Publications by authors named "Nadia Harbeck"

362 Publications

[Hereditary breast and ovarian cancer. What to think about and what to do?]

MMW Fortschr Med 2021 06;163(11):36-40

Zentrum für Familiären Brust- und Eierstockkrebs, Klinik für Gynäkologie und Geburtshilfe, München, Deutschland.

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http://dx.doi.org/10.1007/s15006-021-9946-zDOI Listing
June 2021

Cytoplasmic LXR expression is an independent marker of poor prognosis for patients with early stage primary breast cancer.

J Cancer Res Clin Oncol 2021 Jun 3. Epub 2021 Jun 3.

Department of Obstetrics and Gynecology, Breast Center, LMU University Hospital, Munich, Germany.

Purpose: The aim of this study was to investigate the expression of liver X receptors α/β (LXR) in primary breast cancer (BC) tissues and to analyze its correlations with clinicopathological parameters including patient survival.

Methods: In a well-characterized cohort of 305 primary BC, subcellular distribution of LXR was evaluated by immunohistochemistry. Correlations with clinicopathological characteristics as well as with patient outcome were analyzed.

Results: LXR was frequently localized in both nuclei and cytoplasms of BC cells, with stronger staining in nuclei. Total and nuclear LXR expression was positively correlated with ER and PR status. Overall survival analysis demonstrated that cytoplasmic LXR was significantly correlated with poor survival and appeared as an independent marker of poor prognosis, in stage I but not in stage II-III tumors CONCLUSION: Altogether, these data suggest that cytoplasmic LXR could be defined as a prognostic marker in early stage primary BC.
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http://dx.doi.org/10.1007/s00432-021-03670-yDOI Listing
June 2021

Prognostic Factors for Overall Survival in Patients with Hormone Receptor-Positive Advanced Breast Cancer: Analyses From PALOMA-3.

Oncologist 2021 May 26. Epub 2021 May 26.

Department of Molecular Oncology, Royal Marsden Hospital and Institute of Cancer Research, London, United Kingdom.

Background: This analysis investigated whether baseline characteristics affect the survival benefit derived from palbociclib-fulvestrant and the optimal timing of cyclin-dependent kinase 4/6 inhibitor therapy for advanced breast cancer (ABC) in patients from PALOMA-3.

Patients And Methods: In total, 521 patients were randomized 2:1 to receive palbociclib (125 mg/day, 3/1 schedule)-fulvestrant (500 mg, intramuscular injection, on days 1 and 15 of cycle 1, and then day 1 of each subsequent cycle) or matching placebo-fulvestrant. Median overall survival (OS) and progression-free survival were estimated using the Kaplan-Meier method.

Results: Multivariable analysis identified endocrine sensitivity, nonvisceral disease, no prior chemotherapy for ABC, and Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 as significant prognostic factors for OS. Patients without chemotherapy for ABC had fewer prior lines of treatment in any setting and in the ABC setting versus patients with prior chemotherapy for ABC (two or fewer prior systemic therapies: 69% vs. 42%; no more than one prior line for ABC: 82% vs. 33%, respectively). Median OS was prolonged with palbociclib-fulvestrant in patients without prior chemotherapy for ABC (39.7 vs. 29.5 months; hazard ratio, 0.75; 95% confidence interval [CI]: 0.56-1.01) and was similar in patients with prior chemotherapy for ABC (25.6 vs. 26.2 months; hazard ratio, 0.91 [95% CI: 0.63-1.32]) versus placebo-fulvestrant.

Conclusion: Prognostic factors for OS included endocrine sensitivity, nonvisceral disease, ECOG PS of 0, and no prior chemotherapy for ABC. Exploratory analyses suggest improved OS with palbociclib-fulvestrant versus placebo-fulvestrant in patients with no prior chemotherapy for ABC, prior endocrine sensitivity, and fewer prior regimens of systemic therapy. (Clinical trial identification number: NCT01942135).

Implications For Practice: Prognostic factors for overall survival in HR+/HER2- advanced breast cancer (ABC) include the absence of prior chemotherapy in the advanced setting, endocrine sensitivity, nonvisceral disease, and an ECOG performance status of 0. Improved overall survival benefit was observed with palbociclib-fulvestrant versus placebo-fulvestrant in patients (regardless of menopausal status or visceral involvement) with no prior chemotherapy for ABC, with prior endocrine sensitivity, and fewer prior regimens of systemic therapy. Progression-free survival was prolonged with palbociclib across subgroups (regardless of chemotherapy exposure in ABC). These exploratory findings suggest that patients may receive greater clinical benefit from palbociclib-fulvestrant if they receive the combination before chemotherapy in the advanced setting.
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http://dx.doi.org/10.1002/onco.13833DOI Listing
May 2021

Post-Neoadjuvant Gemcitabine and Cisplatin with Regional Hyperthermia for Patients with Triple-Negative Breast Cancer and Non-pCR after Neoadjuvant Chemotherapy: A Single-Institute Experience.

Breast Care (Basel) 2021 Apr 12;16(2):173-180. Epub 2020 May 12.

Medical Center for Hematology and Oncology MVZ, Munich, Germany.

Background: Patients with triple-negative primary breast cancer (TNBC) who have residual invasive carcinoma after neoadjuvant chemotherapy have poor prognosis. Proven adjuvant approaches to reduce the risk of recurrence and improve outcome in patients with non-pathological complete response (non-pCR) are limited.

Methods: From our institutional registry, a consecutive case series of patients with operable, unilateral, primary invasive noninflammatory early TNBC of stage I-IIIB and pathologically verified residual cancer cells (no pathological complete response) after neoadjuvant chemotherapy underwent adjuvant treatment with gemcitabine plus cisplatin combined with regional hyperthermia. For quality assurance, we analyzed feasibility, efficacy, and toxicity of all treated patients. Outcome was evaluated for the entire group of patients as well as for the subgroups of patients with or without lymph node involvement at baseline (cN0/ cN+).

Results: From August 2012 to January 2019, we offered this treatment to 53 patients at our center as part of routine care. The median follow-up was 38 months. The majority of patients (64.2%) had cT2 tumors at baseline. Twenty-four patients (45%) were clinically node positive as evaluated by sonography. Thirty-nine patients (74%) had grade 3, and 14 patients (26%) had grade 2 tumors. Forty-one patients (76%) showed a regression grade 1 according to Sinn. Patients received a median of six treatment cycles of gemcitabine and cisplatin (range 1-6) combined with 12 applications of regional hyperthermia (median 12, range 2-12). Disease-free survival (DFS) at 3 years was 57.5%. In patients with no lymph node involvement at baseline (cN0), DFS at 3 years was significantly higher than in initially node-positive (cN+) patients (80 vs. 31%; = 0.001). Overall survival (OS) at 3 years was 81.6%. In patients with no lymph node involvement at baseline (cN0), OS at 3 years was significantly higher than in node-positive (cN+) patients (93 vs. 70.4%; = 0.02). Overall, grade 3/4 toxicities were leukopenia (38%), thrombocytopenia (4%), and anemia (4%).

