-Tumoren (3244 von 3762 Patientinnen bzw. 368 von 522 Patientinnen), 88 % bei Patientinnen mit einem Tumordurchmesser von > 5 cm (140 von 159 Patientinnen) und 82 % bei Patientinnen ohne Lymphknotenbefall, aber mit einem hohen klinischen Risiko (1110 von 1352). Schlussfolgerung Die Verteilung des 21-Gens RS bei deutschen Patientinnen, die in der klinischen Routinepraxis getestet wurden, deutet darauf hin, dass gemäß den Ergebnissen der TAILORx-Studie die Chemotherapie bei den meisten dieser Patientinnen keinen Nutzen hat.

Patients with hormone receptor-positive (HR+), HER2-negative (HER2-) early breast cancer (eBC) with a high risk of relapse often undergo adjuvant chemotherapy. However, only a few patients will gain benefit from chemotherapy. Since classical tumor characteristics (grade, tumor size, lymph node involvement, and Ki67) are of limited value to predict chemotherapy efficacy, multigene expression assays such as the Oncotype DXThe RS result was assessed in patients with HR+/HER2- unilateral eBC with 0-3 pathologic lymph nodes who underwent primary surgical treatment at the Department for Women's Health of Tuebingen University, Germany. Therapy recommendations without knowledge of the RS result were compared to therapy recommendations with awareness of the RS result.In total, 245 patients underwent RS assessment. Without knowledge of the RS result, 92/245 patients (37.6%) would have been advised to receive chemotherapy. After RS assessment, 56/245 patients (22.9%) were advised to undergo chemotherapy. Chemotherapy was waived in 47/92 patients (51.1%) that were initially recommended to receive it. Chemotherapy was added in 11/153 patients (7.2%) that were recommended to not receive it initially.Using the RS result to guide adjuvant treatment decisions in HR+/HER2- breast cancer led to a substantial reduction of chemotherapy. In view of the results achieved in prospective studies, the RS result is among other risk-factors suitable for the individualization of adjuvant systemic therapy.

Background/aim Detection of disseminated tumor cells (DTCs) after systemic treatment predicts poor prognosis in breast cancer patients. The aim of our study was to assess the expression of stem-cell marker SOX2 on DTCs and in the primary tumor of patients treated with neoadjuvant chemotherapy (NAT). Materials and methods In 170 DTC-positive patients after NAT an additional slide of bone marrow aspirate was stained by double immunofluorescence to detect SOX2-positive DTCs. The SOX2 status of the primary tumor was assessed using the same antibody. Results The SOX2-status of DTCs was determined in 62 patients and 20 of those (32%) had SOX2 positive DTCs. The SOX2 status of DTCs was not associated with any of the clinicopathological factors. A total of 36% of the patients with a SOX2-negative tumor showed SOX2-positive persistent DTCs. Conclusion SOX2-positive DTCs can be detected in breast cancer patients after NAT, even in patients with SOX2-negative primary tumors. This suggests that these populations may have evolved independently of each other.

The continuous availability of findings from new studies repeatedly results in updated treatment recommendations and guidelines. In the case of breast carcinoma in particular, several studies have been published in the last few years that have transformed how early and advanced breast carcinoma is being treated. However, this by no means means implies that there is agreement among all experts on specific issues. It is precisely the diversity of interpretation of guidelines and study findings that reflects the constantly changing available data and its complexity, as well as the availability of new drugs. In recent years, new substances such as pertuzumab, T-DM1, neratinib and capecitabine have become available to treat patients with early stages of breast carcinoma. Furthermore, the first results on the use of CDK4/6 inhibitors for adjuvant treatment have now been published. Last but not least, the use of multigene tests to avoid the necessity of chemotherapy in certain patients is still under discussion. This review summarises the state of the data and publishes the results of the survey completed by experts at the 2021 St. Gallen Breast Cancer Conference on early-stage breast cancer.

