bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical value of kinase Aurora-A serum level determination in patients with breast cancer qualified for neoadjuvant chemotherapy: Pilot study.
Authors: Kotowicz Beata , Winter Pawel , Fuksiewicz Małgorzata , Jagiello-Gruszfeld Agnieszka I. , Pogoda Katarzyna , Nowecki Zbigniew , Kowalska Maria
Published: May 2020

e12627

Background: Aurora A (AURKA) is serine/threonine kinase that plays a regulatory role in mitosis and multiple signaling pathways. Overexpression of AURKA has been found in many solid tumors including breast cancer. It also has been found to be a prognostic marker indicating resistance to taxane treatment and poor prognosis in ER positive breast cancer. The aim of this study is to assess clinical value of Aurora-A serum level determination in patients with breast cancer qualified for neoadjuvant chemotherapy. Methods: 60 patients with confirmed breast cancer before treatment were qualified for the study, aged 31-77 (median 52 years), including 30 premnopausal and 30 pomenopausal. The control group consisted of 30 healthy women aged 20-80 (median 53 years). Clinical and pathological features were determined in a selected group of patients with breast cancer who subsequently underwent preoperative chemotherapy, i.e. tumor size (T), lymph node status (N), presence of distant metastases (M), estrogen receptor status (ER) and progesterone (PgR), HER2 receptors and Ki 67 proliferative index. The blood serum of the examined patients and healthy women was determined by the enzyme-linked ELISA method in doublets of the AURKA biomarker concentration. Mann-Whitney test and ROC curve analysis were used for statistical calculations. Results: No significant differences were found between the concentrations of AURKA in breast cancer patients and in the control group. In both analyzed groups there were no significant differences in biomarker levels depending on the menopausal status. When assessing the relationship between AURKA concentrations and clinical-pathological features, significant differences were found depending on the state of the lymph nodes (N0 vs N1 + N2) (p = 0.006). There was no correlation between the concentrations of the tested biomarker and the tumor size (T), the state of receptors and the Ki67 index. In patients with a lack of receptors (triple negative vs others), higher levels of Aurora A (p = 0.06) in the blood serum were observed at the level of the statistical trend. Conclusions: The preliminary results obtained indicate the potential usefulness of determining the concentration of the new biomarker Aurora A in the blood serum of patients with breast cancer. The research is continuing.
Neoadjuvant chemotherapy regimens for triple-negative breast cancer: Insights from network meta-analysis.
Authors: Miyashita Hirotaka , Cruz Christina , Malamud Stephen C.
Published: May 2020

e12635

Background: The best regimen for neoadjuvant chemotherapy for triple-negative breast cancer (TNBC) is unknown. Recent studies have shown promising data that adding carboplatin improves the rate of pathological complete response (pCR) in TNBC). Therefore, we performed a network meta-analysis to define the overall most effective neoadjuvant systemic therapy for TNBC. Methods: We searched MEDLINE, Cochrane Library, and EMBASE from inception to December 2019 for studies comparing the efficacy of different neoadjuvant regimens in patients with TNBC. We performed a network meta-analysis comparing the regimens in the selected studies using the random-effects model. We focused on anthracycline (A), bevacizumab (B), everolimus (E), and platinum salts (Pl) because these are the medications commonly added to taxane based regimens. All studies contained a taxane regimen. We analyzed the rate of pCR (ypT0/is, N0) and the incidence of grade 3-4 neutropenia, thrombocytopenia, nausea/vomiting, and diarrhea. Results: We identified a total of 13 randomized control trials for this analysis. We compared eight different classes of regimens. We found that regimens containing Pl were significantly superior to Pl non-containing regimens for the rate of pCR. (risk ratio (RR) for pCR [95% confidence interval (CI)]: 1.66 [1.19-2.31], 1.37 [1.14-1.64], and 1.36 [1.14-1.62] for no medications of special interest vs Pl, A vs A+Pl, and A+B vs A+B+Pl, respectively). Regimens containing B were associated with a significantly better rate of pCR. (RR for pCR [95% CI]: 1.24 [1.06-1.46] and 1.23 [1.01-1.51] for A vs A+B and A+Pl vs A+B+Pl, respectively) In contrast, adding A into the regimen did not improve the rate of pCR. In the safety analysis, regimens containing Pl were associated with a significantly higher incidence of grade 3-4 neutropenia and thrombocytopenia. Regimens containing B showed a higher incidence of grade 3-4 nausea/vomiting, and diarrhea. Conclusions: For TNBC, adding Pl or B into the neoadjuvant therapy regimen brings about a higher pCR rate, though they are associated with an increase in hematologic or gastrointestinal complications. The benefit of adding A to the neoadjuvant chemotherapy regimen for TNBC is not apparent.
Comprehensive analysis of long noncoding RNA expression in circulation of breast cancer patients on neoadjuvant therapy.
Authors: Krastev Boris , Timcheva Constanta , Valev Spartak , Zhbantov Georgi , Stoykov Ivaylo , Stamenov Georgi
Published: May 2020