Conclusion: After standard neoadjuvant chemotherapy containing anthracycline plus cyclophosphamide followed by taxanes, addition of adjuvant gemcitabine plus cisplatin in combination with regional hyperthermia was safe and effective in TNBC patients with non-pCR.
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http://dx.doi.org/10.1159/000507473DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8114059PMC
April 2021

First Experiences with Alpelisib in Clinical Routine: Case Reports from a German Breast Center.

Breast Care (Basel) 2021 Apr 15;16(2):129-134. Epub 2021 Mar 15.

Breast Center, Department of Obstetrics and Gynecology and CCC Munich, LMU University Hospital, Munich, Germany.

Introduction: The phosphatidylinositol-3-kinase (PI3K) inhibitor alpelisib is the only approved agent for treating --mutated, hormone receptor-positive (HR+) human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC). Trials have reported hyperglycemia, diarrhea, and rash as the main grade 3 side effects.

Methods: In a managed access program (ClinicalTrials.gov ID: NCT03706573; start: 06/2019), 8 HR+ HER2- ABC patients with a median 4.5 prior therapy lines were treated with alpelisib at the Breast Center of the Ludwig-Maximilian University (LMU) Hospital, Munich, based on the results of a new-generation sequencing (NGS) panel and mutation analysis by the Molecular Tumor Board of the Comprehensive Cancer Center, Munich.

Results: Median therapy duration was 3.42 months for patients who discontinued and 3.95 months for those still on alpelisib (4 pts). Five had hyperglycemia (1 with grade 3) with fasting glucose levels of up to 450 mg/dL that required hospitalization and insulin therapy. Two experienced rash (grades 1 and 3) and 2 reported grade 3 diarrhea. Supportive therapy as well as interruption and/or dose reduction were necessary to control treatment-associated side effects.

Conclusion: Patient education and a well-trained, interdisciplinary team including diabetologists, from the initiation of alpelisib treatment onwards, are essential to safely treat ABC patients with this new drug and to maintain their quality of life and ensure their survival.
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http://dx.doi.org/10.1159/000514794DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8114069PMC
April 2021

Fifteen Years of .

Breast Care (Basel) 2021 Apr 26;16(2):97-98. Epub 2021 Mar 26.

Comprehensive Cancer Centre, Medical University Vienna, Vienna, Austria.

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http://dx.doi.org/10.1159/000515745DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8114040PMC
April 2021

St. Gallen/Vienna 2021: A Brief Summary of the Consensus Discussion on Customizing Therapies for Women with Early Breast Cancer.

Breast Care (Basel) 2021 Apr 7;16(2):135-143. Epub 2021 Apr 7.

Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.

Because of the COVID-19 pandemic, the 2021 St. Gallen/Vienna Consensus Conference on Early Breast Cancer Treatment Standards had to be held virtually. Despite the challenge of convening global contributors to both the conference itself as well as the important Consensus Panel, the scientific committee and the organizers managed to organize a well-received scientific conference, and also the panel discussion was well received in the worldwide scientific community, as indicated by numerous positive feedbacks already within the first 24 h. The virtual format was unusual, but opened the door for new elements such as Consensus questions proposed from the audience, but also live audience interaction on both days - the Consensus was split into 2 parts in order to accommodate as many time zones globally as possible, leading to almost a doubling of discussion time compared to previous meetings. Also, about 3,400 participants from over 100 countries and all continents came together, including many colleagues who could attend for the first time from world regions with restrictions that so far did not allow the travel to Vienna. Traditionally, the Panel votings and discussions were preceded by 3 days of high-level live-discussions about the lectures that were available on demand already a week before. Also, all the lectures and live discussions in mini-panels are made available online for at least 6 months (https://www.oncoconferences.ch/events/bcc-2021/). The traditional panel votings were once more moderated by Eric Winer from Harvard and included interactive elements such as audience votings and audience questions, presented by Michael Gnant. This rapid report by the editors-in-chief of summarizes the results of the 2021 international panel votings with respect to locoregional and systemic treatment as a quick news update for our readers and clearly does not intend to replace the official St. Gallen Consensus publication that will follow shortly in .
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http://dx.doi.org/10.1159/000516114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8089428PMC
April 2021

Neratinib as extended adjuvant therapy in patients with copositive early breast cancer: German health technology assessment-driven analyses from the ExteNET study.

Eur J Cancer 2021 Jun 7;150:268-277. Epub 2021 May 7.

LMU University Hospital, Breast Center, Dept. OB&GYN, Marchioninistr. 15, Munich, 81377, Germany. Electronic address:

Background: Neratinib is approved in the European Union for extended adjuvant treatment of human epidermal growth factor receptor 2-positive/hormone receptor-positive (copositive) early breast cancer ≤1 year of completion of prior trastuzumab-based therapy. Here, we report analyses of the hormone receptor-positive subgroup (N = 1631) from the ExteNET trial performed for the German health technology assessment (HTA).

Results: With 2 years of median follow-up, HTA analyses revealed a significant advantage in disease-free survival (DFS) for neratinib vs. placebo (absolute/relative risk reduction: 4.1/48.2%; hazard ratio [HR] [95% confidence interval {CI}]: 0.45 [0.29; 0.69]; p = 0.0002), consistent with distant DFS (absolute/relative risk reduction: 3.1/46.3%; HR [95% CI]: 0.52 [0.32; 0.84]; p = 0.0082). The 5-year follow-up confirmed this outcome.Quality of life analyses did not show clinically relevant differences over all time points. Only at month 1, the Functional Assessment of Cancer Therapy - General total score revealed a statistically relevant difference to the disadvantage of neratinib classified as clinically relevant. The tolerability profile of neratinib was dominated by gastrointestinal events, mainly diarrhoea (all grades: 94.4%; grade III: 39.4%; no systematic antidiarrhoeal prophylaxis), nausea (all grades/grade III: 43.9/1.6%), vomiting (26.6/3.2%), abdominal pain (23.8/1.9%), fatigue (28.1/1.9%) and rash (14.3/0.4%). No cumulative or irreversible toxicities were observed. As shown in the CONTROL study and instituted via a risk management plan, diarrhoea management can reduce frequency, cumulative duration and severity of diarrhoea.

Conclusion: Extended adjuvant neratinib provides a clinically relevant benefit with further incremental reduction of relapse risk in the curative setting. Accordingly, the German HTA authority has granted an added benefit for this new treatment option.
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http://dx.doi.org/10.1016/j.ejca.2021.03.045DOI Listing
June 2021

Immune cell composition and functional marker dynamics from multiplexed immunohistochemistry to predict response to neoadjuvant chemotherapy in the WSG-ADAPT-TN trial.