Purpose The PRAEGNANT study is a registry study for metastatic breast cancer patients, focusing on biomarker detection. Recently, within this study, genetic alterations in 37 breast cancer predisposition genes were analyzed and genetic findings were detected for 396 participants. The aim of this project was to return genetic results to the physicians and to analyze actions taken (e.g., disclosure of results to patients, validation of results, clinical impact, and impact on the patient’s quality of life) using a questionnaire. Methods 235 questionnaires were sent out to the study centers, with each questionnaire representing one patient with a genetic finding. The questionnaire consisted of twelve questions in the German language, referring to the disclosure of results, validation of test results, and their impact on treatment decisions and on the patient’s quality of life. Results 135 (57.5%) questionnaires were completed. Of these, 46 (34.1%) stated that results were returned to the patients. In 80.0% (N = 36) of cases where results were returned, the patient had not been aware of the finding previously. For 27 patients (64.3%), genetic findings had not been validated beforehand. All validation procedures (N = 15) were covered by the patients’ health insurance. For 11 (25.0%) patients, physicians reported that the research results influenced current or future decision-making on treatment, and for 37.8% (N = 17) the results influenced whether family members will be genetically tested. Conclusion This study provides novel insights into the return of research results and into clinical and personal benefits of disclosure of genetic findings within a German registry.

Since 2008, guidelines recommend that patients with HER2-positive early breast cancer (BC) should receive adjuvant chemotherapy in combination with trastuzumab in Germany. However, recent studies highlight that a substantial share of patients do not receive trastuzumab. We investigate which patient characteristics are associated with a tumor board recommendation for trastuzumab in Breast Cancer Centers (BCC) certified by the German Cancer Society (DKG) and the German Society for Senology, and if the recommendation differs between BCCs. Multi-level modeling was performed using quality assurance data based on 3052 HER2-positive, operated patients with a first diagnosis of early BC treated between 2006 and 2019 in 17 BCCs in Germany to investigate whether trastuzumab recommendation varies with patient sex, age, and disease characteristics, as well as over time and across BCCs. Tumor board recommendations for trastuzumab differ substantially between BCCs (intraclass correlation coefficient [ICC] null model: 0.11). Our final model (ICC 0.17, Akaike Information Criterion [AIC], 1328.0, R2 0.69) shows that physicians in BCCs more often recommend trastuzumab to patients who are younger than 60 years and those with a recommendation for any additional therapy (chemotherapy, radiation or endocrine therapy) (all p

ZusammenfassungDie Therapie von Patientinnen mit frühem Mammakarzinom war immer schon geprägt von Eskalation durch neue Therapien und Deeskalation durch Identifikation besserer Therapieschemata oder Einführung von besseren Werkzeugen zur Einschätzung der Prognose. Die Anstrengungen der letzten Jahre haben auf einigen dieser Gebiete zu einer soliden Datenlage geführt. Die Ergebnisse der großen Deeskalationsstudien durch Nutzung von Multi-Gen-Tests liegen ebenso vor wie die Ergebnisse einiger Studien, die die neuen Anti-HER2-Substanzen T-DM1 und Pertuzumab in der frühen Therapiesituation untersucht haben. Mehrere groß angelegte Studien zur Untersuchung der Rolle der CDK4/6-Inhibitoren stehen kurz vor dem Abschluss, sodass auch in dieser Therapiesituation mit Neuerungen zu rechnen ist. Diese Übersichtsarbeit soll die Ergebnisse der neuesten Publikationen zusammenfassen und einordnen.

ZusammenfassungNachdem in den letzten Jahren bei der Behandlung von Patientinnen mit fortgeschrittenem Mammakarzinom zunehmend Substanzen mit einer guten Effektivität zum Einsatz kommen, die spezifische Signalwege angreifen, sind nun neue Therapien und Ansätze hinzugekommen, die sich tatsächlich auf ganz spezifische Veränderungen beziehen wie die Behandlung von Patientinnen mit HR+/HER2−-Tumoren mit einer PIK3CA-Mutation. Ebenso ist die Behandlung von Patientinnen mit einer BRCA1- oder BRCA2-Mutation durch die Einführung der PARP-Inhibitoren verbessert worden. Nun wird zunehmend versucht, Therapieindikationen aufgrund molekularer Muster auszudehnen und weitere Patientinnen zu identifizieren, die von einer Therapie profitieren könnten, und die neu etablierten Therapiemethoden in bestehende Therapiesequenzen einzubinden. Diese Übersichtsarbeit fasst die neuesten Erkenntnisse in diesem Zusammenhang zusammen.

