bluuebunny/crossref_metadata_2025 huggingface dataset:
Real-world evidence regarding the efficacy and toxicity of neoadjuvant trastuzumab and pertuzumab in the management of HER2-positive early-breast cancer.
Authors: Hall Benjamin James , Bhojwani Ajay Ashok , Innes Helen , Ahmed Eliyaz , Cliff Joanne , Malik Zaf , O'Hagan Julie Elizabeth , Tolan Shaun , Hall Allison , Hayat Khizar , Errington Douglas , Alam Farida , Thorp Nicky , Flint Helen , Law Andrea , Wong Helen , O'Reilly Susan , Jackson Richard , Cicconi Silvia , Palmieri Carlo
Published: May 2019

e12108

Background: Neoadjuvant (NA) HER2 blockade with trastuzumab (T) and pertuzumab (P) results in pathological complete response (pCR) rates of 39% to 62%. Diarrhoea is reported in up to 73% of cases. No real-world studies have explored the efficacy and toxicity of this treatment. This study aimed to determine the efficacy and toxicity of NA T-P and CT within a routine NHS clinical practice in the UK. Methods: HER2+ BC patients given NA T-P (accessed via the Cancer Drug Fund) between Oct2016-Jan 2018 at Clatterbridge Cancer Centre NHS Foundation Trust were retrospectively identified. Clinico-pathological information, treatment data, nurse led toxicity and echocardiography were reviewed. Data lock: 30th January 2019. Final pathological response data is presented. Results: 78 female patients were identified with a median age of 50 years (IQR: 44.4-60.2). Diagnosis: median tumour size 30mm (IQR 23.0-47.5mm), 62% (48/78) LN+ & 71% ER+. CT regimens: 81% (63/78) given FEC-DHP; of these 19 (30%) switched to weekly paclitaxel (wP) or nab-paclitaxel; 5% (4/78) AC/EC-DHP; 9% (8/78) TCHP of which 1 (13%) switched to wP. All patients underwent definitive surgery: 50% (39/78) mastectomy & 50% (39/78) WLE. 44% (35/78) axillary node clearance (ANC) & 56% (43/78) sentinel node biopsy (4 prior to NA therapy). 91% (32/35) undergoing ANC were LN+ at diagnosis, of which 66% (21/32) were LN- at surgery. pCR rate (ypT0/is, N0) was 47% (37/78), pCR by HR: ER+ 42% (23/55) & ER- 61% (14/23). pCR for 20 cases switched to wP was 60% (12/20). 6% (5/78) achieved pCR in the breast alone (in these LN status ITCx1, micrometsx3 & macrometsx1). Median size of the 46% (36/78) with residual breast tumour was 14.5mm (1-65mm). Outcome: Median follow up 68 weeks with one local and one distant recurrence occurring but no deaths. Toxicity: Ejection fraction did not decline beyond 10% of baseline in any patients. Diarrhoea occurred in 74% of cases, and CTCAE grade 3-4 toxicity occurring in >2% of patients: diarrhoea, fatigue, and infection. Conclusions: This data confirms 1) the real world efficacy of NA T-P 2) a significant number of LN+ patients become LN- and measures to avoid ANC are needed 3) switching to NA wP is not uncommon and may be associated with a higher pCR 4) diarrhoea rates reflect the literature and measures to mitigate it are needed. Updated outcomes will be presented.
Pathologic complete response and serial circulating tumor cell monitoring during neoadjuvant therapy in nonmetastatic triple-negative breast cancer patients.
Authors: Hall Carolyn S. , Hess Kenneth R. , Ravenberg Elizabeth , Clayborn Alyson , Meas Salyna , Moulder Stacy L. , Thompson Alastair Mark , Lucci Anthony
Published: May 2019

e12111

Background: ARTEMIS (A Randomized, TNBC Enrolling trial to confirm Molecular profiling Improves Survival) is a randomized trial to determine if precision guided neoadjuvant chemotherapy (NAC) influences rates of pathologic complete response in the breast and axillary nodes (pCR). We hypothesized that blood circulating tumor cell (CTC) identification before and/or after NAC (just before surgery) would be associated with pCR in non-metastatic TNBC patients. Methods: Blood was assessed for CTCs at baseline (pre-NAC) and after NAC (post-NAC), as part of an IRB approved study, ARTEMIS (2014 – 0185/PA15-1050). CTCs (per 7.5 ml blood) were identified using the Cell Search System (Menarini Silicon Biosystems). Samples > one cell having morphologic criteria for malignancy were deemed CTC+. Fisher exact test was used to evaluate associations between CTC detection and clinicopathologic characteristics, and Chi2 test was used to analyze associations between CTC detection pre- and post- NAC, and pCR. Results: Fifty-nine patients had pre-NAC and 43 patients had post-NAC CTC assessments. One or more CTC was detected in 13/59 (22%) patients pre-NAC and in 16/43 (37%) of post NAC samples. CTC detection was not associated with patient stage, tumor androgen receptor expression, vimentin expression, Ki-67 staining, or tumor-infiltrating lymphocyte levels. Pre-NAC CTC detection was not (chi2 P = 0.98), but post-NAC (chi2 P = 0.0017) CTC identification was negatively associated with pCR. Conclusions: CTC detection post-NAC was negatively associated with pCR in non-metastatic TNBC patients. These findings warrant larger studies studying serial CTC detection throughout treatment to assess response to NAC.
Pathologic response to neoadjuvant therapy with nabpaclitaxel plus carboplatin followed by anthracycline regimen in triple-negative breast cancer.
Authors: Cardenas Juan David , Esteban Carmen , Garcia Carbonero Iciar , Rosero Adriana , Martinez Barroso Katherin , Borregon Rivilla Miguel , Rubio Salvador Ana Rosa , Aguilar Angulo Paul Martin , Garcia Avila Maria , Chacon Jose Ignacio , Ruiz Martin Juan
Published: May 2019