e12644

Background: Though long considered “nonfunctional”, recent evidence is growing that non-coding RNAs, including long non-coding RNAs (lncRNAs), have an active role in tumor biology, mainly as gene expression regulators. Breast cancer is heterogeneous in nature and locally advanced cases are distinct entity in terms of curability. Being borderline between early and metastatic disease, long-term outcome here strongly depends on the efficacy of systemic therapy. To the best of our knowledge, no study has yet investigated global changes of circulating lncRNAs in this patient population during preoperative (neoadjuvant) treatment. Methods: We conducted a small transcriptomic trial on 10 locally advanced breast cancer patients, assessing lncRNA and messenger RNA (mRNA) expression in plasma samples before (S1) and after (S2) initiation of neoadjuvant therapy. Next-generation sequencing was performed with differential gene expression analysis between S1 and S2 groups. We assessed co-expression between lncRNAs and mRNAs, identifying mRNAs whose transcription was potentially regulated by lncRNAs, i.e. “lncRNA target genes”. In order to elucidate biological roles of these target mRNAs, we performed gene ontology (GO) and pathway analysis (Kyoto Encyclopedia of Genes and Genomes, KEGG). Results: 394 lncRNAs and 1085 mRNAs demonstrated statistically significant difference in expression between pretreatment and posttreatment samples. Co-expression analysis revealed positive correlation between 25 lncRNAs and 25 mRNAs located in cis, while potential trans interactions exceeded 105. GO evaluation of lncRNA target genes was significant for 44 terms: 28 for biological process (BP), 9 for cellular component (CC) and 7 for molecular function (MF). The most annotated terms for BP, MF and CC were respectively biosynthetic process, DNA-binding transcription factor activity and nucleus. KEGG analysis showed that 105 of 201 analyzed pathways were statistically significant with most prominent being pathways in cancer and transcriptional misregulation in cancer. Conclusions: Despite limited in size, present study provides broad view on transcriptional landscape in blood circulation, interrogating in vivo dynamics of systemic gene expression during neoadjuvant breast cancer treatment. It demonstrates that substantial number of circulating lncRNAs could be up- or downregulated in the course of therapy and this has the potential to control protein-coding genes that are tightly implicated in cancer biology.
SimBioSys TumorScope: Spatio-temporal modeling of the tumor microenvironment to predict chemotherapeutic response.
Authors: Cole John A , Peterson Joseph R , Earnest Tyler M , Hallock Micahel J , Pfeiffer John R , Pandey Tushar , Braun Eduardo
Published: May 2020

e12650

Background: One of the most important sources of variability affecting each patient’s response to neoadjuvant chemotherapy (NACT) is drug and nutrient perfusion, The SimBioSys TumorScope is a computational decision-support system that is designed to predict the flow of drugs and nutrients throughout the tumor microenvironment, and the subsequent response of the tumor to treatment. By enabling healthcare providers to simulate a range of different standard-of-care treatment regimens in a realistic 3D model of each patient’s tumor, providers can predict which treatments are most effective, and provide the best possible care for their patients. Methods: SimBioSys TumorScope implements a multi-scale simulation technology that couples several biophysical and biochemical models in order to predict how individual patients' tumors respond to NACT. The simulations explicitly track the 3D morphology of the tumor and surrounding tissues (based on MRI images), as well as the concentrations of key nutrients and drugs as they change over time. At each location within the 3D model, these concentrations are used to predict cell growth and death rates. As different regions of the tumor grow or die, its macroscopic shape changes. Results: SimBioSys TumorScope was retrospectively applied to over 300 breast cancer patients that received NACT. Simulations were initialized with pre-treatment MRI data, and run through the entirety of each patient's specified treatment regimen. Predicted changes in tumor volume and longest dimension were then compared against measured values at several time-points after initiation of therapy, yielding Pearson correlations of over 0.93 for both. Work is underway to extend the technology to lung tumors; early results show very different metabolic behaviors from those of breast tumors, and significantly less response to treatment overall. Conclusions: Through accurate spatio-temporal modeling of drug and nutrient perfusion, metabolic behavior, and the physico-chemical interactions that arise between tissues, the SimBioSys TumorScope for Breast Cancer can accurately predict the response of patients treated with NACT.
Impact of malnutrition and anemia at diagnosis in both: Pathological response and tumor-infiltrating-lymphocytes post neoadjuvant chemotherapy.
Authors: Roque Katia MERCEDES , Galvez Nino Marco , Castaneda Altamirano Carlos Arturo , Castillo Garcia Miluska , Sanchez Joselyn , Bernabe Luis A. , Fuentes Hugo Alejandro , Sandival Gustavo , Cotrina José M. , Dunstan Jorge Antonio , Abugattas Julio , Mantilla Raúl , De La Cruz Miguel , Gomez Henry Leonidas
Published: May 2020

e12654

Background: The response after neoadjuvant chemotherapy (NAC) is the main prognostic factor in breast cancer (BC), likewise, malnutrition, anemia and systemic inflammation have also been associated to prognosis in breast cancer. We evaluated the association between pathological response (PR) and tumor infiltrating lymphocytes (TILs) post NAC with nutritional predictors as body mass index (BMI), prognostic nutritional index (PNI), anemia and neutrophil/lymphocyte index (N/L). Methods: This is a retrospective analysis of women diagnosed with BC between 2006 to 2017 at Instituto Nacional de Enfermedades (INEN) who received NAC. Pathological response was classified through residual cancer burden (RCB) and TILs post NAC which were prospectively evaluated by a pathologist. Clinical and pathological features as well as survival status were obtained from patient files. Results: We identified 439 women with BC who received NAC. Median age was 49 years, histological grade 3 was found in 245 patients (55.8%) and stage IIIB was the most frequent at diagnosis with 257 patients (58.5%). Luminal B subtype was the most frequent (43.7%). Rate of pCR was 10.5% and median TILs post NAC was 20%. About nutritional predictors, we use the median as a cutoff to discriminate between high and low values, for BMI was 27.5, for PNI was 56, for hemoglobin was 13.2 and for NLR was 1.84. There was no association for TILs post NAC with BMI (p = 0.38), PNI (p = 0.057) and hemoglobin (p = 0.43). We found a positive association between ILN and TILs post NAC (p = 0.001). On the other hand, we don’t found association for RCB with BMI (p = 0.45), PNI (p = 0.641), ILN (p = 0.2) and hemoglobin (p = 0.15). In the multivariate analysis, only RCB was an independent predictor for DFS (95 % CI, 87-100.5; p = 0.00001) and OS (95 % CI, 101.8-114.1; p = 0.00001). There was no association between BMI, PNI, ILN and anemia with OS and DFS. For the TILs post NAC there was a tendency to association with DFS (p = 0.07) and OS (p = 0.07). Conclusions: There are association between neutrophil/lymphocyte index with TILs after NAC. There was no association between nutritional and systemic predictors with long-term outcomes. The pathologic response is a biomarker for predicting the long-term outcomes of breast cancer patients.
Neoadjuvant chemotherapy in locally advanced breast cancer: Clinicopathological characteristics and correlation with pathological complete response.
Authors: Choudhary Priyanshu , Gogia Ajay , Deo Svs , Mathur Sandeep , Sharma Dayanand
Published: May 2020