Invasive breast cancer (IBC) is the most common malignant disease in women worldwide. In recent years, the landscape of treatment options has rapidly evolved. With the success of checkpoint inhibitors in triple negative IBC, immunotherapy has become standard of care highlighting the strength of T cell-based strategies for anti-tumor therapy. Naturally, the targets of T cell-mediated immune responses are represented by short peptides presented on human leukocyte antigen (HLA) molecules. For several years, huge effort has been made to analyze and characterize HLA-presented tumor antigens to further understand anti-tumor immunity and to identify suitable targets for novel immunotherapy approaches. Aside from membrane-bound HLA molecules, soluble HLA-peptide complexes (sHLA) can be found in a variety of body fluids. These molecules are suggested to impact cellular immune responses, but it is still a matter of debate, whether shifts in sHLA levels contribute to disease outcome or are observed as a consequence of disease. Whereas the role of the non-classical sHLA-G in IBC has been studied showing elevated levels in patients compared to a healthy cohort, data on classical sHLA class I molecules is not yet available. Here, we report on sHLA class I serum levels in patients with IBC after neoadjuvant chemotherapy or combined chemotherapy with antibody treatment (n = 52). We observed higher serum levels of sHLA in neoadjuvant-treated IBC patients without histopathological complete response after neoadjuvant therapy (n = 36) compared to healthy volunteers (n = 84). Patients with locally advanced tumors, according to TNM classification, had a tendency towards lower sHLA levels than patients with small size tumors. Furthermore, sHLA levels were decreased in patients with sentinel node or disseminated axillary lymph node metastases compared to non-metastatic patients. Of note, sHLA levels tended to be elevated in patients with Her2-overexpression (based on immunohistochemistry staining and fluorescence in situ hybridization), whereas for histological hormone receptor expression a tendency towards lower sHLA levels in patients with high expression was observed. Furthermore, sHLA levels were reduced in patients with disseminated tumor cells in bone marrow aspiration. No significant difference in sHLA levels were seen in terms of grading of tumor, prevalence of distant metastasis, menopausal status and elevated tumor markers. Interestingly, we observed a tendency to prolonged progression-free survival in patients with high serum concentrations of sHLA, which will be updated with data from additional patients at the AACR meeting. Taken together, these data provides first insights about sHLA class I in patients with IBC after neoadjuvant treatment suggesting an impact of sHLA and T cell-mediated immune surveillance on survival in patients with IBC. Citation Format: Christian M. Tegeler, Jonas Rieth, André Koch, Dominik Dannehl, Léa L. Volmer, Sabine Matovina, Markus Hahn, Tobias Engler, Andreas D. Hartkopf, Sara Y. Brucker, Juliane S. Walz, Jonas S. Heitmann, Annika Nelde. A correlation of soluble HLA serum levels with clinical data and survival in patients with invasive breast cancer after neoadjuvant treatment. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4376.

Background: It is well-known that tumor biology may change during the course of the disease due to clonal evolution, and such changes might have important implications for response to targeted treatments. Circulating tumor cells (CTCs) could serve as a real-time liquid biopsy to detect changes in tumor biology. It has been demonstrated that patients with HER2-negative metastatic breast cancer (MBC) may have discordant, HER2-positive CTCs in the peripheral blood. However, up to now there is no randomized clinical trial investigating whether treatment decisions based on CTC phenotype provide benefits in terms of improved outcome. The aim of the DETECT III study is to investigate whether patients with initially HER2-negative MBC and HER2-positive CTCs benefit from HER2-targeted therapy with the tyrosine kinase inhibitor lapatinib. In addition, the significance of CTCs as an early predictive marker for response to therapy will be analyzed. Methods: The randomized phase III DETECT III trial (NCT01619111) compares lapatinib in combination with standard therapy versus standard therapy alone in patients with initially HER2-negative MBC and HER2-positive CTCs. Efficacy of lapatinib treatment is evaluated by CTC clearance rate, progression-free survival (PFS) and overall survival (OS). In addition, we investigate the association between CTC results and both PFS and OS to assess the utility of CTCs as an early predictive marker for treatment response. CTC enumeration and phenotyping was performed using the CellSearch® technology (Menarini Silicon Biosystems; Bologna, Italy). Survival data are analyzed using log rank tests, univariable and adjusted multivariable cox regressions. Results: First results on CTC clearance rates, PFS and OS of 105 prospectively randomized patients will be presented. Conclusion: This first randomized clinical trial in breast cancer patients with treatment decisions being based on the phenotype of CTCs will show whether patients with HER2 negative MBC and HER2 positive CTCs benefit from additional HER2-targeted therapy with lapatinib. This finding might be increasingly important as novel HER2-targeted drugs become available. Citation Format: Tanja Fehm, Volkmar Mueller, Maggie Banys-Paluchowski, Peter A Fasching, Thomas WP Friedl, Andreas Hartkopf, Jens Huober, Christian Loehberg, Brigitte Rack, Sabine Riethdorf, Andreas Schneeweiss, Diethelm Wallwiener, Franziska Meier-Stiegen, Oliver Hoffmann, Lothar Müller, Pauline Wimberger, Eugen Ruckhaeberle, Jens Blohmer, Wolfgang Janni. Efficacy of the tyrosine kinase inhibitor lapatinib in the treatment of patients with HER2-negative metastatic breast cancer and HER2-positive circulating tumor cells - results from the randomized phase III DETECT III trial [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD3-12.