e12117

Background: Triple-negative breast cancer (TNBC) remains a poor prognosis subtype of breast cancer (BC). We are lacking of definitive effective combinations in this tumor. So, it is warranted to explore new combinations. Neo-adjuvant setting is one of the most effective scenarios to explore a treatment efficacy. We aimed to evaluate efficacy of Nab-paclitaxel plus Carboplatin followed byanthracycline regimen by pathologic complete response (pCR: no disease in breast and axilla) in women with TNBC. Secondary endpoints were toxicity profile and breast conserving surgery. Methods: Women with stage II or III disease were included. Hormone receptors and HER2 negativity was confirmed by immunohistochemistry and/or FISH. Patients received Nab-paclitaxel 125 mg/m2 plus Carboplatin AUC 2 intravenously on days 1, 8 every 21 for four cycles followed by Epirubicin 90 mg/m2 and Cyclophosphamide 600 mg/m2 intravenously every 2 weeks for 4 cycles and subsequent surgery. Breast Magnetic Resonance was done in all cases at diagnosis and before surgery. We obtained informed consent from all patients. Results: Thirty-two patients with confirmed clinical stage II (56.3%) or III (43.7%) TNBC were treatedbetween January 2015 and February 2019. The median age of the patients was 53.1 years (30.3-77.6 years). The average of received chemotherapy was 12 doses (7-14). The mean dose of nab-paclitaxel plus carboplatin was 8 doses. All patients received surgery with or without radiotherapy. There was only one case (3.1%) of progression during neoadjuvant treatment. The rate of pCR was 50% (16) in breast and axilla, partial response 43.8% (14) and stable disease 3.1% (1). Conservative surgery was performed in 50% of patients (16). The 3/4 grade toxicities were asthenia 3.1% (1), nausea/vomiting 6.3% (2), thrombocytopenia 6.3% (2), leukopenia 6.3% (2), neutropenia 40.6% (13), febrile neutropenia 6.3% (2), diarrhea 3.1% (1), allergy 3.1% (1), peripheral neurotoxicity 3.1% (1). After a median follow-up of 18.3 months (5.0–41.9) 93.8% (30) of patients are alive. Two patients (6.3%) had early local relapse and distant relapse, respectively, and are deceased due to progression disease. Conclusions: Nab-paclitaxel plus carboplatin followed by anthracycline regimencombination as neoadjuvant treatment in TNBC achieved an encouraging rate of pCR, allowing conservative surgery in half of our patients. Toxicities were not severe in most patients and hematologic toxicity was manageable with G-CSF.
Phase II study of preoperative chemotherapy versus standard postoperative chemotherapy in HR-negative HER2-positive breast cancer patients.
Authors: Xiu Meng , Zhang Pin
Published: May 2019

e12118

Background: HR-/HER2+ breast cancer is a subtype with aggressive characteristic and poor survival. More clinical evidence are needed for choice of therapeutic strategies. Methods: Patients with T1-3N0-3M0 received preoperative chemotherapy (PTX 175 mg/m2, CBP AUC 4, q2w*6) combined with trastuzumab (2mg/kg qw) or standard postoperative chemotherapy such as ddAC-PH, AC-PH, TCH. The primary endpoint was RFS. Results: 86 patients were enrolled, 43 received preoperative chemotherapy (pre arm) and the other 43 received postoperative chemotherapy (post arm). There was no significant difference in baseline between the two arms. 22.1% of patients were stage IIA, 25.6% IIB, 34.9% IIIA, and 18.6% IIIC. At a median follow-up of 33.4 months, 16 patients had relapsed (pre arm 8, post arm 8). The median time from diagnosis to relapse was 22.8 months (7.1-49.2) and 23.8 months (11.4-37.4) in pre and post arm. Kaplan-Meier survival analysis estimated that the 3-year RFS were similar (pre vs post: 73.4% vs 75.4%, p= 0.631). Only 1 death occurred in post arm. Table showed that in subgroups, there was no statistical difference in risk of recurrence between pre and post arms. In pre arm, ORR was 97.7% clinically, and pCR (ypT0/TisN0) was 39.0%. No patients achieved pCR relapsed, and the residual invasive lesions indicated poor prognosis. Table showed that Neo-Bioscore 4-5 was related to recurrence event significantly ( p= 0.021). The rate of breast-conserving in pre arm was higher (19.5% vs 9.3%), and PCb regiments every 2 weeks had similar adverse effects with standard chemotherapy, and less patients had dose reductions (18.6% vs 25.6%). Conclusions: Preoperative chemotherapy versus standard postoperative chemotherapy results in similar RFS among HR-/HER2+ patients. Preoperative chemotherapy can identify prognosis of patients early by Neo-Bioscore and adjuvant therapy should be strengthened for high-risk patients. PCb every 2 weeks combined with trastuzumab can be an option of preoperative therapy for HER2+ breast cancer. Clinical trial information: NCT02934828. [Table: see text]
Phase II trial of metronomic capecitabine and cyclophosphamide with lapatinib and trastuzumab in patients with HER2-positive metastatic breast cancer.
Authors: Kang Irene , Spicer Darcy V. , Lu Janice M. , Groshen Susan G. , Tsao-Wei Denice , Garcia Agustin A.
Published: May 2019