J Immunother Cancer 2021 May;9(5)

West German Study Group, Moenchengladbach, Germany.

Background: The association of early changes in the immune infiltrate during neoadjuvant chemotherapy (NACT) with pathological complete response (pCR) in triple-negative breast cancer (TNBC) remains unexplored.

Methods: Multiplexed immunohistochemistry was performed in matched tumor biopsies obtained at baseline and after 3 weeks of NACT from 66 patients from the West German Study Group Adjuvant Dynamic Marker-Adjusted Personalized Therapy Trial Optimizing Risk Assessment and Therapy Response Prediction in Early Breast Cancer - Triple Negative Breast Cancer (WSG-ADAPT-TN) trial. Association between CD4, CD8, CD73, T cells, PD1-positive CD4 and CD8 cells, and PDL1 levels in stroma and/or tumor at baseline, week 3 and 3-week change with pCR was evaluated with univariable logistic regression.

Results: Compared with no change in immune cell composition and functional markers, transition from 'cold' to 'hot' (below-median and above-median marker level at baseline, respectively) suggested higher pCR rates for PD1-positive CD4 (tumor: OR=1.55, 95% CI 0.45 to 5.42; stroma: OR=2.65, 95% CI 0.65 to 10.71) and PD1-positive CD8 infiltrates (tumor: OR=1.77, 95% CI 0.60 to 5.20; stroma: OR=1.25, 95% CI 0.41 to 3.84; tumor+stroma: OR=1.62, 95% CI 0.51 to 5.12). No pCR was observed after 'hot-to-cold' transition in PD1-positive CD8 cells. pCR rates appeared lower after hot-to-cold transitions in T cells (tumor: OR=0.26, 95% CI 0.03 to 2.34; stroma: OR=0.35, 95% CI 0.04 to 3.25; tumor+stroma: OR=0.00, 95% CI 0.00 to 1.04) and PD1-positive CD4 cells (tumor: OR=0.60, 95% CI 0.11 to 3.35; stroma: OR=0.22, 95% CI 0.03 to 1.92; tumor+stroma: OR=0.32, 95% CI 0.04 to 2.94). Higher pCR rates collated with 'altered' distribution (levels below-median and above-median in tumor and stroma, respectively) of T cell (OR=3.50, 95% CI 0.84 to 14.56) and PD1-positive CD4 cells (OR=4.50, 95% CI 1.01 to 20.14).

Conclusion: Our exploratory findings indicate that comprehensive analysis of early immune infiltrate dynamics complements currently investigated predictive markers for pCR and may have a potential to improve guidance for individualized de-escalation/escalation strategies in TNBC.
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http://dx.doi.org/10.1136/jitc-2020-002198DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8108653PMC
May 2021

Implementation of Precision Oncology for Patients with Metastatic Breast Cancer in an Interdisciplinary MTB Setting.

Diagnostics (Basel) 2021 Apr 20;11(4). Epub 2021 Apr 20.

Department of Obstetrics and Gynecology and CCC Munich LMU University Hospital, Ludwig Maximilians University (LMU), 81377 Munich, Germany.

The advent of molecular diagnostics and the rising number of targeted therapies have facilitated development of precision oncology for cancer patients. In order to demonstrate its impact for patients with metastatic breast cancer (mBC), we initiated a Molecular Tumor Board (MTB) to provide treatment recommendations for mBC patients who had disease progression under standard treatment. NGS (next generation sequencing) was carried out using the Oncomine multi-gene panel testing system (Ion Torrent). The MTB reviewed molecular diagnostics' results, relevant tumor characteristics, patient's course of disease and made personalized treatment and/or diagnostic recommendations for each patient. From May 2017 to December 2019, 100 mBC patients were discussed by the local MTB. A total 72% of the mBC tumors had at least one molecular alteration (median 2 per case, range: 1 to 6). The most frequent genetic changes were found in the following genes: (19%) and (17%). The MTB rated 53% of these alterations as actionable and treatment recommendations were made accordingly for 49 (49%) patients. Sixteen patients (16%) underwent the suggested therapy. Nine out of sixteen patients (56%; 9% of all) experienced a clinical benefit with a progression-free survival ratio ≥ 1.3. Personalized targeted therapy recommendations resulting from MTB case discussions could provide substantial benefits for patients with mBC and should be implemented for all suitable patients.
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http://dx.doi.org/10.3390/diagnostics11040733DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8074310PMC
April 2021

Update Breast Cancer 2020 Part 5 - Moving Therapies From Advanced to Early Breast Cancer Patients.

Geburtshilfe Frauenheilkd 2021 Apr 14;81(4):469-480. Epub 2021 Apr 14.

Frauenklinik, Universitätsklinikum Augsburg, Augsburg, Germany.

In recent years, significant progress has been made in new therapeutic approaches to breast cancer, particularly in patients with HER2-positive and HER2-negative/hormone receptor-positive (HR+) breast cancer. In the case of HER2-positive tumours, these approaches have included, in particular, treatment with pertuzumab, T-DM1, neratinib and, soon, also tucatinib and trastuzumab deruxtecan (neither of which has yet been authorised in Europe). In patients with HER2-/HR+ breast cancer, CDK4/6 inhibitors and the PIK3CA inhibitor alpelisib are of particular importance. Further novel therapies, such as Akt kinase inhibitors and oral SERDs (selective estrogen receptor down regulators), are already being investigated in ongoing clinical trials. These therapeutic agents are not only being introduced into curative, (neo-)adjuvant therapeutic settings for HER2-positive tumours; a first favourable study on abemaciclib as an adjuvant therapy has now also been published. In patients with triple-negative breast cancer, after many years of negative study results with the Trop-2 antibody drug conjugate (ADC) sacituzumab govitecan, a randomised study has been published that may represent a significant therapeutic advance. This review describes the latest developments in breast cancer subsequent to the ESMO Congress 2020.
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http://dx.doi.org/10.1055/a-1397-7170DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8046519PMC
April 2021

Systemic pro-inflammatory response identifies patients with cancer with adverse outcomes from SARS-CoV-2 infection: the OnCovid Inflammatory Score.

J Immunother Cancer 2021 03;9(3)

Department of Medical Oncology, Catalan Institute of Oncology, University Hospital Josep Trueta, Girona, Spain.

Background: Patients with cancer are particularly susceptible to SARS-CoV-2 infection. The systemic inflammatory response is a pathogenic mechanism shared by cancer progression and COVID-19. We investigated systemic inflammation as a driver of severity and mortality from COVID-19, evaluating the prognostic role of commonly used inflammatory indices in SARS-CoV-2-infected patients with cancer accrued to the OnCovid study.