In the era of personalized medicine, the ability of pre-selecting individualized therapeutic options and pre-defining their suitability in advance of clinical treatment might facilitate decision making in breast cancer treatment and hence, improve patient outcome. In order to preclinically validate anti-cancer drug efficacy, it is crucial to design a model system that reveals the influence of cellular interactions of the tumor microenvironment and cellular heterogeneity on drug response. Within the PRIMO (Personalized Medicine for tailored cancer therapies) project, such a 3D preclinical model system comprised of patient-derived microtumors (PDM) and autologous tumor-infiltrating lymphocytes (TILs) isolated from fresh primary breast cancer tissue using limited digestion and subsequent culture in defined media in the absence of serum is established. Herein, the heterogeneous cellular composition of isolated PDM is analyzed by FFPE immunohistochemistry and compared to corresponding primary tumor tissue. The composition of autologous TILs influencing individual treatment responses is characterized by multi-color flow cytometry detecting different cell populations, such as tumor-specific CD8+ or regulatory CD4+ T-cells. By using the DigiWest technology, a proprietary high throughput immune assay screening tool, in-depth protein profiling of up to 200 analytes from low amounts of PDM material is performed. The generated protein profiles of PDM are compared to their corresponding primary tumor tissue as well as the pathological receptor grading. Furthermore, differences in activation of key signal transduction pathways are detected and related to treatment responses to small molecules, chemotherapeutics as well as immunotherapeutic agents within PDM and PDM-TIL co-cultures assessed by a functional viability assay in a microplate format. To expand this preclinical model system, we established PDM-co-cultures adding further immune cell types including natural killer (NK) cells or dendritic cells (DC). In summary, immunohistochemical analyses combined with protein profiling of breast cancer PDM enables drug-mode-of-action analyses, biomarker identification together with personalized therapeutic sensitivity prediction. The platform presented here expands the preclinical repertoire of relevant test systems for efficacy testing of drugs and investigational compounds, pre-identified by protein pathways as well as genetic profiling in personalized medicine of breast cancer. Citation Format: Nicole Anderle, Felix Ruoff, Simge Yuez, André Koch, Andreas Hartkopf, Sara Brucker, Michael Pawlak, Markus Templin, Christian Schmees. A fast and effective 3D preclinical assay system comprised of patient derived breast cancer microtumors combined with DigiWest protein signaling pathway analyses for therapeutic response prediction (Project PRIMO) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS17-42.