e12508

Background: Metronomic chemotherapy is an emerging paradigm of cancer therapy in which low doses of chemotherapy are delivered at frequent intervals. Activity in patients with metastatic breast cancer (MBC) has been demonstrated in several phase II clinical trials. Methods: We proposed a regimen with metronomic chemotherapy and dual HER2 inhibition in HER2 positive patients with MBC. We hypothesized that this regimen will be highly active in MBC and have a favorable toxicity profile. Patients were treated on a 21-day cycle with capecitabine 1500mg PO daily, cyclophosphamide 50mg daily, lapatinib 1000mg PO daily and trastuzumab 6mg/kg IV once per 21-day cycle. This regimen was continued until disease progression or unacceptable toxicity. Primary endpoint was progression free survival (PFS). Secondary endpoints were overall response rate (ORR), clinical benefit rate (CBR), overall survival (OS), and safety and tolerability of this regimen. Eligibility criteria were patients 18 years of age and older who had histologically confirmed HER2-positive metastatic breast cancer with prior trastuzumab use in the adjuvant or metastatic setting with no more than two prior regimens for MBC. Results: Ten patients were accrued from Jan 2014-Oct 2016. Median age was 52 (range 38 - 79) years. Median number of chemotherapy regimens for metastatic disease was 0.5 (range 0-2). Median PFS was 13.7 (95% CI: 2.6, 16.6) months. Median OS was 29.6 (95% CI: 11.8, 60.5+) months. ORR was 30%, and CBR was 70%. Grade 3 or 4 toxicities were identified in 6 patients. The most common toxicities of any grade were fatigue (100%), diarrhea (80%), anemia, neutropenia, ALT increase, nausea and hand-foot syndrome 50% each. One patient achieved CR for over 3 years and continues on treatment at time of this report. 8 patients progressed and 1 patient withdrew from study without response evaluation. The trial was closed due to lack of accrual. Conclusions: The proposed regimen of metronomic capecitabine and cyclophosphamide with lapatinib and trastuzumab appears to be active in patients with HER2 positive MBC but with significant toxicity. Clinical trial information: NCT01873833.
Drug-related pneumonitis during everolimus therapy in patients with metastatic breast cancer: Incidence, radiographic findings, and correlation with clinical outcome.
Authors: Gong Chengcheng , Xiao Qin , Hu Xi-Chun , Gu Yajia , Wang Biyun
Published: May 2019

e12519

Background: Everolimus (EVE) in combination with endocrine therapy are approved for the treatment of HR+/HER2- metastatic breast cancers (MBC) patients. mTOR inhibitor-associated pneumonitis is one of the most worrying and common adverse drug events leading to treatment discontinuation. We investigated the incidence of drug-related pneumonitis (DRP) during EVE therapy in MBC patients and characterize radiographic patterns and clinical impact of pneumonitis. Methods: We retrospectively reviewed the data of MBC patients treated with EVE in Fudan University Shanghai Cancer Center from June 2013 to June 2017, who had baseline and at least one follow-up chest CT available for review (NCT 03730428). Serial chest CT scans were reviewed for abnormalities suspicious for DRP by an independent review of two radiologists. Log rank and Cox proportional hazards regression analysis were used for the time-to-event analysis. Results: DRP was radiographically detected in 45/86 patients (52.3%). Over 80% of DRP occurred in the first 4 months of treatment (cumulative risk 52.3%). Most patients with DRP were asymptomatic (n = 31, 68.9%). Among 14 patients with clinical manifestation, common symptoms included cough, fever and shortness of breath. DRP mostly distributed in bilateral lower lobes. Ground glass opacities and reticular opacities were seen in most of the cases. Elderly patients (OR 1.09, p = 0.002) and patients with baseline pneumonitis (OR 3.96, p = 0.023) are more likely to develop DRP. Patients who developed DRP had significantly longer progression free survival (median 6.8 vs 4.1 months, p = 0.024) and overall survival (OS, median 42.8 vs 21.3 months, p = 0.016). DRP was a predictor of improved OS by multivariate Cox analysis (HR 0.49, 95%CI 0.25-0.97, p = 0.040). Conclusions: DRP was noted in half of the MBC patients treated with EVE. Our preliminary data suggested that DRP would be a predictor for better outcome, which should be further investigated. Given the incidence and outcomes of patients with DRP, close monitoring, prompt diagnoses and appropriate treatment for DRP are critical for the preservation of patients’ quality of life and achievement of maximal treatment outcomes.
17-β estradiol promotes autophagy and induces cellular senescence in breast cancer cells.
Authors: Bajbouj Khuloud , Shafarin Jasmin , Hamad Mawieh
Published: May 2019

e12523

Background: The fact that estrogen (17-β estradiol or E2) is a known carcinogen notwithstanding, mounting evidence suggest that E2 has the potential to exert anti-cancer effects against various forms of cancer. Using in vitro models we, and others, have previously demonstrated that E2 disrupts intracellular iron metabolism in such a way that arrests cell cycling in breast and ovarian cancer cells. However, the cellular and molecular correlates underlying this cytostatic effect of E2 in cancer cells remain elusive. Methods: In this study, metastatic (MDA-MB-231) and non-metastatic (MCF-7) breast cancer cells treated with 20 nM E2 were assessed for mitochondrial function, cell proliferation, apoptosis and senescence at different time points post treatment. Results: E2 treatment resulted in a significant mitochondrial membrane depolarization; an outcome that associated with a significant loss of mitochondrial function and the accumulation of auto-phagosomes. It also significantly upregulated the expression of the cell cycle regulating cyclin-dependent kinase inhibitor, p21 protein and enhanced the activation (de-phosphorylation) of the tumour suppressor retinoblastoma (Rb) protein. Although, as previously shown, E2 did not induced classis apoptosis; it resulted in a significant elevation in senescence-associated β- galactosidase levels. Conclusions: In summary, these findings suggest that E2 treatment mediates its anti-cancer potential by disrupting mitochondrial function and precipitating autophagy and cell senescence.
Tumor mutational burden and spectrum in hormone receptor-positive breast cancer patients from India.
Authors: Minhas Sachin , Bhalla Sunita , Veldore Vidya , Ganvir Madhusudan , Ramprasad VL , Aggarwal Shyam
Published: May 2019