e12658

Background: The data regarding incidence, response rates to neoadjuvant chemotherapy (NACT) and factors affecting pathological complete response (pCR) rate in locally advanced breast cancer (LABC) patients are lacking from India. Methods: This ambispective study was carried out at B.R.A., I.R.C.H, AIIMS, New Delhi, in between period of January 2013 to December 2019. We screened 1500 cases of breast cancer who presented to our institute and found 600 cases to be LABC,425 patients were started on NACT, 284 had undergone surgery and were included in our analysis. Results: The median age of diagnosis was 46 years (range 24-72years). Fifty four percent cases were postmenopausal, 54% had a left sided cancer,45 % right sided cancer,1 % had bilateral breast cancer. The median duration of symptoms was 5 months. The clinical stage according to AJCC staging system was Stage IIB – 11%(32), IIIA -21 % (58), IIIB- 60%(169) and IIIC- 8%(24) .Sixty five percent(186) cases presented with clinical skin involvement and 80% (228) patients has clinical node positivity.In our cohort 52% (148) cases were hormone positive (ER/PR positive), 42 %(119) cases were HER2/neu positive, 30%(84) were triple negative breast cancer (TNBC), 23 % (67) were positive for ER/PR and HER2/neu. Ninety percent of the cases were able to receive the planned neoadjuvant treatment before surgery. Post NACT 83% cases had a modified radical mastectomy (MRM) and 17% were able to undergo breast conserving surgery (BCS).Overall pCR was achieved in 59(21%) cases, 17% in hormone positive cases, 25% in HER2/neu positive cases (30% in cases receiving HER2/neu directed therapy vs 20% in cases who didn’t receive HER2 /neu directed therapy) and 27% in TNBC cases. During the study period 54 cases (19%) had relapsed,8 cases (3%) had a local relapse and a 46 cases (16%) had a systemic relapse. Grade ¾ toxicity occurred in 25 % cases, the most common were diarrhea, neutropenia, CINV, oral mucositis and thrombocytopenia and other rare toxicities (DVT, hand foot syndrome,myalgia). Febrile neutropenia was recorded in 2.5 % cases. There were 2 induction deaths. Stage II, absence of ER/PR expression showed statistically significant correlation with path CR rates. Conclusions: Locally advanced breast cancer constitutes around 40% cases at our institute. Post NACT pCR was achieved in 21% of cases, HER2/neu positive cases and TNBC showed higher pCR rates. The factors affecting pCR rate were absence of ER/PR expression and stage II disease.
Acquired immune deficiency of cancer: Evaluation of NK cell number as a predictor of overall survival in breast cancer.
Authors: Williams R. Michael , Yunis Edmond J
Published: May 2020

e13003

Background: Cancer specialists, be they molecular geneticists or oncology clinicians, now accept the fact that a cancer results after a deleterious mutation in the apoptosis program AND failure of the immune system, innate (non-specific) and adaptive (specific), to eliminate the now abnormal transformed cell and it's progeny. Just as the acquired immune deficiency syndrome existed as a syndrome BEFORE the HIV virus was described, the disease AIDS/HIV was designated because the virus explained the syndrome and made HIV/AIDS a disease. We believe cancer works the same way. Cancer is a failure of surveillance by the immune system which leads to a disease, one we have described as AIDS/cancer (J Immunol May 1, 2019, 202, 1S, 182.79). Methods: Commercially available laboratory analysis of peripheral blood (Quest Diagnostics) and standard treatment protocols for breast cancer. Results: The immune system can be evaluated with samples of peripheral blood where cell subsets, antibody levels, etc. are measurable. Here we present results from over 200 unselected breast cancer patients, independent of Stage. All patients were treated with standard protocols. The initial number of NK cells in peripheral blood, but not other cell subsets or immunoglobulin levels, are a, and likely the, most significant predictor for survival. Kaplan Meier survival analysis, done when 20% of the entire population had died, showed that none of the patients in the upper quartile for NK cell number had died. Survival differences, comparing the top 50% vs. bottom 50% in initial NK number. were also highly significant (P < 0.05). Conclusions: We conclude that the innate immune system, reflected as numbers of NK cells in the blood are the most significant predictor of survival.
New potential therapeutic-sequence strategies of TDM1 in the revolutionary era of metastatic HER2-positive breast cancer treatment: A monocentric retrospective experience.
Authors: Sanò Maria Vita , Castellana Luisa , Caffarelli Silvia , Fallica Giuseppa , Chiarenza Maurizio , Ali Marco , Dimarco Rosanna , Vita Maria Grazia Di Leo , Picone Antonio , Aiello Rosa Anna , Caponnetto Domenica , Casella Tiziana , Caruso Michele
Published: May 2020