Methods: In a multicenter cohort of SARS-CoV-2-infected patients with cancer in Europe, we evaluated dynamic changes in neutrophil:lymphocyte ratio (NLR); platelet:lymphocyte ratio (PLR); Prognostic Nutritional Index (PNI), renamed the OnCovid Inflammatory Score (OIS); modified Glasgow Prognostic Score (mGPS); and Prognostic Index (PI) in relation to oncological and COVID-19 infection features, testing their prognostic potential in independent training (n=529) and validation (n=542) sets.

Results: We evaluated 1071 eligible patients, of which 625 (58.3%) were men, and 420 were patients with malignancy in advanced stage (39.2%), most commonly genitourinary (n=216, 20.2%). 844 (78.8%) had ≥1 comorbidity and 754 (70.4%) had ≥1 COVID-19 complication. NLR, OIS, and mGPS worsened at COVID-19 diagnosis compared with pre-COVID-19 measurement (p<0.01), recovering in survivors to pre-COVID-19 levels. Patients in poorer risk categories for each index except the PLR exhibited higher mortality rates (p<0.001) and shorter median overall survival in the training and validation sets (p<0.01). Multivariable analyses revealed the OIS to be most independently predictive of survival (validation set HR 2.48, 95% CI 1.47 to 4.20, p=0.001; adjusted concordance index score 0.611).

Conclusions: Systemic inflammation is a validated prognostic domain in SARS-CoV-2-infected patients with cancer and can be used as a bedside predictor of adverse outcome. Lymphocytopenia and hypoalbuminemia as computed by the OIS are independently predictive of severe COVID-19, supporting their use for risk stratification. Reversal of the COVID-19-induced proinflammatory state is a putative therapeutic strategy in patients with cancer.
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http://dx.doi.org/10.1136/jitc-2020-002277DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7985977PMC
March 2021

Phase II study of metronomic treatment with daily oral vinorelbine as first-line chemotherapy in patients with advanced/metastatic HR+/HER2- breast cancer resistant to endocrine therapy: VinoMetro-AGO-B-046.

J Cancer Res Clin Oncol 2021 Mar 20. Epub 2021 Mar 20.

Department of Gynaecology and Obstetrics, University Medical Centre, Mainz, Germany.

Purpose: Metronomic chemotherapy (MCT) is an increasingly used treatment option in hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) advanced/metastatic breast cancer (MBC) after failure of endocrine-based therapies.

Methods: VinoMetro was a multicentre, open-label, single-arm, phase II study of metronomic oral vinorelbine (VRL; 30 mg/day) as a first-line chemotherapy (CT) in patients with HR+/HER2- MBC after endocrine failure. The primary endpoint was the clinical benefit rate (CBR) at 24 weeks.

Results: Between January 2017 and April 2019, nine patients were enrolled. The CBR was 22.2% (90% confidence interval [CI] 4.1-55.0), p = 0.211. The median progression-free survival (PFS) was 12.0 weeks (95% CI 11.3-12.7). Grade 3-4 adverse events (AEs) occurred in 22.2% of patients. One patient died of febrile neutropenia.

Conclusion: VinoMetro (AGO-B-046) was closed early after nine patients and occurrence of one grade 5 toxicity in agreement with the lead institutional review board (IRB). Metronomic dosing of oral VRL in HR+/HER2- MBC as first-line CT after failure of endocrine therapies showed only limited benefit in this population.

Trial Registration Number And Date Of Registration: ClinicalTrials.gov Identifier: NCT03007992; December 15, 2016.
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http://dx.doi.org/10.1007/s00432-021-03599-2DOI Listing
March 2021

Magnetic resonance imaging and ultrasound for prediction of residual tumor size in early breast cancer within the ADAPT subtrials.

Breast Cancer Res 2021 Mar 18;23(1):36. Epub 2021 Mar 18.

West German Study Group, Ludwig-Weber-Strasse 15, 41061, Moenchengladbach, Germany.

Background: Prediction of histological tumor size by post-neoadjuvant therapy (NAT) ultrasound and magnetic resonance imaging (MRI) was evaluated in different breast cancer subtypes.

Methods: Imaging was performed after 12-week NAT in patients enrolled into three neoadjuvant WSG ADAPT subtrials. Imaging performance was analyzed for prediction of residual tumor measuring ≤10 mm and summarized using positive (PPV) and negative (NPV) predictive values.

Results: A total of 248 and 588 patients had MRI and ultrasound, respectively. Tumor size was over- or underestimated by < 10 mm in 4.4% and 21.8% of patients by MRI and in 10.2% and 15.8% by ultrasound. Overall, NPV (proportion of correctly predicted tumor size ≤10 mm) of MRI and ultrasound was 0.92 and 0.83; PPV (correctly predicted tumor size > 10 mm) was 0.52 and 0.61. MRI demonstrated a higher NPV and lower PPV than ultrasound in hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-positive and in HR-/HER2+ tumors. Both methods had a comparable NPV and PPV in HR-/HER2- tumors.

Conclusions: In HR+/HER2+ and HR-/HER2+ breast cancer, MRI is less likely than ultrasound to underestimate while ultrasound is associated with a lower risk to overestimate tumor size. These findings may help to select the most optimal imaging approach for planning surgery after NAT.

Trial Registration: Clinicaltrials.gov , NCT01815242 (registered on March 21, 2013), NCT01817452 (registered on March 25, 2013), and NCT01779206 (registered on January 30, 2013).
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http://dx.doi.org/10.1186/s13058-021-01413-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7977310PMC
March 2021

Protroca: A Noninterventional Study on Prophylactic Lipegfilgrastim against Chemotherapy-Induced Neutropenia in Nonselected Breast Cancer Patients.

Breast Care (Basel) 2021 Feb 6;16(1):50-58. Epub 2020 Apr 6.

West German Study Group, Mönchengladbach, Germany.

Background: Protroca evaluated the efficacy and safety of primary and secondary prophylaxis of neutropenia with lipegfilgrastim (Lonquex®) in breast cancer patients receiving neoadjuvant or adjuvant chemotherapy (CT).

Patients And Methods: Of the 255 patients enrolled, 248 patients were evaluable for the intent-to-treat (ITT) and 194 patients for the per-protocol set. Primary and secondary end points after lipegfilgrastim treatment were assessed.

Results: Nine patients of the ITT set receiving lipegfilgrastim as primary prophylaxis ( = 222) had febrile neutropenia of grade 3-4 (5 patients) or infection of grade 3-4 (4 patients); 1/26 of those receiving secondary prophylaxis had an event. Dose reductions were performed in 9.5% of the patients. Postponement of cancer CT cycles for >3 days occurred in <15% of patients; 10.8% (92/851 AEs) and 8% (2/25 SAEs) of documented adverse events and serious adverse events, respectively, were related to lipegfilgrastim.

