Vergleich von HER2-, Östrogen- und Progesteron Rezeptor-Profilen bei Patienten mit primärem Mammakarzinom und synchroner axillärer Lymphknotenmetastase

Die grundlegenden Therapieentscheidung der primären Mammakarzinom-Erkrankung beruhen auf Bestimmung des Östrogen- (ER) / Progesteron- (PR) und HER2-Rezeptorprofils. Dabei werden diese bei Diagnosestellung anhand von Gewebsmaterial des Primärtumors, welches üblicherweise in Form einer Stanzbiopsie gewonnen wird, immunhistochemisch bestimmt. Anhand dieses Rezeptorprofils erfolgt die Festlegung des primären Therapieregimes. Es konnte jedoch gezeigt werden, dass das Rezeptorprofil sich im Verlaufe einer Erkrankung ändern kann. Diese Erkenntnis beruht auf verschiedenen Studien, die Rezeptorprofile zwischen Primärtumoren und Fernmetastasen verglichen haben. Dies hat zu einer Berücksichtigung in den sowohl deutschen, als auch internationalen Mammakarzinom-Leitlinien geführt, die mittlerweile die erneute Gewinnung von Gewebsmaterial und Neubestimmung des Rezeptorprofils im Falle einer Metastasierung empfehlen. Diese Empfehlungen beziehen sich jedoch bislang ausschließlich auf die metastasierte- oder Rezidiv-Situation der Erkrankung. Es wird selten in Erwägung gezogen, dass es bereits in der Primärsituation zu Unterschieden und Änderungen im Rezeptorprofil zwischen Primärtumor und simultaner, axillärer Lymphknotenmetastase kommen kann. Bislang erfolgt im Falle einer axillären Metastasierung noch keine routinemäßige Bestimmung des Rezeptorprofils. Kommt es zu Unterschieden des Rezeptorprofils zwischen Primärtumor und simultaner Lymphknotenmetastase, handelt es sich aufgrund mangelhafter Datenlage noch um Einzelfallentscheidungen, inwieweit die weitere Therapie bei einem Rezeptorzugewinn oder -verlust angepasst wird. Dabei muss hier grundsätzlich abgewogen werden, ob der Patientin eine Übertherapie zugemutet, oder eine zusätzliche Therapie vorenthalten werden kann. Das Ziel dieser Arbeit war ein Vergleich der ER, PR und HER2-Rezeptorprofile zwischen Primärtumor und synchroner, axillärer Lymphknotenmetastase zum Zeitpunkt der primären Mammakarzinom-Erkrankung.:Abkürzungsverzeichnis 1. Einführung in die Thematik 1.1 Historie des Mammakarzinoms 1.2 Epidemiologie 1.3 Diagnostik 1.3.1 Diagnostische Sicherung 1.3.2 Östrogen und Progesteron-Rezeptorstatus und Grenzwerte 1% vs. 10% 1.3.3 HER2-Rezeptorstatus 1.3.4 Ki67-Bestimmung 1.4 Einteilungsformen 1.4.1 TNM-Klassifikation 1.4.2 Intrinsische Subtypen 1.5 Therapieformen 1.5.1 Operative Therapie 1.5.2 Axilläres Management 1.5.3 Neoadjuvante systemische Therapie 1.5.4 Neoadjuvant endokrine Therapie 1.6 Rezeptoränderungen 1.6.1 Daten aus der metastasierten Situation 1.6.2 Fragestellung 2. Publikation 3. Zusammenfassung der Arbeit 3.1 Fragestellung 3.2 Patienten und Methoden 3.3 Ergebnisse 3.3.1 Patientenkollektiv 3.3.2 Anwendung der unterschiedlichen Grenzwerte (≥1% vs. ≥10%) 3.3.3 Änderungsraten 3.3.4 Rezeptorverluste und -zugewinne 3.3.5 Analyse der intrinsischen Subtypen 3.3.6 Korrelationsanalyse 3.4 Schlussfolgerung 4. Literaturverzeichnis 5. Anhang 5.1 Darstellung des eigenen Beitrags 5.2 Erklärung über den wissenschaftlichen Beitrag der Promovendin 5.3 Erklärung über die eigenständige Abfassung der Arbeit 5.4 Lebenslauf 5.5 Verzeichnis der wissenschaftlichen Veröffentlichungen und Vorträge 5.6 Danksagun

Heterogeneity between Core Needle Biopsy and Synchronous Axillary Lymph Node Metastases in Early Breast Cancer Patients: A Comparison of HER2, Estrogen and Progesterone Receptor Expression Profiles during Primary Treatment Regime