e13014

Background: EMILIA study showed benefits in terms of both progression free survival (PFS) and overall survival (OS) administering Ado-trastuzumab emtansine (T-DM1) vs lapatinib-capecitabine in HER2+ mBC patients (pts) treated at least with a previous trastuzumab-taxane-based therapy. However a paucity of data is available on TDM1 efficacy after dual anti HER2 blockade with pertuzumab and trastuzumab (PT). Instead TH3RESA trial revealed the positive impact on OS of T-DM1 also in heavily pre-treated (at least 2 lines of T, lapatinib and taxanes regimens) pts. We conducted a retrospective analysis reporting innovative findings on the sequence of anti-HER2 treatments and how it could be potentially optimized. Methods: Between June 15, 2014 and January 31, 2020 we identified HER2+ (IHC: 3+ or 2+/FISH amplified) mBC pts treated with T-DM1, either as second-line after progression on dual blockade PT (Cohort PT) or after ≤ 3 anti her2-combined regimens (trastuzumab o lapatinib plus chemotherapy) (Cohort T). 74 pts received T-DM1: Cohort T n = 34 (all females, median age = 52,7), Cohort PT n = 40 (39 females, 1 male, median age = 52,2). Within Cohort T: 64,7 % of pts (n = 22) received T-DM1 after 1 previous anti her2-combined regimen, 20,6 % (n = 7) and 14,7 % (n = 5) in third and fourth lines, respectively. Instead, the whole Cohort PT received second line T-DM1 after pertuzumab/trastuzumab. Results: Median progression- free survival was 10,2 in Cohort T and 3,7 months in Cohort PT. As regards the best response rate, 8,8 % (n = 3/34) and 52,5 % (n = 21/40) of pts reported a progressive disease (PD) into the Cohorts T and PT, respectively: stable disease (SD) 38,2 % (n = 13/34) versus 15 % (n = 6/40); partial response (PR) 23,5 % (n = 8/34) vs 15 % (n = 6/40); complete response (CR) 23,5 % (n = 8/34) vs 12,5 % (n = 5/40). Almost 2/3 (n = 21/34) of Cohort T and half (n = 20/40) of Cohort PT pts had a 3+ IHC status. Conclusions: Our data suggest a lower efficacy of T-DM1 after progression on dual HER2-blockade PT. After all, EMILIA trial did not robustly evaluate the role of T-DM1 in this specific subset of pts. Obviously, larger prospective studies are necessary in order to optimize the best sequence strategy in the treatment of metastatic HER2+ BC, in light of the increasingly innovative anti-HER2 agents.
Real-world effectiveness of post-T-DM1 treatments in HER2-positive metastatic breast cancer: KBCSG-TR1917 observational study.
Authors: Masuda Norikazu , Yoshinami Tetsuhiro , Yasojima Hiroyuki , Kittaka Nobuyoshi , Takahashi Masato , Ohtani Shoichiro , Kim Seung Jin , Kurakami Hiroyuki , Yamamoto Naoko , Yamada Tomomi , Takata Takehiko , Nakayama Takahiro
Published: May 2020

e13020

Background: For patients with HER2-positive, unresectable and/or metastatic breast cancer (HER2+ mBC), T-DM1 is now the standard of care after trastuzumab and/or pertuzumab-based therapy. On the other hand, there is limited evidence after T-DM1 treatment. To clarify the treatment options and the effectiveness of drug therapy just after T-DM1 (post–T-DM1 therapy), we performed a multicenter observational study in patients with HER2+ mBC. Methods: This study enrolled consecutive patients who met eligibility criteria; Japanese female patients with HER2+ mBC, 20 years of age or older, who received at least one subsequent drug treatment except for an investigational drug after discontinuing T-DM1 between Jan 2014 and Dec 2018. To investigate the effectiveness of post–T-DM1 therapy, the real-world progression-free survival (rwPFS), time to treatment failure (TTF), overall survival (OS), objective response rate (ORR) and clinical benefit rate (CBR) were evaluated. Tumor response was exactly assessed by investigators according to RECISTv1.1. Results: Of 205 patients who were treated with T-DM1 at five institutions, 138 patients were enrolled and 128 patients were included in the analysis (data-cut off: Jul 31 2019). The median age of the patients was 59 years (range 27–84), and the median duration of T-DM1 treatment was 5.1 months (range 0.0–41.4). Ninety-two patients (71.9%) had an ECOG PS score of 0 or 1. Of the 128 patients, 34 (26.6%) patients received lapatinib + capecitabine therapy, 35 (27.3%) trastuzumab-based therapy (excluding pertuzumab), 36 (28.1%) pertuzumab-containing therapy, and 23 (18.0%) other therapy except for anti-HER2 therapy. In the 111 patients with measurable lesions, ORR was 22.5% (95% CI: 15.1–31.4). The median rwPFS was 5.7 months (95% CI: 4.8–6.9), median TTF 5.6 months (95% CI: 4.6–6.4), median OS 22.8 months (95% CI: 18.2–32.4), and the CBR was 47.7% (95% CI: 38.8–56.7) in the 128 patients. Conclusions: We clarified that the effectiveness of post–T-DM1 therapy was limited among the current standard treatment options. Therefore, to improve the prognosis in the later settings of HER2+ mBC, novel treatment options are warranted in the future. Clinical trial information: UMIN000038296 .
Metastasis by semi-quantitative oestrogen receptor expression in stage I-III early diagnosed triple positive breast cancer patients.
Authors: Van de Kerkhof Jasmine , Floris Giuseppe , Desmedt Christine , Laenen Annouschka , Slembrouck Laurence , Punie Kevin , Smeets Ann , Nevelsteen Ines , Van Nieuwenhuysen Els , Weltens Caroline G , Janssen Hilde , Han Sileny N. , Van Gorp Toon , Berteloot Patrick , Vergote Ignace , Wildiers Hans , Neven Patrick
Published: May 2020