Conclusions: Application of lipegfilgrastim was effective as primary and secondary prophylaxis in the prevention of CT-induced neutropenia in breast cancer.
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http://dx.doi.org/10.1159/000506622DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7923841PMC
February 2021

Stability of person-specific blood-based infrared molecular fingerprints opens up prospects for health monitoring.

Nat Commun 2021 03 8;12(1):1511. Epub 2021 Mar 8.

Department of Physics, Ludwig Maximilian University of Munich, Garching, Germany.

Health state transitions are reflected in characteristic changes in the molecular composition of biofluids. Detecting these changes in parallel, across a broad spectrum of molecular species, could contribute to the detection of abnormal physiologies. Fingerprinting of biofluids by infrared vibrational spectroscopy offers that capacity. Whether its potential for health monitoring can indeed be exploited critically depends on how stable infrared molecular fingerprints (IMFs) of individuals prove to be over time. Here we report a proof-of-concept study that addresses this question. Using Fourier-transform infrared spectroscopy, we have fingerprinted blood serum and plasma samples from 31 healthy, non-symptomatic individuals, who were sampled up to 13 times over a period of 7 weeks and again after 6 months. The measurements were performed directly on liquid serum and plasma samples, yielding a time- and cost-effective workflow and a high degree of reproducibility. The resulting IMFs were found to be highly stable over clinically relevant time scales. Single measurements yielded a multiplicity of person-specific spectral markers, allowing individual molecular phenotypes to be detected and followed over time. This previously unknown temporal stability of individual biochemical fingerprints forms the basis for future applications of blood-based infrared spectral fingerprinting as a multiomics-based mode of health monitoring.
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http://dx.doi.org/10.1038/s41467-021-21668-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7940620PMC
March 2021

Optimal Strategies for Successful Initiation of Neratinib in Patients with HER2-Positive Breast Cancer.

Clin Breast Cancer 2021 Feb 6. Epub 2021 Feb 6.

Department of Medicine, University of California San Francisco Comprehensive Cancer Center, San Francisco, CA.

Neratinib is an irreversible, pan-human epidermal growth factor inhibitor that has shown efficacy across human epidermal growth factor receptor 2 (HER2)-positive breast cancer settings. Neratinib is indicated for use as extended adjuvant therapy for HER2-positive early-stage breast cancer or, in combination with capecitabine, in the treatment of HER2-positive metastatic breast cancer. The primary tolerability concern with neratinib is diarrhea, and severe diarrhea early in treatment can lead to a substantial proportion of patients discontinuing neratinib, which may lead to reduced or nonexistent efficacy. In order to establish a set of treatment recommendations for use of neratinib, on May 12, 2020, an expert panel of oncologists and gastroenterologists met virtually to discuss the role of neratinib in the treatment of patients with HER2-positive breast cancer. The panel reviewed the current data on neratinib, including efficacy across settings and diarrhea management strategies. Based on these data and their clinical experience, the panelists developed a set of recommendations to guide selection of patients for neratinib, implement weekly dose escalation at initiation of therapy, and prophylactically manage diarrhea.
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http://dx.doi.org/10.1016/j.clbc.2021.02.001DOI Listing
February 2021

Pembrolizumab versus investigator-choice chemotherapy for metastatic triple-negative breast cancer (KEYNOTE-119): a randomised, open-label, phase 3 trial.

Lancet Oncol 2021 04 4;22(4):499-511. Epub 2021 Mar 4.

International Breast Cancer Center, Quiron Group, Madrid and Barcelona, Spain; Vall d'Hebron Institute of Oncology, Barcelona, Spain.

Background: Pembrolizumab showed durable antitumour activity and manageable safety in metastatic triple-negative breast cancer in the single-arm KEYNOTE-012 and KEYNOTE-086 trials. In this study, we compared pembrolizumab with chemotherapy for second-line or third-line treatment of patients with metastatic triple-negative breast cancer.

Methods: KEYNOTE-119 was a randomised, open-label, phase 3 trial done at 150 medical centres (academic medical centres, community cancer centres, and community hospitals) in 31 countries. Patients aged 18 years or older, with centrally confirmed metastatic triple-negative breast cancer, Eastern Cooperative Oncology Group performance status of 0 or 1, who had received one or two previous systemic treatments for metastatic disease, had progression on their most recent therapy, and had previous treatment with an anthracycline or taxane were eligible. Patients were randomly assigned (1:1) using a block method (block size of four) and an interactive voice-response system with integrated web-response to receive intravenous pembrolizumab 200 mg once every 3 weeks for 35 cycles (pembrolizumab group), or to single-drug chemotherapy per investigator's choice of capecitabine, eribulin, gemcitabine, or vinorelbine (60% enrolment cap for each; chemotherapy group). Randomisation was stratified by PD-L1 tumour status (positive [combined positive score (CPS) ≥1] vs negative [CPS <1]) and history of previous neoadjuvant or adjuvant treatment versus de-novo metastatic disease at initial diagnosis. Primary endpoints were overall survival in participants with a PD-L1 combined positive score (CPS) of 10 or more, those with a CPS of 1 or more, and all participants; superiority of pembrolizumab versus chemotherapy was tested in all participants only if shown in those with a CPS of one or more. The primary endpoint was analysed in the intention-to-treat population; safety was analysed in the all-subjects-as-treated population. This Article describes the final analysis of the trial, which is now completed. This trial is registered with ClinicalTrials.gov, number NCT02555657.

Findings: From Nov 25, 2015, to April 11, 2017, 1098 participants were assessed for eligibility and 622 (57%) were randomly assigned to receive either pembrolizumab (312 [50%]) or chemotherapy (310 [50%]). Median study follow-up was 31·4 months (IQR 27·8-34·4) for the pembrolizumab group and 31·5 months (27·8-34·6) for the chemotherapy group. Median overall survival in patients with a PD-L1 CPS of 10 or more was 12·7 months (95% CI 9·9-16·3) for the pembrolizumab group and 11·6 months (8·3-13·7) for the chemotherapy group (hazard ratio [HR] 0·78 [95% CI 0·57-1·06]; log-rank p=0·057). In participants with a CPS of 1 or more, median overall survival was 10·7 months (9·3-12·5) for the pembrolizumab group and 10·2 months (7·9-12·6) for the chemotherapy group (HR 0·86 [95% CI 0·69-1·06]; log-rank p=0·073). In the overall population, median overall survival was 9·9 months (95% CI 8·3-11·4) for the pembrolizumab group and 10·8 months (9·1-12·6) for the chemotherapy group (HR 0·97 [95% CI 0·82-1·15]). The most common grade 3-4 treatment-related adverse events were anaemia (three [1%] patients in the pembrolizumab group vs ten [3%] in the chemotherapy group), decreased white blood cells (one [<1%] vs 14 [5%]), decreased neutrophil count (one [<1%] vs 29 [10%]), and neutropenia (0 vs 39 [13%]). 61 (20%) patients in the pembrolizumab group and 58 (20%) patients in the chemotherapy group had serious adverse events. Three (<1%) of 601 participants had treatment-related adverse events that led to death (one [<1%] in the pembrolizumab group due to circulatory collapse; two [1%] in the chemotherapy group, one [<1%] due to pancytopenia and sepsis and one [<1%] haemothorax).