e12524

Background: Breast cancer is the most common type of cancer found in females in India. Moreover, more than 50% of the breast cancers in India are found to be hormone receptor positive (HR+). In this research we calculated the Tumor Mutational Burden (TMB) and studied the spectrum of mutations in HR+ breast cancer patients from India. Methods: Thirty five patients of HR+ breast cancer were enrolled in this study. Their FFPE tumor DNA was subjected to hybrid capture-based NGS assay which provided a comprehensive coverage of 170 key cancer-related genes. TMB was measured as the total number of non-synonymous coding mutations per megabase (mutations/MB). Results: Almost 50 percent (seventeen out of thirty five) of samples were found to be having either high or very high mutational burden with TMB values ranging between 148.84/MB to 734.65/MB. Nine out of thirty five samples had medium mutational burden with TMB values ranging between 59.15/MB to 137.39/MB and an equal number of samples were found to be having low mutational burden with TMB values ranging between 15.26/MB to 53.43/MB. Furthermore, we also made some interesting observations with respect to the mutational spectrum of these tumors. The most frequently mutated genes were PIK3CA and TP53. We also discovered BRCA1 and BRCA2 mutations in our study population which was a notable observation as BRCA mutations occur rarely in HR+ breast cancer in other populations of the world. The complete list of genes found to be mutated in our population is given in table. Conclusions: These preliminary results show that a substantial number of HR+ breast cancer patients could have high mutational burden. Recent clinical trials like KEYNOTE-028 suggest that such patients may get benefit from immune checkpoint inhibitor drugs. These results indicate that the Indian population has a higher TMB and a slightly different mutation spectrum compared to the other populations of the world. The study also indicates that generalizations regarding the use immunotherapy in different populations should not be made as the genetic make-up of every global population is slightly different and unique. Thus, there is a need to conduct studies like this in a much larger and different populations of the world. [Table: see text]
REACHAUT: First-line (1L) ribociclib (RIB) + endocrine therapy (ET) in HR+, HER2- metastatic breast cancer (MBC) in the real-world setting.
Authors: Singer Christian F. , Öhler Leopold , Egle Daniel , Greil Richard , Petru Edgar , Balic Marija , Marhold Maximilian , Pfeiler Georg , Brunner Christine , Kwasny Werner , Galid Arik Armon , Tinchon Christoph , Eisterer Wolfgang , Haslbauer Ferdinand , Hubalek Michael , Redl Andreas , Hock Karin , Hennebelle Mathias , Mraz Bernhard , Steger Guenther G.
Published: May 2019

e12527

Background: RIB + aromatase inhibitor (AI) is approved as 1L treatment (tx) for HR+, HER2− MBC. Real-world data on efficacy and safety of RIB+AI are limited. REACHAUT, a prospective, noninterventional trial assessed the safety of RIB+AI in 1L setting in postmenopausal patients (pts) with HR+, HER2− MBC in a real-world setting. First interim analysis results about safety are presented. Methods: 75 postmenopausal pts with HR+, HER2− MBC, QTc < 450 msec, and no prior ET for advanced disease were enrolled at 13 sites. 1L chemotherapy (CT) was allowed. Results: At data cutoff (25-Jan-2019), 61 pts were evaluable for safety (ongoing, n = 44; discontinued, n = 17). Median duration of follow-up was 29 d. Median age at baseline was 65 y ( < 65 y, n = 28; ≥65 y, n = 33); ECOG performance status was 0 (n = 39) and 1 (n = 12). 42.6% had visceral (lung, liver) metastases (mets), while 34.4% had bone only mets. Most common prior tx included CT (29.5% in neoadjuvant/adjuvant/metastatic setting) and ET (41%). Pts received RIB in 1L (93.4%) and second-line (6.6%) setting. In 80.3% pts receiving RIB, the ET partner included letrozole (57.4%), exemestane (11.5%), anastrozole (9.8%). Median duration of RIB exposure was 100 d. Median time to first AE was 14 d. 83.6% pts experienced AEs with mild (63.9%) to moderate (50.8%) severity. Serious AEs were noted in 6.6% pts. Most common AEs were neutropenia (42.6%) and QTc prolongation (24.6%). 4.9% pts had hepatobiliary AEs. Due to AEs, dose adjustments (4.9%) and dose interruptions (19.8%) were needed. No deaths were reported; median PFS was not reached. Subgroup analysis by age ( < 65 y vs ≥65 y) showed that the incidence of AEs was 55.9% vs 44.1%. Neutropenia was reported in 46.4% pts aged < 65 y vs 39.3% pts aged ≥65 y; QT prolongation events were noted in 21.4% pts aged < 65 y vs 27.2% pts aged ≥65 y. Dose adjustments and dose interruptions were needed in 14.3% and 46.4% pts aged < 65 y vs 15.2% and 45.5% pts aged ≥65 y. Conclusions: Overall safety of RIB+AI in routine clinical practice in REACHAUT was consistent with that reported in the MONALEESA-2 study. In real-world setting, pt age ( < 65 y vs ≥65 y) had minimal impact on AEs. Clinical trial information: NIS006622.
Different maintenance strategies versus observation in patients with hormone receptor-positive metastatic breast cancer after first-line chemotherapy: A real-world study and meta-analysis.
Authors: Hong Huangming , Wang Ying , Yu Yunfang , Li Chenchen , Ren Wei , Tang Jun , Ye Guolin , Yao Herui
Published: May 2019