e13031

Background: Some breast cancer subtype-specific demographics and histopathological characteristics can be associated with metastatic outcome. Semi-quantitative oestrogen receptor (sqER) is prognostic in ER-positive HER2-negative tumours. Here, we studied sqER for outcome in early diagnosed triple positive breast cancers (TPBC;ER+/PR+/HER2+). Methods: Retrospective monocentric study of all consecutive early diagnosed TPBC (July 2002 - Dec 2017). Immunohistochemistry (IHC) was used for ER, PR and HER2; IHC ≥1% ER/PR was pos; HER2 was FISH-confirmed. Low sqER was defined as Allred score < 7/8. Local therapy was surgery +/- radiotherapy; systemic treatment was (neo)-adjuvant chemotherapy and trastuzumab and endocrine treatment. The clinicopathological variables we studied apart from sqER were age, menopausal status, BMI, parity, tumor grade and clinical stage at diagnosis. Variables were analysed by a Fishers Exact or Mann-Whitney U test. All reported p-values are two-sided. Cox regression was used to investigate howqER is associated with distant metastasis. Results: We included 415 female patients. 18% had low sqER; these were younger and more likely premenopausal at diagnosis; p < 0.001. Other studied variables didn’t differ by sqER-expression. 7% developed metastasis after a mean follow up of 86 months. High sqER-TPBCs as compared to low sqER-TPBCs were less likely to metastasize (HR 0.42; 95 CI 0.19-0.91). Conclusions: Low sqER in TPBC, present in about a fifth of these tumours, is typically associated with younger age and premenopausal status at diagnosis. Low sqER TPBC are more likely to metastasize when compared to TPBC with high sqER levels. [Table: see text]
The neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios predict efficacy of CDK 4/6 inhibitors in women with hormone receptor-positive/HER2-negative advanced breast cancer.
Authors: Zattarin Emma , Fabbroni Chiara , Ligorio Francesca , Nichetti Federico , Lobefaro Riccardo , Rivoltini Licia , Capri Giuseppe , Bianchi Giulia Valeria , De Braud Filippo G. , Vernieri Claudio
Published: May 2020

e13032

Background: Cyclin-dependent kinase (CDK) 4/6 inhibitors combined with endocrine therapies (ETs) are a mainstay of treatment for patients (pts) with hormone receptor-positive advanced breast cancer (HR+ aBC). Preclinical evidence indicates that their ability to stimulate antitumor immunity may crucially contribute to their anticancer activity. The neutrophil-to-lymphocyte ratio (NLR) and the platelet-to-lymphocyte ratio (PLR) reflect systemic inflammation and immune system functional status and could be associated with CDK 4/6 inhibitor efficacy in pts with HR+ aBC. Methods: A retrospective, monocentric study was performed to investigate the association between NLR or PLR, as measured at baseline and after the first three treatment cycles, and progression free survival (PFS) in HR+ aBC pts treated with CDK 4/6 inhibitors. The thresholds for NLR and PLR were defined using the maximally selected rank statistics. Cox proportional hazard model was used to evaluate the impact of these parameters on PFS at univariate and multivariable analysis. Results: We evaluated a total number of 162 pts. Of them 142 were treated with palbociclib, 17 with ribociclib and 3 with abemaciclib plus ETs between January 2017 and December 2019 at our Institution. NLR and PLR at baseline were not associated with PFS. Conversely, high NLR ( > 3) and high PLR ( > 323.6) after three treatment cycles were associated with significantly lower PFS (p = 0.011 and p = 0.013, respectively). Multivariable analysis confirmed an independent association between high NLR or PLR and lower PFS (aHR 3.66, 95% CI 1.44-9.33, p = 0.007 and aHR 2.79, 95% CI 1.36-5.70, p = 0.005, respectively). Conclusions: To the best of our knowledge this is the first study to show a significant association between high NLR or PLR values and lower PFS in HR+ aBC pts treated with CDK 4/6 inhibitors. The association was not present with baseline values but only when NLR or PLR were measured after three treatment cycles, suggesting potential immunomodulatory activity of CDK 4/6 inhibitors.
CDK4/6 inhibitors and hormone therapy in hormone receptor-positive advanced breast cancer: Real-world data and intrinsic subtypes defined by PAM50.
Authors: Diaz Redondo Tamara , Lavado-Valenzuela Rocío , Dominguez-Recio Maria Emilia , Ruíz Sofía , González Flores Encarnación , Lopez-Lopez Jose Antonio , de Luque Vanessa , Morales-Estevez Cristina , Robles-Lasarte Marta , Perales-Adan Jesus , Saez Lara Enrique , Alvarez Martina , Sanchez-Muñoz Alfonso , Godoy Ana , Villar Ester , Carabantes Francisco , Baena-Cañada Jose Manuel , Jerez Jose Manuel , Ribelles Nuria , Alba Emilio
Published: May 2020