Interpretation: Pembrolizumab did not significantly improve overall survival in patients with previously treated metastatic triple-negative breast cancer versus chemotherapy. These findings might inform future research of pembrolizumab monotherapy for selected subpopulations of patients, specifically those with PD-L1-enriched tumours, and inform a combinatorial approach for the treatment of patients with metastatic triple-negative breast cancer.

Funding: Merck Sharp & Dohme.
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http://dx.doi.org/10.1016/S1470-2045(20)30754-3DOI Listing
April 2021

CDK4/6 inhibitors in HR+/HER2- advanced/metastatic breast cancer: a systematic literature review of real-world evidence studies.

Future Oncol 2021 Jun 5;17(16):2107-2122. Epub 2021 Mar 5.

CRG-EVERSANA Canada, Inc., Burlington, ON L7N 3H8, Canada.

This review aims to qualitatively summarize the published real-world evidence (RWE) for CDK4/6 inhibitors (CDK4/6i) approved for treating HR+, HER2-negative advanced/metastatic breast cancer (HR+/HER2- a/mBC). A systematic literature review was conducted to identify RWE studies of CDK4/6i in HR+/HER2- a/mBC published from 2015 to 2019. This review identified 114 studies, of which 85 were only presented at scientific conferences. Most RWE studies investigated palbociclib and demonstrated improved outcomes. There are limited long-term and comparative data between CDK4/6i and endocrine monotherapy, and within the CDK4/6i class. Available RWE suggests that CDK4/6i are associated with improved outcomes in HR+/HER2- a/mBC, although additional studies with longer follow-up periods are needed.
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http://dx.doi.org/10.2217/fon-2020-1264DOI Listing
June 2021

Reply to K. Hashimoto and A. Shimomura.

J Clin Oncol 2021 May 25;39(13):1507-1508. Epub 2021 Feb 25.

Stephen R. D. Johnston, MD, PhD, Royal Marsden NHS Foundation Trust, London, United Kingdom; Nadia Harbeck, MD, PhD, Breast Center, Department of Obstetrics and Gynecology, LMU University Hospital, Munich, Germany; Masakazu Toi, MD, PhD, Kyoto University Hospital, Kyoto, Japan; Miguel Martin, MD, PhD, Hospital General Universitario Gregorio Marañon, Universidad Complutense, Ciberonc, GEICAM, Madrid, Spain; Joyce O'Shaughnessy, MD, Baylor University Medical Center, Texas Oncology, US Oncology, Dallas, TX; and Priya Rastogi, MD, University of Pittsburgh, NSABP Foundation, Pittsburgh, PA.

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http://dx.doi.org/10.1200/JCO.20.03477DOI Listing
May 2021

Neoadjuvant and adjuvant end-points in health technology assessment in oncology.

Eur J Cancer 2021 Apr 19;147:40-50. Epub 2021 Feb 19.

Department of Hematology, Oncology and Tumour Immunology, Charité Campus Benjamin Franklin, University Medicine Berlin, 12200 Berlin, Germany. Electronic address:

Health technology assessment (HTA) of clinical and economic value of a new intervention is an integral step in providing the access of patients to innovative cancer care and treatment. Overall survival (OS) is the preferred criterion for demonstrating the therapeutic efficacy in HTA given its direct clinical and patient relevance. However, with often long life expectancy of patients with early cancer, analysis of OS becomes less practical. Partially due to this reason, pathological complete response (pCR) and time-to-event end-points like disease-free survival are frequently incorporated into the pivotal clinical trials in the neoadjuvant and adjuvant settings. However, there exists a discrepancy between different national HTA bodies regarding the acknowledgement of patient relevance of these end-points. In this article, we analysed the perspectives of patients on different aspects of end-points used in clinical trials in early cancer. Gathered evidence strongly suggests that complete tumour eradication and reduced risk of recurrence provide important psychological benefits thus signifying that pCR and time-to-event end-points are directly relevant to patients. Additionally, we reviewed opinions on patient relevance of neoadjuvant and adjuvant therapy end-points adopted by HTA bodies during the recent evaluations. We found that improvements in end-points used in the adjuvant setting were commonly considered as valuable to patients. In contrast, opinions on patient relevance of neoadjuvant therapy end-points varied between the national HTA bodies. Universal acknowledgement of patient relevance of therapeutic end-points for early cancer by HTA bodies is necessary to balance the inequality in uptake of innovative therapies into national healthcare systems.
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http://dx.doi.org/10.1016/j.ejca.2021.01.006DOI Listing
April 2021

Early response by MR imaging and ultrasound as predictor of pathologic complete response to 12-week neoadjuvant therapy for different early breast cancer subtypes: Combined analysis from the WSG ADAPT subtrials.

Int J Cancer 2021 Feb 3. Epub 2021 Feb 3.

West German Study Group, Moenchengladbach, Germany.

We evaluated the role of early response after 3 weeks of neoadjuvant treatment (NAT) assessed by ultrasound (US), magnetic resonance imaging (MRI) and Ki-67 dynamics for prediction of pathologic complete response (pCR) in different early breast cancer subtypes. Patients with HR+/HER2+, HR-/HER2- and HR-/HER2+ tumors enrolled into three neoadjuvant WSG ADAPT subtrials underwent US, MRI and Ki-67 assessment at diagnosis and after 3 weeks of NAT. Early response was defined as complete or partial response (US, MRI) and ≥30% proliferation decrease or <500 invasive tumor cells (Ki-67). Predictive values and area under the receiver operating characteristic (AUC) curves for prediction of pCR (ypT0/is ypN0) after 12-week NAT were calculated. Two hundred twenty-six had MRI and 401 US; 107 underwent both MRI and US. All three methods yielded a similar AUC in HR+/HER2+ (0.66-0.67) and HR-/HER2- tumors (0.53-0.63), while MRI and Ki-67 performed better than US in HR-/HER2+ tumors (0.83 and 0.79 vs 0.56). Adding MRI+/-Ki-67 increased AUC of US in HR-/HER2+ tumors to 0.64 to 0.75. MRI and Ki-67 demonstrated highest sensitivity in HR-/HER2- (0.8-1) and HR-/HER2+ tumors (1, both). Negative predictive value was similar for all methods in HR+/HER2+ (0.71-0.74) and HR-/HER2- tumors (0.85-1), while it was higher for MRI and Ki-67 compared to US in HR-/HER2+ subtype (1 vs 0.5). Early response assessed by US, MRI and Ki-67 is a strong predictor for pCR after 12-week NAT. Strength of pCR prediction varies according to tumor subtype. Adding MRI+/-Ki-67 to US did not improve pCR prediction in majority of our patients.
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http://dx.doi.org/10.1002/ijc.33495DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8048810PMC
February 2021

Expected Medium- and Long-Term Impact of the COVID-19 Outbreak in Oncology.