e12529

Background: Current guidelines lack definitive evidence regarding the clinical outcomes associated with different maintenance strategies for hormone-receptor (HR) positive metastatic breast cancer (MBC). We aimed to evaluate different maintenance modalities after first-line chemotherapy in this setting. Methods: We conducted a multicenter real world study to compare maintenance chemotherapy, endocrine therapy and observation in patients with HR positive MBC who achieved disease control after first-line chemotherapy. The primary endpoint was overall survival (OS), secondary endpoint was progression-free survival (PFS). We further examined the results from fourteen multicenter prospective studies in a meta-analysis. Results: A total of 928 patients were enrolled in the real world study. The median age was 48 years (range, 18 to 76 years). Of these patients, 269 received chemotherapy, 330 received endocrine therapy and 329 received observation as their maintenance treatment. OS was significantly longer in the chemotherapy group and endocrine therapy group than in the observation group (median 33.0 vs 36.0 vs 19.0 months, respectively, P < 0.001), as was PFS (median 12.0 vs 14.0 vs 8.0 months, respectively, P < 0.001). However, there was no significant difference of OS between chemotherapy group and endocrine therapy group (HR, 0.947, 95% CI: 0.743-1.207, P = 0.656), so did PFS (HR, 0.969, 95% CI: 0.787-1.194, P = 0.765). In the meta-analysis of all cohorts (2706 participants), maintenance endocrine therapy provide similar PFS and OS compare with chemotherapy, but with lower odds of G1-G2 adverse events. Conclusions: Our study provided strong evidence for OS and PFS benefits of maintenance therapy over observation after first-line chemotherapy in HR positive MBC patients. Maintenance endocrine therapy was noninferior to chemotherapy with less treatment-related toxicity, which was worthy of a clinical recommendation.
Mixed invasive ductal-lobular carcinoma: Clinicopathological characterization and clinical outcomes.
Authors: Nasrazadani Azadeh , Li Yujia , Tseng George , Xavier Jennifer , Hugar Sarah , Lee Adrian V. , Lucas Peter C. , Jankowitz Rachel Catherine , Oesterreich Steffi , McAuliffe Priscilla F.
Published: May 2019

e12531

Background: Mixed Invasive Ductal-Lobular Carcinoma (IDC-L) is a histological subtype of invasive breast carcinoma comprised of both ductal and lobular morphologies. There is limited information on the relative proportions of the individual components in IDC-L and on outcomes compared to invasive lobular carcinoma (ILC) and invasive ductal carcinoma (IDC). Methods: Clinical information was abstracted from 16,308 patients with invasive breast cancer seen at UPMC Magee Women’s Hospital from 1990-2017 using the UPMC Network Cancer Registry. A systematic chart review was performed on a subset of patients annotated with IDC-L (n=806); however, a thorough review of pathology reports led to the exclusion of all but 408 patients for further analysis, due to the lack of a standardized definition of IDC-L. Of the 408 cases, 92% were estrogen receptor (ER)+. Survival of patients with ER+ IDC-L (n=376) was compared to ER+ IDC (n=9,716) and ER+ ILC (1,465). For a subset of IDC-L cases (n=54), distributions of individual subtype components were abstracted from pathology reports. Results: IDC-L made up 2.5% of the total cases (408/16,308). IDC-L tumors were on average 31% ductal and 69% lobular (p =0.001). Survival analysis showed worse disease free survival (DFS) (p=0.05) and overall survival (OS) (p=0.002) in patients with ER+ ILC compared to ER+ IDC, with ER+ IDC-L patients showing a median OS superior to ILC yet inferior to IDC counterparts (ns). Conclusions: Identification of patients with IDC-L through cancer registry protocols representative of standard practices by national cancer registries revealed a lack of a standardized definition of mixed IDC-L. Reliance on accuracy of these diagnoses calls in to question the reliability of prior clinico-pathologic analyses reported on this topic. DFS and OS of IDC-L patients falls between that of IDC and ILC patients while ILC patients showed significantly worse outcome. The predominant distribution of lobular morphology in IDC-L tumors suggests this subtype may have additional characteristics similar to lobular rather than ductal carcinomas. Comprehensive clinical and molecular characterization of a carefully identified IDC-L cohort is underway.
CDK 4/6 inhibitors (CDKi) + endocrine therapy (ET) in ER-positive metastatic breast cancer (mBC) patients according ET sensitivity: A systematic review and meta-analysis.
Authors: Piezzo Michela , Riemma Maria , Cianniello Daniela , Caputo Roberta , Fusco Giuseppina , Di Gioia Germira , Cerillo Ivana , Licenziato Marina , Buonfanti Gaetano , Cocco Stefania , Di Lauro Vincenzo , De Laurentiis Michelino
Published: May 2019

e12532

Background: Addition of CDKi to ET in ER-positive mBC has proven effective in improving both progression-freesurvival (PFS) and Objective Response Rate (ORR). However, no randomized clinical trial (RCT) has so far shown a significant increase of Overall Survival (OS). We carried out a metanalysis of all RTCs to better characterize the efficacy of CDK4/6i in some relevant subgroups, with particular reference to OS. Methods: Literature search of main databases was carried out up to 08 Dec 2018. Hazard ratios (HRs) for PFS and OS and risk ratios (RRs) for ORR were extracted/calculated for each trial and then pooled by using both fixed and random effect model. Confidence intervals (CIs) at 95% were calculated for each statistics. Kaplan-Meier meta-curves were generated by pooling data of all trials, among ET sensitive and ET resistant pts. Results: Eight RCTs were included accounting for a total of 4580 pts, 2802 receiving a CDKi (palbociclib, ribociclib or abemaciclib) in association with ET (NSAI, tamoxifene or fulvestrant) and 1778 receiving ET alone or plus placebo. Pooled analysis of HRs showed a significant improvement in PFS, regardless ET sensitivity, disease site, number of metastatic sites and treatment free interval. Analysis of OS included 3 RCTs with a total of 1243 pts and showed a statistically significant improvement of OS (HR 0.769 [95% CI 0.638, 0.926], p-value 0.006). Pooled estimate for RR showed higher ORR in CDK 4/6 arm both in ET sensitive (RR 1.35 [95% CI 1.19, 1.52]) and ET resistant group (RR 2.19 [95% CI 1.66, 2.89]). Similarly, pts with measurable disease showed a RR of 1.34 (95% CI 1.20, 1.50) in ET sensitive group and 2.26 (95% CI 1.72, 2.96) in ET resistant group. Pooled survival curves showed an absolute benefit in PFS, both in ET sensitive (median PFS: NR vs 15 months) and ET resistant (median PFS: 19.2 vs 8.9 months). Conclusions: Our findings suggest that addition of CDKi to ET improve clinical outcome in terms of PFS, ORR and OS, irrespective of pts/tumor characteristics.
Prognostic values of cell free DNA, CA 15.3, and ESR1 circulating mutations variations in hormone receptor (HR)-positive metastatic breast cancer (MBC) patients under aromatase inhibitor (AI).
Authors: Augusto Laetitia , Beaussire Ludivine , Lequesne Justine , Perdrix Anne , Sefrioui David , Fontanilles Maxime , Leheurteur Marianne , Di Fiore Frédéric , Sarafan-Vasseur Nasrin , Clatot Florian
Published: May 2019