Introduction: RIBECCA is a national, multi-center, open-label, single-arm phase IIIb trial assessing the efficacy and safety of ribociclib in combination with letrozole in a patient population similar to the populations of MONALEESA-2, -3 and -7, including premenopausal and postmenopausal patients without pretreatment as well as patients with up to 3 previous treatment lines for advanced disease. Here we present the final analysis for the primary endpoint. Methods:The study enrolled women or men with metastatic or locally advanced breast cancer irrespective of their menopausal status, who were not amenable to curative treatment by surgery or radiotherapy. Histological or cytological confirmation of HR+, HER2- breast cancer was required. 502 patients were enrolled in two Cohorts. Cohort A (n=319): postmenopausal women and men without pretreatment for advanced disease; Cohort B (n=183): premenopausal women without pretreatment for advanced disease and pre- or postmenopausal women and men with ≤ 1 line of chemotherapy and/or ≤ 2 lines of endocrine therapy in the advanced situation. The primary endpoint was to assess the clinical benefit rate (CBR, defined as CR, PR or SD, or NCRNPD) at 24 weeks for the overall study population. Secondary endpoints included: progression free survival (PFS), overall survival (OS), safety, and changes in quality of life as assessed by EORTC QLQ-C30 and -BR23 questionnaires. Results: The study ended 84 weeks after the enrollment of the last patient. The median observation time was 10.6 months (0.1-38 months). Baseline characteristics: of 502 pts, 5 were male, 497 were female(46 pre-or perimenopausal, 451 postmenopausal); median age: 64 yrs; ECOG 0-1: 96.8%; 71.1 % of pts had bone metastases (40.8% bone only), 30.6% liver, 27.5% lung and 30.1% other metastases. 97.3% had at least 1 metastatic site: 48.7% had 1, 35.1% had 2, 12.9% had 3 and 1.6% had 4 metastatic sites, respectively. 78.9% received at least one prior antineoplastic therapy: 4.9% received neoadjuvant, 56.8% adjuvant and 37.8% palliative treatment as last antineoplastic therapy before study start. The most common treatment emergent AEs (all grades) were neutropenia and/or neutrophil count decreased (60.6%), nausea (42%), fatigue (39.2%), alopecia (35.1%), leukopenia or WBC decreased (30.7%), nasopharyngitis (28.5%), diarrhea (25.3%), ALT increased (22.9%) and AST increased (20.7%). The CBR at week 24 for the overall study population was 69.2%. Median PFS was 16.5 [95%CI 13.7; 19.3] months in the overall study population, 21.8 [15.4; 25.3] months and 9.3 [8.1; 16.3] months in Cohort A and B, respectively. At 72 weeks, the Kaplan-Meier estimate for OS was 86.8% [83.3; 89.6]. Because of the low number of events during the study period, median OS could not be determined. Conclusion: The results of the final analysis confirmed clinical benefit of ribociclib and letrozole in this patient population. No new safety signals emerged. Citation Format: Mattea Reinisch, Arndt Nusch, Thomas Decker, Andreas Hartkopf, Bernhard J Heinrich, Christian M Kurbacher, Roswitha Fuchs, Hans Tesch, Petra Krabisch, Sara Y Brucker, Tanja Fehm, Wolfgang Janni, Sherko Kuemmel, Diana Lüftner, Andreas Schneeweiss, Martin Schuler, Claudia Voges, Joerg Schubert, Peter A Fasching. Ribecca - a phase 3b, multi-center, open label study for women with estrogen receptor positive, locally advanced or metastatic breast cancer treated with ribociclib (lee011) in combination with letrozole: Final results [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS10-31.

Purpose To investigate the oncologic and reproductive outcome of a conservative treatment with progestin agents in early-stage grade 1 endometrial cancer (G1EC), grade 2 endometrial cancer (G2EC) or complex atypical hyperplasia (CAH) in young premenopausal women. Methods Women treated for early-stage endometrial cancer or atypical hyperplasia of the endometrium with a conservative therapy between 2006 and 2018 were enrolled in this retrospective analysis. Progestin agents were orally administered on a daily basis for 3 months for at least one cycle. Endometrial tissue was obtained by hysteroscopy and Dilatation & Curettage (D&C) being performed before and after end of treatment. Therapeutic response was assessed by pathological examination. Results A total of 14 patients were included. After treatment with progestin agents, 11 of these patients initially showed a complete or partial response. Three patients with early-stage endometrial cancer did not respond. Of the three patients with initially diagnosed atypical hyperplasia, none showed any remaining disease later. Of the eight patients with initially diagnosed endometrial cancer, who had responded to first treatment, three patients were re-diagnosed with endometrial cancer later. One patient with initial endometrial cancer became pregnant but aborted in the 10th week. Conclusion Due to its good efficacy, progestin agents offer a feasible therapeutic option in the fertility-preserving treatment of early-stage endometrial cancer in young premenopausal women. However, recurrence rate remains high. Therefore, a close follow-up is mandatory, also in responders. Patients should be informed of limitations and risks of conservative treatment. Yet after completion of family planning, hysterectomy should be performed.