P Krabisch

Bio: P Krabisch is an academic researcher. The author has contributed to research in topics: Internal medicine & Oncology. The author has an hindex of 1, co-authored 1 publications receiving 735 citations.

Implementation of CDK4/6 Inhibitors and its Influence on the Treatment Landscape of Advanced Breast Cancer Patients – Data from the Real-World Registry PRAEGNANT

Abstract: Abstract 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.

Current clinical practice and outcome of neoadjuvant chemotherapy for early breast cancer: analysis of individual data from 94,638 patients treated in 55 breast cancer centers

Abstract: Neoadjuvant chemotherapy (NACT) is frequently used in patients with early breast cancer. Randomized controlled trials have demonstrated similar survival after NACT or adjuvant chemotherapy (ACT). However, certain subtypes may benefit more when NACT contains regimes leading to high rates of pathologic complete response (pCR) rates. In this study we analyzed data using the OncoBox research from 94,638 patients treated in 55 breast cancer centers to describe the current clinical practice of and outcomes after NACT under routine conditions. These data were compared to patients treated with ACT. 40% of all patients received chemotherapy. The use of NACT increased over time from 5% in 2007 up to 17.3% in 2016. The proportion of patients receiving NACT varied by subtype. It was low in patients with HR-positive/HER2-negative breast cancer (5.8%). However, 31.8% of patients with triple-negative, 31.9% with HR-negative/HER2-positive, and 26.5% with HR-positive/HER2-positive breast cancer received NACT. The rates of pCR were higher in patients with HR-positive/HER2-positive, HR-negative/HER2-positive and triple-negative tumors (36, 53 and 38%) compared to HR-positive/HER2-negative tumors (12%). PCR was achieved more often in HER2-positive and triple-negative tumors over time.This is the largest study on use and effects of NACT in German breast cancer centers. It demonstrates the increased use of NACT based on recommendations in current clinical guidelines. An improvement of pCR was shown in particular in HER2-positive and triple-negative breast cancer, which is consistent with data from randomized controlled trails.

Association between pCR, TILs, and Ki-67 at baseline and after 2 weeks in patients with triple-negative breast cancer (TNBC) treated with atezolizumab and chemotherapy +/- a preceding atezolizumab monotherapy window: A translational analysis of the neoMono trial.

Abstract: 595 Background: neoMono randomized patients (pts) with triple negative breast cancer (TNBC) to receive (Arm A) or not to receive (Arm B) 2-week Atezolizumab monotherapy prior to neoadjuvant 24-week Atezolizumab + chemotherapy. In prespecified interim analysis, no difference regarding pathological complete response (pCR) was observed among all pts. However, in regard to pCR rates, pts with PD-L1 positive TNBC seem to benefit from addition of the monotherapy window. Here we analyze the association between central TILs and Ki-67 at baseline (BL) / after 2 weeks (2w) and pCR. Methods: Ki-67 expression (% positive tumor cells) was analyzed using immunohistochemistry. Analysis of stromal TILs was performed according to the International TILs Working Group. Differences from BL at the 2w time point were denoted as Ki-67-diff and TIL-diff, respectively. Associations between pCR and BL/2w measurements were analyzed using logistic regression. Akaike information criterion (AIC) was used to evaluate goodness-of-fit between models. Since the a priori chosen biomarker thresholds ( < = 30% [Ki-67] and < = 60% [TILs]) resulted in very low subgroup sizes, k-means clustering analysis was performed and association of the cluster labels with pCR was then investigated. Results: The analysis included 50 (Arm A) and 51 (Arm B) pts. The threshold of Ki-67 ( < = 30%) was reached in 98% (BL) and 92% (2w), that of TILs ( < = 60%) in 11% (BL) and 18% (2w), respectively. PD-L1 (BL) was < = 1 in 26%. In separate logistic regression models (including BL and change), both BL-Ki-67 and BL-TILs were significantly though moderately associated with pCR. A combined model using both biomarkers yielded the best AIC. BL-Ki-67 and BL-TILs, as well as TIL-diff were highly significantly though again moderately associated with pCR. Cluster analysis I (using BL-Ki-67, Ki-67-diff, and PD-L1) yielded cluster 1 (medium BL-Ki-67 and subsequent increase) with a pCR rate of 50% compared to 77% in cluster 2 (high BL-Ki-67 and decreasing Ki-67). Similarly, cluster analysis II (using BL-TILS, TILS-diff and PD-L1) yielded cluster 3 (low BL-TILs/non-essential TILs change) with a low pCR rate of 55% compared to 84.4% and 85.7% for clusters 4 (low BL-TILs /substantial increase) and 5 (high BL-TILs/non-essential change), respectively. In a combined regression model of all clusters above, clusters 2 and 4 had the highest pCR probability. Conclusions: Our results demonstrate that while BL-Ki-67 and BL-TILs are highly informative of pCR probability, Ki-67-diff and even more so TIL-diff added further significant information. Analysis of the full neoMono dataset will allow us to investigate this association further and to potentially develop a predictive algorithm regarding pCR based on baseline and dynamic biomarkers.