e12534

Background: Circulating cell free DNA (cfDNA), CA 15.3 and circulating tumor DNA (ctDNA) have been associated with survival in MBC. These 3 biomarkers have never been compared. Methods: We retrospectively included all patients treated in our center between 2010 and 2012 for a HR+ MBC, who had clinical progression during the first line of aromatase inhibitor (AI) and available plasma samples. CfDNA level (ng/mL), CA 15.3 level (U/mL) and ESR1 circulating mutation level (Y537N, Y537S, Y537C and D538G, identified by ddPCR) were determined at time of clinical progression (Tp) and 3 months before (Tp-3). Biomarkers values at Tp and Tp-3 as well as their variations were analyzed according to clinical progression and overall survival (OS). Results: 91 patients were analyzed. CA 15.3 was elevated ( > 30 U/mL) in 71/91 (78%) at Tp and 62/91 (68%) at Tp-3. Higher CA 15.3 was associated with worse OS, especially at Tp (HR = 1.0006/unit at both times, p = 0.009 at Tp; p = 0.08 at Tp-3). Higher cfDNA was associated with worse OS, both at Tp and Tp-3 (HR = 1.006/unit, p < 0.0001 and HR = 1.007/unit, p = 0.02, respectively). An ESR1 mutation was detected in 14/91 at Tp-3 (15%) and 28/91 at Tp (31%). ESR1 mutation detection was strongly correlated with OS both at Tp and Tp-3 (HR = 2.4, p = 0.0005 and HR = 1.97, p = 0.03, respectively). Between Tp-3 and Tp, overall median CA 15.3 and ESR1 mutation level increased (p < 0.0001 and p = 0.007, respectively) and were related to poorer OS (HR = 1.007/unit, p = 0.0002 and HR = 3.1, p = 0.05). In contrast, CfDNA was not correlated at all with clinical progression (36/91 increase, 36/91 decrease, and 19/91 stable cfDNA). ROC curve analysis identified a 59% CA 15.3 increase as the best cut-off for predicting progression, but with poor performance (AUC = 0.64). Multivariate analysis showed that CA 15.3 at Tp (HR = 1.0006/unit, p = 0.006), cfDNA at Tp (HR = 1.005/unit, p = 0.01), ESR1 detection at Tp (HR = 2.7, p = 0.0002) and CA 15.3 increase between Tp-3 and Tp (HR = 1.006/unit, p = 0.003) were associated with poor OS. Conclusions: All 3 biomarkers are correlated with OS in MBC treated with AI. CfDNA variation is poorly related to clinical progression while CA 15.3 variation or ESR1 mutation detection are much more reliable. Overall the better performance is observed with ESR1 mutation detection.
CDK4/6 inhibitors in advanced hormone receptor-positive/HER2-negative breast cancer: A network meta-analysis (NMA) of randomized controlled trials (RCTs).
Authors: Husnain Muhammad , Riaz Irbaz Bin , Gondal Farva R. , Malik Saad , Sipra Qurat Ul Ain Riaz , Raina Ammad , Islam Mahnoor , Lopes Gilberto
Published: May 2019

e12545

Background: Palbociclib(P), Ribociclib(R) and Abemaciclib(A) in combination with Endocrine therapy (ET) have demonstrated progression free survival (PFS) in patients with metastatic hormone receptor positive, HER2-negative breast cancer as compared to ET alone. In the absence of head to head clinical trials and to provide clinical guidance, we performed an indirect comparison for P, R and A using network Meta-Analysis (NMA). Methods: MEDLINE, EMBASE and the Cochrane Library were searched to identify RCTs comparing P+ET, R+ET, A+ ET vs ET alone. NMA for PFS and toxicity endpoints was conducted using a multivariate random-effects meta-regression, using a consistency model, as described by White and colleagues. We used a frequentist approach and provided a point estimate from the network and a 95% CI from the frequency distribution of the estimate. We also estimated the relative ranking of the different treatments for each outcome using the distribution of the ranking probabilities and the surface under the cumulative ranking curves (SUCRA). Risk of bias was assessed using Cochrane Collaboration tool. Results: 8 RCTs were identified including 4580 patients. Risk of bias was low. 5 RCTs tested CDK 4/6 inhibitors in endocrine naive and 2 in the refractory setting, while MONALESSA-3 included patients both with endocrine naive and endocrine resistant disease. In the endocrine naïve patients, PFS for P was similar when compared indirectly with R (HR, 0.95, 95% CI 0.67-1.35) or A (HR, 1.00, 95% CI 0.62-1.61). Similarly, indirect comparison between R vs A did not show any statistical significant (HR, 0.95, 95% CI 0.62-1.45). In endocrine refractory patients, P showed no difference when compared indirectly to A (HR 1.12, 95% CI 0.67-1.87) or R (HR 0.98, 95% CI 0.52-1.86). R vs A did not show any statistically significant PFS either (HR, 1.14, 95% CI 1.61-4.51). P was ranked first in terms of PFS in frontline setting (SUCRA of 70.5) while R ranked first in the refractory setting (SUCRA of 39.5). QT prolongation was reported for R only. P caused more neutropenia while A caused more fatigue, anemia and diarrhea, although the results were not statistically significant. Conclusions: The efficacy of using either palbociclib, ribociclib or abemaciclib in combination with ET was similar in terms of PFS in either endocrine naïve or resistant disease. Palbociclib causes more neutropenia, abemaciclib causes more fatigue, anemia and diarrhea while ribociclib causes QT prolongation.
CENP-U function on TNBC.
Authors: Zhang Jin
Published: May 2019