e13035

Background: CDK 4/6 inhibitors plus hormone therapy(HT) has been approved by FDA and EMA for the treatment of hormone receptor positive HER2 negative advanced breast cancer (HR+/HER2-BC) with improvement in PFS consistently demonstrated in several clinical trials. Benefit in OS has also been demonstrated in Monaleesa3 and Monarch2 clinical trials. To date we don`t have real-world data and no single biomarker has been validated to identify subgroups that would benefit most from this new drugs. Methods: This is a multicenter, real life, observational study. From January 2015 to December 2019 we recruited 98 patients with immunohistochemical(IHC) HR+/HER2-BC treated with CDK4-6 inhibitor plus HT. All patients were classified into intrinsic molecular subtypes based on PAM50 signature done centrally in diagnostic/metastatic biopsies. Results: The clinical and treatment characteristic are in table. In IHC studies all population were classified as luminalA (40%) and LuminalB (60%) but we found HER2 enriched patients (6%) defined by PAM50. The median PFS for all population was 14 months and median PFS for Luminal A subtype was 12 months and 15 months for Luminal B with no statistically significant differences between them. Conclusions: Based on the results obtained, the intrinsic molecular subtype defined by PAM50 does not appear to be associated with differences in PFS in our study group. However, a study with a larger number of patients would be necessary. Inhibitors of CDK4/6, have established a central role in the management of HR+/HER2-BC. There is a clear benefit in PFS and OS but we still don’t know which patients will benefit from this therapy and who will not while the side effects such chronic neutropenia, QTC prolongation and diarrhea could have a negative impact on their quality of life. Its mandatory to explore a good biomarker to direct therapy. [Table: see text]
Monitoring of PIK3CA and ESR1 mutations in circulating tumor DNA as predictive and prognostic biomarkers in patients with endocrine-resistant ER+/HER2- advanced breast cancer.
Authors: Fuentes Antrás Jesús , García-Barberán Vanesa , Gonzalo Irene , Moreno Fernando , López-Cade Igor , Ramírez-Ruda Carmen , Bueno Oskia , Ascaso del Rio Ana , Pascual Alejandro , Ocana Alberto , Caldes Trinidad , Garcia-Saenz Jose Angel
Published: May 2020

e13045

Background: Combination therapeutic strategies including CDK4/6 inhibitors and an endocrine backbone are the standard of care of treatment for patients with estrogen receptor positive (ER+)/HER2- advanced breast cancer (ABC). Endocrine agents mainly include aromatase inhibitors, which target ER-driven transcription, and fulvestrant, which functions as ER antagonist. PI3K-AKT-mTOR is a key point of resistance to endocrine therapy, activated in 40% of these patients by mutations concentrated in critical regions of PIK3CA, coding for the p110 catalytic subunit α of PI3K. Additionally, 30% of patients previously exposed to non-steroidal aromatase inhibitors develop mutations in the ligand binding domain of ESR1, causing endocrine resistance by constitutive activation of the ER. Furthermore, metastasis and primary tumors may show a highly heterogenous mutational landscape. Monitoring the dynamic changes of these mutations in ctDNA may provide a non-invasive, real-time and accessible tool to convey predictive/prognostic information and guide decisions on sequential endocrine therapies. Methods: Pre-planned interim analysis results of an observational, prospective cohort pilot study to assess the predictive and prognostic value of monitoring PIK3CA and ESR1 mutations in ctDNA of patients with endocrine-resistant ER+/HER2- ABC. We have studied longitudinal liquid biopsies from 30 patients using digital PCR to interrogate PIK3CA mutations (H1047R / E545K) and ESR1 mutations (D538G / Y537S). Blood samples were drawn at the time of progression to endocrine therapy, at 8 weeks of subsequent endocrine line and at new progression. This exploratory analysis will provide preliminary data on clinical homogeneity, treatment regimens, median follow-up and progression-free survival, mutation incidence and intraindividual variation of mutant allele frequency and copy number. The percentage of progressors at 24 weeks of follow-up according to the mutational status will be evaluated by using the Fisher’s exact test. The predictive potential of ctDNA biomarkers will be characterized by ROC curve analysis. Tracking ctDNA mutations to predict endocrine resistance in a real-world setting represents a critical step towards precision medicine in oncology.
Real-world incidence, duration, and severity of treatment-emergent (TE) neutropenia among patients (pts) with metastatic breast cancer (MBC) treated with ribociclib (RIB) or palbociclib (PAL).
Authors: Schwartzberg Lee S. , Zarate Juan Pablo , Chandiwana David , Yu Chu-Ling , Balu Sanjeev , Kanakamedala Hemanth , Turner Stuart J
Published: May 2020

e13048

Background: Neutropenia is the most common adverse event following administration of CDK4/6 inhibitors RIB and PAL for hormone receptor–positive (HR+) MBC. There are limited comparative real-world data on TE neutropenia in pts receiving these agents. Here we report incidence, duration, and severity data on TE neutropenia in such pts from an electronic health record dataset and administrative claims. Methods: This retrospective study comprised 2 mutually exclusive cohorts of pts with MBC receiving RIB or PAL. Pts were matched 1:1 based on age and year of treatment start. Prior baseline activity of ≥6 mo was required. The MarketScan claims databases was used to evaluate incidence rates of TE neutropenia from Jan 1, 2015, to Dec 31, 2018, in pts receiving RIB or PAL. Rate ratio was calculated using a Poisson model. Data on neutropenia severity and duration were obtained from Optum de-identified Electronic Health Record dataset. Neutropenia severity was defined by neutrophil counts from lab tests (grade 1/2, 1000- < 1500/μL; grade 3, 500- < 1000/μL; grade 4 < 500/μL) within the first 180 days of treatment. Neutropenia duration was estimated using Kaplan-Meier analysis and defined as the time between first abnormal neutrophil result and a lab result demonstrating neutropenia resolution. Results: After 1:1 matching, 152 pts from the MarketScan database were included in both the PAL and RIB cohorts; 168 matched pts were included from the Optum dataset. Neutropenia was reported in 38 pts (25%) in the PAL group and 25 pts (17%) in the RIB group. The rate of neutropenia per person–treatment year was 0.5 (95% CI, 0.4-0.7) in PAL pts vs 0.4 (95% CI, 0.3-0.6) in RIB pts. The rate ratio of neutropenia between treatments (PAL vs RIB) was 1.4 (95% CI, 0.8-2.3), which was not statistically significant, likely due to small sample size. Rates of neutropenia by severity with PAL vs RIB were 32% vs 32% for grade 1/2, 35% vs 26% for grade 3, and 4% vs 4% for grade 4, respectively. The rate ratio for grade 3 or grade 4 neutropenia (PAL vs RIB) was 1.3 (95% CI, 0.9-1.8). Median neutropenia duration was 29 vs 20 days ( P< .01) with PAL vs RIB. Conclusions: Treatment of HR+ MBC with RIB and PAL requires optimal management of TE neutropenia. Real-world data showed that pts with MBC receiving PAL had a numerically higher rate of neutropenia than pts receiving RIB. Rates of grade 3 neutropenia were higher with PAL vs RIB, and duration of neutropenia was longer with PAL vs RIB. Economic burden analyses of neutropenia will be presented.
Resensitization of palbociclib-resistant MCF-7 cells by inhibiting TGF-β-induced epithelial-mesenchymal transition.
Authors: Chang Minsun , Park Sujeong , An Byung Ha
Published: May 2020