JCO Glob Oncol 2021 02;7:162-172

Medical Oncology, CHU Sart Tilman Liège and University of Liège, Liège, Belgium.

Purpose: The COVID-19 pandemic has affected healthcare systems globally, leading to reorganization of medical activities. We performed an international survey aimed to investigate the medium- and long-term impact on oncology units.

Materials And Methods: An 82-item survey was distributed from June 17 to July 14, 2020 among medical oncologists worldwide.

Results: One hundred nine medical oncologists from 18 countries in Europe (n = 93), United States (n = 5), and Latin America (n = 11) answered the survey. A systematic tracing of COVID-19-positive patients was continued in the postacute phase by 77.1% of the centers; 64.2% of the respondents participated in a local registry and 56% in international or national registries of infected patients. Treatment adaptations were introduced, and surgery was the most affected modality being delayed or canceled in more than 10% of patients in 34% of the centers, whereas early cessation of palliative treatment was reported in 32.1% of the centers; 64.2% of respondents reported paying attention to avoid undertreatments. The use of telemedicine has been largely increased. Similarly, virtual tools are increasingly used particularly for medical education and international or national or multidisciplinary meetings. 60.6% of the participants reduced clinical activity, and 28.4% compensated by increasing their research activity. Significant reduction of clinical trial activities is expected in 37% of centers this year. The well-being of healthcare staff would not recover by the end of the year according to 18% of the participants.

Conclusion: The COVID-19 outbreak has had a major impact on oncologic activity, which will persist in the future, irrespective of geographical areas.
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http://dx.doi.org/10.1200/GO.20.00589DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8081548PMC
February 2021

European Breast Cancer Conference 12, October 2-3, 2020: Interview with the Chairs.

Breast Care (Basel) 2020 Dec 30;15(6):594-598. Epub 2020 Oct 30.

IOB Institute of Breast Cancer, Quiron Group, Barcelona, Spain.

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http://dx.doi.org/10.1159/000512355DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7768148PMC
December 2020

Risk-adapted adjuvant therapy of luminal early breast cancer in 2020.

Authors:
Nadia Harbeck

Curr Opin Obstet Gynecol 2021 02;33(1):53-58

Breast Center, Dept OB&GYN and CCCMunich, LMU University Hospital, Munich, Germany.

Purpose Of Review: The present review summarizes recent original publications addressing the topic of risk-adapted adjuvant therapy in early breast cancer (EBC). As neoadjuvant therapy has become a standard for triple negative and HER2+ EBC, it focusses on luminal EBC.

Recent Findings: Gene expression assays have become standard of care in luminal EBC, at least for patients with node negative disease. Two prospective randomized clinical trials, TAILORx (Oncotype DX) and MINDACT (MammaPrint) have presented additional analyses underlining the clinical utility of the tests. In times of COVID-19, immunohistochemically determined ER, PR, and Ki67 and early Ki67 response to endocrine therapy can be used to safely allocate patients for preoperative endocrine therapy and delay surgeries if resources are scarce. In patients with luminal high-risk disease, adding a CDK 4/6 inhibitor (abemaciclib) improves patient outcome already after short-term follow-up.

Summary: Determination of recurrence risk will remain important in luminal EBC for optimal therapy decisions. In the future, risk-adapted treatment concepts will include decision making for chemotherapy but also for endocrine-based approaches.
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http://dx.doi.org/10.1097/GCO.0000000000000679DOI Listing
February 2021

The run-in phase of the prospective WSG-ADAPT HR+/HER2- trial demonstrates the feasibility of a study design combining static and dynamic biomarker assessments for individualized therapy in early breast cancer.

Ther Adv Med Oncol 2020 23;12:1758835920973130. Epub 2020 Nov 23.

Breast Center, Department OB&GYN and CCCLMU, LMU University Hospital, Marchioninistrasse 15, Munich DE-81377, Germany.

Background: Endocrine sensitivity, as determined by response of the proliferation marker Ki-67 to short-term preoperative endocrine therapy (ET), is currently not included in adjuvant treatment decisions in hormone receptor (HR)+/human epidermal growth factor receptor 2 (HER2)- breast cancer (BC).

Methods: The prospective WSG-ADAPT HR+/HER2- trial included patients with N0/N1 early BC who were candidates for adjuvant chemotherapy based on clinical-pathological criteria alone. The trial utilized a genomic assessment [the Recurrence Score (RS)] plus endocrine sensitivity testing to guide treatment. All patients received 3 (±1) weeks of preoperative induction ET. According to protocol, patients with RS 0-11 or RS 12-25 plus endocrine proliferation response (EPR, post-induction Ki-67 ⩽ 10%) were to be spared adjuvant chemotherapy.

Results: The ADAPT HR+/HER2- trial run-in phase included 407 patients with baseline RS, of whom 386 (median age: 54 years) had complete data for Ki-67 at both baseline and post-induction. RS distribution: 23.1% RS 0-11, 58.3% RS 12-25, and 18.7% RS 26-100. EPR occurred in 84.3%, 76.0%, and 36.1% of these RS groups, respectively. Differences in EPR proportions (RS 26-100 others, RS 0-11 others) were significant (both  < 0.001); Ki-67 quotients were higher for RS 26-100 ( = 0.02, Mann-Whitney). In premenopausal women ( = 146, mostly tamoxifen-treated), median quotient of Ki-67 level (post/pre) was significantly higher than in postmenopausal women ( = 222, mostly aromatase-inhibitor treated; 0.67 0.25,  < 0.001). EPR was significantly associated with baseline estrogen-receptor status as determined by immunohistochemistry ( = 0.002) or real-time polymerase chain reaction ( < 0.001). Also, a strong correlation was observed between RS measured pre- and post-ET (R = 0.7,  = 181).

Conclusions: This phase of the WSG-ADAPT HR+/HER2- trial confirms trial design estimates of RS and EPR. It indicates that the ADAPT concept of combining static and dynamic biomarker assessment for individualized therapy decisions in early BC is feasible using the EPR criterion post-induction Ki-67 ⩽ 10%.

Clinicaltrialsgov Identifier: NCT01779206.
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http://dx.doi.org/10.1177/1758835920973130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7692353PMC
November 2020

NGS-guided precision oncology in metastatic breast and gynecological cancer: first experiences at the CCC Munich LMU.

Arch Gynecol Obstet 2021 05 4;303(5):1331-1345. Epub 2020 Dec 4.