e12546

Background: Centromere protein (CENP-U) gene, as an important constitutive kinetochore component, plays significant roles in cell caryomitosis. Our previous research found that about 25 % of transgenic mice with CENP-U amplified had suffered breast cancer in body surface. Also, in highly aggressive breast cancer cell lines, CENP-U presented the highest expression. Furthermore, the CENP-U protein expression obviously increased in human invasive breast carcinoma compared with the normal gland and intra-ductal tissue. Methods: Gene knockdown was accomplished by transient transfection. In addition, cell proliferation was analyzed with 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay and 5-Ethynyl-2'-deoxyuridine (EdU) assay while cell apoptosis was measured by flow cytometry using an annexin V-FITC apoptosis detection kit. Then, VEGF secretion in the supernatant was detected with an enzyme-linked immunosorbent assay (ELISA). Furthermore,Vascular endothelial markers of nude mouse were discovered by immunohistochemistry. And the signaling activation in the breast cancer cells was accessed by western blot using specific antibodies. Results: The MTT and EdU assay showed that CENP-U promoted the proliferation of the triple negative breast cancer (TNBC) cells while CENP-U downregulated promoted cell apoptosis. Furthermore, the ELISA results revealed that CENP-U significantly promoted the production and secretion of VEGF in TNBC cells. In addition, CENP-U downregulated inhibits tumor growth and angiogenesis in vivo. Importantly, CENP-U targeted HIF-1α,VEGFA, p-AKT and stat3, which were shown by the specific antibodies in the western blot. Conclusions: The results showed that CENP-U influence the proliferation, apoptosis and angiogenesis especially of TNBC cells. But the affected signaling pathways require further study.
The role of miR200c in leptin-mediated triple-negative breast cancer progression to an epithelial-to-mesenchymal transition.
Authors: Wang Lucas , Harlow Brittany , Bowers Laura , Hursting Stephen , deGraffenried Linda A , Brenner Andrew Jacob
Published: May 2019

e12548

Background: Almost 40% of women with breast cancer are obese at diagnosis. Obesity is associated with a worse prognosis in triple negative breast cancer (TNBC). Preclinical studies have shown that leptin is an important factor associated with TNBC by promoting cancer stem cell (CSC) enrichment and/or epithelial-to-mesenchymal transition (EMT). Transcription factors SNAIL, TWIST and ZEB are critical components in enhancing EMT in cancer cells. The specific mechanism(s) by leptin regulates SNAIL, TWIST and ZEB expression remain unclear, limiting the development of effective interventions to improve outcomes in obese TNBC patients. Recent studies have demonstrated that miR200c, downstream of leptin receptor signaling, regulates the expression of SNAIL1, TWIST and ZEB. We will test the hypothesis that leptin contributes to obesity-induced EMT/CSC in TNBC through modulation of miR200c. Methods: Ob-R (leptin receptor) expression was suppressed in TNBC MDA-MB-231 and E-Wnt cells using shRNA (Ob-R null). Ob-R and Ob-R null cells were exposed to sera pooled from lean or obese women, as well as lean sera supplemented with leptin, after which expression of SNAIL, TWIST, ZEB and miR200c was measured by qPCR, while activation of the JAK-STAT pathway was assessed by Western blotting. Results: TNBC cells exposed to obese and high leptin conditions demonstrated increased expression of EMT markers compared to levels expressed under lean conditions. The Ob-R WT and null cells were used to determine the specific role of leptin signaling in regulating expression of SNAIL, TWIST and ZEB through miR200c. Conclusions: Both obese and high leptin conditions result in increased expression of EMT regulators, suggesting that effective targeting of this pathway may provide clinical benefit in the obese breast cancer patient. Elucidating the specific mediators of this pathway will guide development of novel and more potent medical therapies.
Effect of RNA-binding protein MSI2 deficiency on progression in triple-negative breast cancer via stabilizing TP53INP1.
Authors: Wei Ping , Li Ming , Yang Wentao , Zhou Xiaoyan
Published: May 2019

e12555

Background: The RNA-binding protein Musashi-2 (MSI2) has been implicated in the tumorigenesis and tumor progression of human cancers. This study investigated the clinical significance of MSI2 and the potential molecular mechanisms involved in triple-negative breast cancer (TNBC) progression. Methods: The Illumina sequencing platform was used to analyze the mRNA transcriptome in TNBC vs. normal tissues, while quantitative reverse transcription–polymerase chain reaction and immunohistochemistry validated MSI2 expression in breast cancer tissues and the effects of MSI2 on TNBC cells were assayed in vitro and in viv o. RNA immunoprecipitation (RIP) DNA and RNA sequencing was performed to identify the potential MSI2-targeted mRNAs. RIP and luciferase analyses were used to confirm the mRNA targets of MSI2. Results: MSI2 expression was significantly downregulated in TNBC vs. normal tissues and was associated with a poor overall survival of patients. MSI2 overexpression in vitro and in vivo inhibited TNBC cell proliferation and invasion as well as the extracellular signal-regulated kinase 1/2 (ERK1/2) activity. Molecularly, MSI2 expression promoted the stability of TP53INP1 mRNA by its interaction with the TP53INP1 mRNA 3ʹ-untranslated region. Furthermore, knockdown of TP53INP1 expression was able to reverse MSI2-induced suppression of TNBC cell invasion, whereas ectopic expression of TP53INP1 and inhibition of the ERK1/2 activity blocked MSI2 knockdown-induced TNBC cell invasion. Conclusions: The current study demonstrated that downregulated MSI2 expression was associated with TNBC progression and a poor prognosis and that MSI2 expression inhibited TNBC proliferation and invasion by induction of TP53INP1 stability and inhibition of ERK1/2 activity.
Innate and adaptive immunotherapy: An orchestration of immunogenic cell death by overcoming immune suppression and activating NK and T-cell therapy in patients with third line or greater TNBC.
Authors: Nangia Chaitali Singh , Kistler Mira , Sender Leonard S. , Lee John H. , Jones Frank R. , Jafari Omid , Soon-Shiong Patrick
Published: May 2019