e13061

Background: Inhibition of cyclin-dependent kinases 4 and 6 (CDK4/6) is the most recent therapeutic method to treat estrogen receptor (ER)-positive breast cancer. Three CDK4/6 inhibitors have been approved by the FDA. The acquired resistance to CDK4/6 inhibitors are expected to have a negative impact on success of breast cancer therapy. It is critical to understand the molecular mechanisms underlying drug resistances to devise a better regimen or overcome drug resistance. Methods: The derivative MCF-7 (MCF-7:PR) cells which exert acquired resistance to palbociclib (PCB), one of the FDA-approved CDK4/6 inhibitors, are recently established. The EMT characteristics, major mechanisms for the EMT, and inhibition of TGF-β signaling pathways are studied in MCF-7:PR cells. Results: The mesenchymal markers are increased and the epithelial ones are decreased at both mRNA and protein levels in our cell line model. Transwell migration and would healing assays also demonstrated that MCF-7:PR cells exert EMT properties. Hyperactivation of TGF-β/Smad signaling was observed in MCF-7:PR cells. Chemical inhibition of TGF-β signaling lead to diminished cell migration and resistance to PCB. Conclusions: Resistance to PCB in MCF-7 cells resulted in significant changes in cell motility and molecular markers associated with EMT. In particular, TGF-β signaling is closely related to EMT and its inhibition reversed the EMT and cellular response to PCT. Our findings suggest that the modulation of EMT via inhibition of TGF-β signaling can be one of strategies to bypass PCB resistance in ER-positive breast cancer.
Bone scintigraphy and PET-CT: A necessary alliance for bone metastasis detection in breast cancer?
Authors: Santos Joana Cristo , Abreu Miguel Henriques , Santos Miriam Seoane , Duarte Hugo , Alpoim Tiago , Sousa Susana , Abreu Pedro Henriques
Published: May 2020

e13070

Background: Bone is one of the main sites of breast cancer metastasis. Staging of this kind of disease spread can be performed in locally advanced cases with PET-CT in conjunction with Bone Scintigraphy. The purpose of this work is to compare the efficiency of bone metastasis detection between PET-CT and bone scintigraphy. Methods: Prospective analysis of locally advanced breast cancer patients treated in a Comprehensive Cancer Center between 2014 and 2019 that performed PET-CT and Bone Scintigraphy in the staging. Interval between the two exams could not exceed 2 months. Clinical and pathological characteristics of the disease were collected from electronic files and independently clinical images reports were considered to evaluate the ability of each imaging modalities to identify bone disease. In discrepancy cases a re-analysis of the images by two independent nuclear physicians was performed to validate the findings. Results: We analyzed 204 cases. The majority of them had ductal carcinomas (72.5%), cT2/3 (70%), cN1/2(61.8%) and G2/3 (94.6%), luminal B- like, HER2 positive disease (49.2%). In this cohort, bone metastasis was documented in 52 (25.5%) patients. PET-CT presented 97.0% of accuracy, surpassing the 94.1% presented by Bone Scintigraphy. The latter failed to correctly detect bone metastasis in 11 (5.4%) patients and only outperformed PET-CT in 3 (1.5%) patients. The main difference between the two modalities was the non-detection of cranium lesions in PET-CT images. Conclusions: PET-CT showed higher efficiency in bone metastasis detection than Bone Scintigraphy, probably because it detects lytic lesions. The non-detection of cranium ones can be harmful and so modifications in the image acquisition are required to improve the quality of PET-CT, avoiding other exams in bone staging.
Macrocytosis as a predictor of response to capecitabine in solid cancers: A meta-analysis.
Authors: Almugbel Fahad , Al-Showbaki Laith , Nadler Michelle , Desnoyers Alexandra , Saleh Ramy , Amir Eitan
Published: May 2020

e13080

Background: Capecitabine is an effective oral chemotherapy that is widely used in a number of solid cancers both as monotherapy or in combination with other anti-cancer drugs. It has been suggested that mean corpuscular volume (MCV) is associated with response to capecitabine. Methods: We searched PubMed for studies exploring the association between capecitabine and macrocytosis or MCV. We extracted the hazard ratios (HR) reporting progression-free (PFS) or overall survival (OS) data when comparing macrocytosis to normal/low MCV. If HR were not directly reported, we estimated them from survival plots using the Parmar method. HR were then pooled in a meta-analysis using generic inverse variance and random effects modeling. Results: Among the 13 identified studies, five were eligible for analysis, comprising a total of 446 patients. One study was a randomized trial and four were retrospective cohort studies. Mean patient age was 53 and cancer sites included breast (n = 226; 50%), colon (n = 131; 29 %) and stomach (n = 89; 19%). Capecitabine was used in combination with other drugs in 64% of patients. There was no association between macrocytosis and PFS (HR 0.91, 0.60-1.38, p = 0.65). Among the 3 studies reporting OS data, there was a significant negative association between macrocytosis and worse OS (HR 1.79, 1.38-2.34, p < 0.001). Conclusions: Macrocytosis in patients treated with Capecitabine was found to have no impact on PFS, but was associated with an inferior OS. This finding suggests that macrocytosis is more likely to be a prognostic factor rather than a predictive biomarker of response to capecitabine.
Assessment for markers of poor prognosis in a real-world evidence study of treatment patterns in patients with HR+/HER2- locally advanced or metastatic breast cancer in Korea and Taiwan.
Authors: Novick Diego , Rajan Narayan , Cheng Rebecca Ming-Huei , Lee Sae Young , Koo Dong Hyun , Wei Alice , Szende Agota , Colman Sam
Published: May 2020