The effect of denosumab on disseminated tumor cells (DTCs) of breast cancer patients with neoadjuvant treatment: a GeparX translational substudy

Abstract: Abstract Background Disseminated tumor cells (DTCs) in the bone marrow are observed in about 40% at primary diagnosis of breast cancer and predict poor survival. While anti-resorptive therapy with bisphosphonates was shown to eradicate minimal residue disease in the bone marrow, the effect of denosumab on DTCs, particularly in the neoadjuvant setting, is largely unknown. The recent GeparX clinical trial reported that denosumab, applied as an add-on treatment to nab-paclitaxel based neoadjuvant chemotherapy (NACT), did not improve the patient’s pathologic complete response (pCR) rate. Herein, we analyzed the predictive value of DTCs for the response to NACT and interrogated whether neoadjuvant denosumab treatment may eradicate DTCs in the bone marrow. Methods A total of 167 patients from the GeparX trial were analyzed for DTCs at baseline by immunocytochemistry using the pan-cytokeratin antibody A45-B/B3. Initially DTC-positive patients were re-analyzed for DTCs after NACT ± denosumab. Results At baseline, DTCs were observed in 43/167 patients (25.7%) in the total cohort, however their presence did not predict response to nab-paclitaxel based NACT (pCR rates: 37.1% in DTC-negative vs. 32.6% DTC-positive; p = 0.713). Regarding breast cancer subtypes, the presence of DTCs at baseline was numerically associated with response to NACT in TNBC patients (pCR rates: 40.0% in DTC-positive vs. 66.7% in DTC-negative patients; p = 0.16). Overall, denosumab treatment did not significantly increase the given DTC-eradication rate of NACT (NACT: 69.6% DTC-eradication vs. NACT + denosumab: 77.8% DTC-eradication; p = 0.726). In TNBC patients with pCR, a numerical but statistically non-significant increase of DTC-eradication after NACT + denosumab was observed (NACT: 75% DTC-eradication vs. NACT + denosumab: 100% DTC-eradication; p = 1.00). Conclusion This is the first study worldwide, demonstrating that neoadjuvant add-on denosumab over a short-term period of 24 months does not increase the DTC-eradication rate in breast cancer patients treated with NACT.

Maintenance Olaparib in Patients with Newly Diagnosed Advanced Ovarian Cancer

Abstract: Background Most women with newly diagnosed advanced ovarian cancer have a relapse within 3 years after standard treatment with surgery and platinum-based chemotherapy. The benefit of the o...

Olaparib plus Bevacizumab as First-Line Maintenance in Ovarian Cancer.

Abstract: Background Olaparib has shown significant clinical benefit as maintenance therapy in women with newly diagnosed advanced ovarian cancer with a BRCA mutation. The effect of combining mainte...

State-of-the-art strategies for targeting the DNA damage response in cancer

Abstract: Genomic instability is a key hallmark of cancer that arises owing to defects in the DNA damage response (DDR) and/or increased replication stress. These alterations promote the clonal evolution of cancer cells via the accumulation of driver aberrations, including gene copy-number changes, rearrangements and mutations; however, these same defects also create vulnerabilities that are relatively specific to cancer cells, which could potentially be exploited to increase the therapeutic index of anticancer treatments and thereby improve patient outcomes. The discovery that BRCA-mutant cancer cells are exquisitely sensitive to inhibition of poly(ADP-ribose) polymerase has ushered in a new era of research on biomarker-driven synthetic lethal treatment strategies for different cancers. The therapeutic landscape of antitumour agents targeting the DDR has rapidly expanded to include inhibitors of other key mediators of DNA repair and replication, such as ATM, ATR, CHK1 and CHK2, DNA-PK and WEE1. Efforts to optimize these therapies are ongoing across a range of cancers, involving the development of predictive biomarker assays of responsiveness (beyond BRCA mutations), assessment of the mechanisms underlying intrinsic and acquired resistance, and evaluation of rational, tolerable combinations with standard-of-care treatments (such as chemotherapeutics and radiation), novel molecularly targeted agents and immune-checkpoint inhibitors. In this Review, we discuss the current status of anticancer therapies targeting the DDR.

Epithelial ovarian cancer: Evolution of management in the era of precision medicine

Abstract: Ovarian cancer is the second most common cause of gynecologic cancer death in women around the world. The outcomes are complicated, because the disease is often diagnosed late and composed of several subtypes with distinct biological and molecular properties (even within the same histological subtype), and there is inconsistency in availability of and access to treatment. Upfront treatment largely relies on debulking surgery to no residual disease and platinum-based chemotherapy, with the addition of antiangiogenic agents in patients who have suboptimally debulked and stage IV disease. Major improvement in maintenance therapy has been seen by incorporating inhibitors against poly (ADP-ribose) polymerase (PARP) molecules involved in the DNA damage-repair process, which have been approved in a recurrent setting and recently in a first-line setting among women with BRCA1/BRCA2 mutations. In recognizing the challenges facing the treatment of ovarian cancer, current investigations are enlaced with deep molecular and cellular profiling. To improve survival in this aggressive disease, access to appropriate evidence-based care is requisite. In concert, realizing individualized precision medicine will require prioritizing clinical trials of innovative treatments and refining predictive biomarkers that will enable selection of patients who would benefit from chemotherapy, targeted agents, or immunotherapy. Together, a coordinated and structured approach will accelerate significant clinical and academic advancements in ovarian cancer and meaningfully change the paradigm of care.