In breast cancer therapeutic decisions are based on the expression of estrogen (ER), progesterone (PR), the human epidermal growth factor 2 (HER2) receptors and the proliferation marker Ki67. However, only little is known concerning heterogeneity between the primary tumor and axillary lymph node metastases (LNM) in the primary site. We retrospectively analyzed receptor profiles of 215 early breast cancer patients with axillary synchronous LNM. Of our cohort, 69% were therapy naive and did not receive neoadjuvant treatment. Using immunohistochemistry, receptor status and Ki67 were compared between core needle biopsy of the tumor (t-CNB) and axillary LNM obtained during surgery. The discordance rates between t-CNB and axillary LNM were 12% for HER2, 6% for ER and 20% for PR. Receptor discordance appears to already occur at the primary site. Receptor losses might play a role concerning overtreatment concomitant with adverse drug effects, while receptor gains might be an option for additional targeted or endocrine therapy. Hence, not only receptor profiles of the tumor tissue but also of the synchronous axillary LNM should be considered in the choice of treatment

Inversion of the uterus with placenta adherens and successful reposition

Objective!#!To evaluate association of preoperative cone biopsy with the probability of recurrent disease after radical hysterectomy for cervical cancer.!##!Methods!#!This is a retrospective single-center study. Patients with cervical cancer stage IA1 with LVSI to IIA2 and squamous, adenosquamous and adenocarcinoma subtype were included. Patients were analyzed for general characteristics and recurrence-free survival (RFS).!##!Results!#!In total, of 480 patients with cervical cancer, 183 patients met the inclusion criteria (117 with laparoscopic and 66 with open surgery). The median tumor diameter was 25.0 mm (range 4.6-70.0 mm) with 66 (36.2%) patients having tumors smaller than 2 cm. During median follow-up of 54.0 months (range 0-166.0 months), the RFS for the laparoscopic cohort was 93.2% and 87.5% at 3 and 4.5 years, and 79.3% for the open cohort after 3 and 4.5 years, respectively. In total, 17 (9.3%) patients developed recurrent disease, 9 (7.3%) after laparoscopic, and 8 (12.1%) after open surgery. No preoperative cone biopsy (OR 9.60, 95% CI 2.14-43.09) as well as tumor diameter > 2 cm (OR 5.39, 95% CI 1.20-24.25) were significantly associated with increased risk for recurrence. In multivariate analysis, only missing preoperative cone biopsy was significantly associated with increased risk for recurrence (OR 5.90, 95% CI 1.11-31.29) CONCLUSION: There appears to be a subgroup of patients (preoperative cone biopsy, tumor diameter < 2 cm) with excellent survival and low risk for recurrence after radical hysterectomy which might benefit from the advantages of laparoscopic surgery

Heterogeneity between Core Needle Biopsy and Synchronous Axillary Lymph Node Metastases in Early Breast Cancer Patients: A Comparison of HER2, Estrogen and Progesterone Receptor Expression Profiles during Primary Treatment Regime

In breast cancer therapeutic decisions are based on the expression of estrogen (ER), progesterone (PR), the human epidermal growth factor 2 (HER2) receptors and the proliferation marker Ki67. However, only little is known concerning heterogeneity between the primary tumor and axillary lymph node metastases (LNM) in the primary site. We retrospectively analyzed receptor profiles of 215 early breast cancer patients with axillary synchronous LNM. Of our cohort, 69% were therapy naive and did not receive neoadjuvant treatment. Using immunohistochemistry, receptor status and Ki67 were compared between core needle biopsy of the tumor (t-CNB) and axillary LNM obtained during surgery. The discordance rates between t-CNB and axillary LNM were 12% for HER2, 6% for ER and 20% for PR. Receptor discordance appears to already occur at the primary site. Receptor losses might play a role concerning overtreatment concomitant with adverse drug effects, while receptor gains might be an option for additional targeted or endocrine therapy. Hence, not only receptor profiles of the tumor tissue but also of the synchronous axillary LNM should be considered in the choice of treatment

Heterogeneity between Core Needle Biopsy and Synchronous Axillary Lymph Node Metastases in Early Breast Cancer Patients: A Comparison of HER2, Estrogen and Progesterone Receptor Expression Profiles during Primary Treatment Regime

In breast cancer therapeutic decisions are based on the expression of estrogen (ER), progesterone (PR), the human epidermal growth factor 2 (HER2) receptors and the proliferation marker Ki67. However, only little is known concerning heterogeneity between the primary tumor and axillary lymph node metastases (LNM) in the primary site. We retrospectively analyzed receptor profiles of 215 early breast cancer patients with axillary synchronous LNM. Of our cohort, 69% were therapy naive and did not receive neoadjuvant treatment. Using immunohistochemistry, receptor status and Ki67 were compared between core needle biopsy of the tumor (t-CNB) and axillary LNM obtained during surgery. The discordance rates between t-CNB and axillary LNM were 12% for HER2, 6% for ER and 20% for PR. Receptor discordance appears to already occur at the primary site. Receptor losses might play a role concerning overtreatment concomitant with adverse drug effects, while receptor gains might be an option for additional targeted or endocrine therapy. Hence, not only receptor profiles of the tumor tissue but also of the synchronous axillary LNM should be considered in the choice of treatment