e13083

Background: To assess how patient characteristics impact treatment patterns and real-world effectiveness among patients with hormone receptor (HR+)/human epidermal growth receptor 2-negative (HER2-) locally advanced and metastatic breast cancer (ABC) in Korea and Taiwan. Methods: We conducted a retrospective chart review comprising 227 female patients aged ≥ 18 years and diagnosed HR+/HER2- ABC in Korea and Taiwan between 2015-2017. Those having at least one of the following characteristics, shown previously to negatively impact prognosis, formed the poor prognostic cohort (PPC): ECOG PS > 0, not bone-only disease, liver metastases, or negative PgR status. Anonymized data on patient characteristics, treatment pathways, progression-free survival, and grade 3 or higher adverse events (AEs) of interest was abstracted. Descriptive statistics and Kaplan Meier methods were used to assess the outcomes. Results: The mean (range) age was 57.1 (29 - 83) years. A total of 193 (85.0%) patients were PPC. Endocrine regimens were the most frequent first-line therapies used by 50.3% and 67.6% of patients in the PPC and non-PPC cohorts, respectively. Chemotherapy regimens were used by 25.9% and 17.6% as initial systemic therapy and by 60.1% and 35.3% at any time following diagnosis of ABC, for PPC and non-PPC, respectively. The median progression-free survival time, based on first-line therapy, was 8.3 (95%CI: 6.9 – 10.4) months for PPC versus 11.5 (95%CI: 5.5 – 12.0) months in non-PPC. The proportion of patients with at least 1 grade 3 or higher AEs of interest during first-line therapy was higher in the PPC cohort compared to the non-PPC cohort, 54.4% vs. 44.1% respectively. The most common AEs reported were leukopenia, asthenia/fatigue and neutropenia occurring in 27.5%, 28.0% and 20.7% of the PPC cohort and 23.5%, 2.9%, and 14.7% of the non-PPC cohort, respectively. Conclusions: The existence of one or more poor prognostic factors is associated with a higher chemotherapy use any time following diagnosis of ABC, as well as lower median progression-free survival and a higher likelihood of having an adverse event during first line therapy, compared to non-PPC cohort. These results suggest that patient poor prognostic characteristics can be drivers for therapy selection.
BRCA1/2 and CHEK2 mutation prevalence in patients with breast and/or ovarian cancer in the South of Russia.
Authors: Petrusenko Natalia A. , Timoshkina Natalya N. , Vashchenko Larisa N. , Yakubova Darya , Verenikina Ekaterina V. , Menshenina Anna P. , Zhukova Galina V. , Kit Oleg I.
Published: May 2020

e13088

Background: The development of breast cancer (BC) and ovarian cancer (OC), as well as their chemoresistance may be due to the presence of mutations in many genes, but most often in BRCA1/2 and CHEK2. Early diagnosis and subsequent preventive interventions improve the survival of patients with mutations in the BRCA1/2 genes. Genotyping of the gene inactivation events predicts a high sensitivity of BC and OC to platinum-containing cytostatics. Our purpose was to study the spectrum of germline mutations in the BRCA1/2 and CHEK2 genes in BC and/or OC patients in the South of Russia. Methods: The study included 622 patients of 10 nationalities with BC and/or OC from the South of Russia. Genomic DNA was isolated from peripheral blood leukocytes; mutations were detected by Real-Time PCR in the BRCA1 (185delAG, 300T > C, 2080delA, 4154delA, 5382insC, 3819delGTAAA, 3875delGTCT), BRCA2 (6174delT), CHEK2 (1100delC, IVS2+1G > A, 470T > C) genes. Results: Mutations in the BRCA1/2 gene were found in 13.5% of cases, in CHEK2 – 6.2%. In the BRCA1/2 gene, the frequency of 5382insC mutation was 76.2%; 4153 delA – 9.5%; 300T > G – 7.1%; 2080delA – 3.6%; 185delAG, 3875delGTCT, 6174delT - 1.2% each. In the CHEK2 gene: 470Т > C – 73.1%; IVS2+1G > A – 23.1%; 1100delC – 3.8%. Two patients showed a combination of 5382insC mutation in the BRCA1 gene and 470T > C mutation in the CHEK2 gene. The observed prevalence of mutations in BRCA1 was generally consistent with that for European countries (p = 0.062). Identification of 470T > C mutation in CHEK2 in two cases confirmed the final diagnosis of Li-Fraumeni syndrome (OMIM: 609265); however, we failed to establish a family history of cancer in one patient. A high-risk cancer group was formed for prophylactic purposes based on the data of genotyping for major mutations in the BRCA1/2 and CHEK2 genes in patients with BC/OC and their healthy relatives. Conclusions: The frequency of BRCA1/2 and CHEK2 mutations in the studied multinational population of Caucasian patients with BC and/or OC was 17.2%. The 5382insC BRCA1/2 (76.2%) and 470Т > C CHEK2 (73.1%) mutations were the most frequent which corresponded to the occurrence of these SNPs in populations of European countries.