Department of Obstetrics and Gynecology and CCC Munich LMU University Hospital, Ludwig Maximilians University (LMU), Munich, Germany.

Purpose: Comprehensive genomic profiling identifying actionable molecular alterations aims to enable personalized treatment for cancer patients. The purpose of this analysis was to retrospectively assess the impact of personalized recommendations made by a multidisciplinary tumor board (MTB) on the outcome of patients with breast or gynecological cancers, who had progressed under standard treatment. Here, first experiences of our Comprehensive Cancer Center Molecular Tumor Board are reported.

Methods: All patients were part of a prospective local registry. 95 patients diagnosed with metastatic breast cancer or gynecological malignancies underwent extended molecular profiling. From May 2017 through March 2019, the MTB reviewed all clinical cases considering tumor profile and evaluated molecular alterations regarding further diagnostic and therapeutic recommendations.

Results: 95 patients with metastatic breast or gynecological cancers were discussed in the MTB (68% breast cancer, 20% ovarian cancer, 5% cervical cancer, 3% endometrial cancer and 4% others). Genes with highest mutation rate were PIK3CA and ERBB2. Overall, 34 patients (36%) received a biomarker-based targeted therapy recommendation. Therapeutic recommendations were implemented in nine cases; four patients experienced clinical benefit with a partial response or disease stabilization lasting over 4 months.

Conclusion: In the setting of a multidisciplinary molecular tumor board, a small but clinically meaningful group of breast and gynecological cancer patients benefits from comprehensive genomic profiling. Broad and successful implementation of precision medicine is complicated by patient referral at late stage disease and limited access to targeted agents and early clinical trials.

Trial Registration Number: 284-10 (03.05.2018).
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http://dx.doi.org/10.1007/s00404-020-05881-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8053190PMC
May 2021

Metastatic Breast Cancer: Is There a Differential Therapy Efficacy between Visceral and Non-Visceral Metastatic Breast Cancer?

Breast Care (Basel) 2020 Oct 4;15(5):527-533. Epub 2019 Dec 4.

Department of Obstetrics and Gynecology, Breast Center, University Hospital, LMU Munich, Munich, Germany.

Purpose: Differential efficacy of newly registered therapies in subgroups of metastatic breast cancer (MBC) is an important consideration for subsequent use in clinical practice. Unfortunately, such subgroup analyses often are exploratory and rarely statistically adequately powered and may thus be misleading. This analysis aimed to explore a potentially different treatment response to i.v. therapies between visceral and non-visceral MBC.

Methods: In a systematic literature analysis (PubMed) comprising phase III registration studies for MBC from 1994 to 2014, differences in outcome were evaluated regarding progression-free survival, time to progression, overall survival (OS), and visceral versus non-visceral disease. The impact of HER2 and hormone receptor status was also considered. A total of 16 studies comprising 13,083 patients were selected by considering the information given in the medical product's professional information and the decision of the US Food and Drug Administration or the European Medicine Agency for approval of the respective therapeutic agents now used in the treatment of MBC.

Results: No statistically significant differences regarding treatment response and therapy benefit were found in MBC patients with visceral versus non-visceral metastases based on reported hazard ratios and confidence intervals in registration trials. Interesting but nonsignificant differences were found regarding a distinct therapy benefit regarding different metastasis locations in 4 studies.

Conclusion: For targeted i.v. therapies based on biomarker selection, there is a trend - although not significant - toward a benefit (OS) from combination therapies favoring visceral disease. However, at the present time, metastasis localization should not be used as a predictive marker for choice of systemic therapy in MBC.
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http://dx.doi.org/10.1159/000504527DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7650101PMC
October 2020

STAT3 activation in HER2-positive breast cancers: Analysis of data from a large prospective trial.

Int J Cancer 2021 Mar 23;148(6):1529-1535. Epub 2020 Nov 23.

Institut Jules Bordet, Université Libre de Bruxelles (U.L.B), Brussels, Belgium.

The JAK/STAT3 signaling pathway may be aberrantly activated and have various and conflicting roles in breast cancer. The current study explored prognostic implications of activated STAT3 in human epidermal growth factor receptor 2 (HER2)-positive primary breast cancers in the context of a large prospective study (ALTTO). Activated STAT3 was determined by immunohistochemical analysis of STAT3 phosphorylation (Y705) performed on the primary tumors. This analysis evaluated whether patients with activated STAT3 had disease-free survival (DFS) and overall survival (OS) different from patients without activated STAT3. A total of 5694 patients out of the 8381 patients enrolled in ALTTO were included in this analysis (67.9%), and 2634 of them (46%) had evidence of STAT3 activation (minimum tumor Allred score ≥2). The median follow-up was 6.93 years (6.85-6.97 years), at the end of which 1035 (18.18%) and 520 (9.13%) patients experienced DFS and OS events, respectively. Patients with STAT3 activation experienced improved DFS compared to those without it (multivariable hazard ratio [HR], 0.84; 95% confidence interval [CI] 0.74-0.95; P = .006). There were no group differences in OS (multivariable HR, 0.92; 95% CI 0.78-1.10; P = .37). This effect was limited to ER-positive tumors. In conclusion, these findings support the role of STAT3 activation as a marker of favorable outcome in ER-positive/HER2-positive breast cancer patients.
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http://dx.doi.org/10.1002/ijc.33385DOI Listing
March 2021

Interleukin-6 trans-signaling is a candidate mechanism to drive progression of human DCCs during clinical latency.

Nat Commun 2020 10 5;11(1):4977. Epub 2020 Oct 5.

Department of Pathology, University of Regensburg, 93053, Regensburg, Germany.

Although thousands of breast cancer cells disseminate and home to bone marrow until primary surgery, usually less than a handful will succeed in establishing manifest metastases months to years later. To identify signals that support survival or outgrowth in patients, we profile rare bone marrow-derived disseminated cancer cells (DCCs) long before manifestation of metastasis and identify IL6/PI3K-signaling as candidate pathway for DCC activation. Surprisingly, and similar to mammary epithelial cells, DCCs lack membranous IL6 receptor expression and mechanistic dissection reveals IL6 trans-signaling to regulate a stem-like state of mammary epithelial cells via gp130. Responsiveness to IL6 trans-signals is found to be niche-dependent as bone marrow stromal and endosteal cells down-regulate gp130 in premalignant mammary epithelial cells as opposed to vascular niche cells. PIK3CA activation renders cells independent from IL6 trans-signaling. Consistent with a bottleneck function of microenvironmental DCC control, we find PIK3CA mutations highly associated with late-stage metastatic cells while being extremely rare in early DCCs. Our data suggest that the initial steps of metastasis formation are often not cancer cell-autonomous, but also depend on microenvironmental signals.
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http://dx.doi.org/10.1038/s41467-020-18701-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7536220PMC
October 2020