Multi-Parameter Analysis of Disseminated Tumor Cells (DTCs) in Early Breast Cancer Patients with Hormone-Receptor-Positive Tumors

Background: Patients with hormone-receptor-positive (HR+) breast cancer are at increased risk for late recurrence. One reason might be disseminated tumor cells (DTCs), which split off in the early stages of the disease and metastasize into the bone marrow (BM). Methods: We developed a novel multi-parameter immunofluorescence staining protocol using releasable and bleachable antibody–fluorochrome-conjugates. This sequential procedure enabled us to analyze six distinct phenotypical and therapy-related markers on the same DTC. We characterized BM aspirates from 29 patients with a HR+ tumor and a known positive DTC status—based on the standardized detection of epithelial cells in BM. Results: Using the immunofluorescence staining, a total of 153 DTCs were detected. Luminal A patients revealed a higher DTC count compared with luminal B. The majority of the detected DTCs were CK-positive (128/153). However, in 16 of 17 luminal A patients we found HER2-positive DTCs. We detected CK-negative DTCs (25/153) in 12 of 29 patients. Of those cells, 76% were Ki67-positive and 68% were HER2-positive. Moreover, we detected DTC clusters consisting of mixed characteristics in 6 of 29 patients. Conclusions: Using sequential multi-parameter imaging made it possible to identify distinct DTC profiles not solely based on epithelial features. Our findings indicate that characterization rather than quantification of DTCs might be relevant for treatment decisions

Multi-Parameter Analysis of Disseminated Tumor Cells (DTCs) in Early Breast Cancer Patients with Hormone-Receptor-Positive Tumors

Background: Patients with hormone-receptor-positive (HR+) breast cancer are at increased risk for late recurrence. One reason might be disseminated tumor cells (DTCs), which split off in the early stages of the disease and metastasize into the bone marrow (BM). Methods: We developed a novel multi-parameter immunofluorescence staining protocol using releasable and bleachable antibody–fluorochrome-conjugates. This sequential procedure enabled us to analyze six distinct phenotypical and therapy-related markers on the same DTC. We characterized BM aspirates from 29 patients with a HR+ tumor and a known positive DTC status—based on the standardized detection of epithelial cells in BM. Results: Using the immunofluorescence staining, a total of 153 DTCs were detected. Luminal A patients revealed a higher DTC count compared with luminal B. The majority of the detected DTCs were CK-positive (128/153). However, in 16 of 17 luminal A patients we found HER2-positive DTCs. We detected CK-negative DTCs (25/153) in 12 of 29 patients. Of those cells, 76% were Ki67-positive and 68% were HER2-positive. Moreover, we detected DTC clusters consisting of mixed characteristics in 6 of 29 patients. Conclusions: Using sequential multi-parameter imaging made it possible to identify distinct DTC profiles not solely based on epithelial features. Our findings indicate that characterization rather than quantification of DTCs might be relevant for treatment decisions

Desmoplasia in cervical cancer is associated with a more aggressive tumor phenotype

Abstract In cancer of the uterine cervix, the role of desmoplasia, i.e., peritumoral stromal remodeling characterized by fibroblast activation and increased extracellular matrix deposition, is not established. We conducted a retrospective cohort study based on data from 438 patients who had undergone surgical treatment for cervical cancer as part of the prospective Leipzig Mesometrial Resection study between 1999 and 2021. Using non-parametric tests, Kaplan–Meier plotting, and Cox regression modeling, we calculated the prognostic impact of desmoplasia and its association with other risk factors. Desmoplasia was present in 80.6% of cases and was associated with a higher frequency of lymphovascular space involvement (76.5 vs. 56.5%, p < 0.001) and venous infiltration (14.4 vs. 2.4%, p < 0.001). Lymph node metastasis (23.0 vs. 11.8%, p < 0.05) and parametrial involvement (47.3 vs. 17.6%, p < 0.0001) were also more common in patients with desmoplasia. The presence of desmoplasia was associated with inferior overall (80.2% vs. 94.5% hazard ratio [HR] 3.8 [95% CI 1.4–10.4], p = 0.002) and recurrence-free survival (75.3% vs. 87.3%, HR 2.3 [95% CI 1.2–4.6], p = 0.008). In addition, desmoplasia was associated with significantly less peritumoral inflammation (rho − 0.43, p < 0.0001). In summary, we link desmoplasia to a more aggressive phenotype of cervical cancer, reduced peritumoral inflammation, and inferior survival