e12566

Background: Triple-negative breast cancer (TNBC) is a heterogenous subtype of breast cancer that is frequently aggressive and has limited treatment options. We hypothesize that effective and sustained response against TNBC requires a coordinated approach that: 1. reverses the immune-suppressive tumor microenvironment, 2. induces immunogenic tumor cell death and 3. reengages NK and T-cell tumor response against a 4. cascade of tumor antigens. To test this hypothesis, we have developed a temporospatial approach that combines metronomic low dose chemotherapy, SBRT, off-the-shelf cryopreserved allogeneic NK cells, yeast and adenoviral tumor-associated antigen vaccines, an IL-15RαFc superagonist, and checkpoint inhibition. Methods: A phase 1b trial in patients with previously-treated metastatic TNBC was initiated. Treatment occurred in 3-week cycles of low-dose chemotherapy (aldoxorubicin, cyclophosphamide, cisplatin, nab-paclitaxel, 5-FU/L), antiangiogenic therapy (bevacizumab), SBRT, engineered allogeneic CD16 NK-92 cells (haNK), IL-15RαFc (N-803), adenoviral vector-based CEA, MUC1, brachyury, and HER2 vaccines, yeast vector-based Ras, brachyury and CEA vaccines, and an IgG1 PD-L1 inhibitor, avelumab. The primary endpoint is incidence of treatment-related adverse events (TRAEs). Secondary endpoints include ORR, DCR, PFS, and OS. Results: 8 subjects with 3rd-line or greater TNBC have received at least 3 treatment cycles (mean = 6 cycles). All treatment was administered in an outpatient setting. All subjects had at least 1 grade ≥3 TRAE, primarily chemotherapy-related neutropenia. Grade ≥3 haNK-related AEs (fever and fatigue) were observed in 2 subjects. 2 subjects experienced SAEs. 7 subjects remain alive, with 6 subjects receiving ongoing study treatment. 1 CR (confirmed) and 2 PRs (one confirmed) have been observed to date. Conclusions: These preliminary data suggest that low-dose chemo-radiation combined with innate and adaptive immunotherapy can be administered safely in an outpatient setting with a manageable safety profile. Clinical trial information: NCT03387085.
Asymptomatic versus symptomatic metastatic breast cancer: Potential effects on prognosis and treatment strategies.
Authors: Kuba Sayaka , Yamanouchi Kosho , Maeda Shigeto , Yano Hiroshi , Minami Shigeki , Moriuchi Hiroki , Matsumoto Megumi , Otsubo Ryota , Morita Michi , Sakimura Chika , Inamasu Eiko , Yamaguchi Junzo , Kanetaka Kengo , Takatsuki Mitsuhisa , Nagayasu Takeshi , Eguchi Susumu
Published: May 2019

e12568

Background: Early breast cancer (BC) patients in Japan can receive a follow-up CT scan, which can diagnose asymptomatic metastatic (M)BC. How symptomatic and asymptomatic MBC differ regarding prognosis and whether treatment strategies should differ is unclear. Methods: A retrospective, multicenter, cohort study was performed. We reviewed records of MBC women treated at four institutions between 2008 and 2018. Follow-up CTs were not routinely performed. Patients were divided into three BC subtypes: Luminal (ER+, PgR+, or both, but HER2-), HER2 (HER2+), and triple negative (TN) (ER-, PgR-, HER2-). Results: Of 205 MBC patients, 120 were luminal, 51 HER2, and 34 TN. Ninety were diagnosed with symptomatic and 115 with asymptomatic MBC. Symptomatic MBC patients had the following symptoms: locoregional metastasis (43%), bone pain (25%), cough or dyspnea (16%), and brain-related symptoms (10%). Diagnosis of asymptomatic MBC was based on follow-up imaging (71%) and elevated tumor markers (27%). The proportion of the patients with symptomatic MBC were different in each subtype: 38% luminal, 45% HER2, and 65% TN (p = 0.02). Among luminal patients, median overall survival (OS) after metastasis was longer for those with asymptomatic versus symptomatic MBC (62 vs 41 M, respectively; p = 0.04), although disease-free interval (48 vs 54 M, respectively; p = 0.40) and OS after breast surgery (119 vs 126 M, respectively; p = 0.93) did not differ significantly. Conversely, among TN patients, those with asymptomatic MBC had significantly longer median OS after metastasis and after breast surgery. Although the median period of cumulative endocrine therapy after metastasis did not differ between groups, luminal BC patients with asymptomatic MBC received chemotherapy longer than those with symptomatic MBC (20 vs 12 M, respectively; p = 0.02). Most patients switched to chemotherapy because of endocrine resistance without life threatening disease. To diagnose asymptomatic MBC might lead to longer use chemotherapy. Conclusions: Physicians should take symptomatic versus asymptomatic MBC into consideration in predicting prognosis to optimize treatment strategies.
Hybrid capture-based genomic profiling of circulating tumor DNA from patients with metastatic breast cancer.
Authors: Guan Xiaoxiang , Zhu Hong , Xie Wenzhuan , Zhao Jing , Wang Guoqiang , Zhang Yuzi , Zhao Zhengyi , Cai Shangli
Published: May 2019

e12569

Background: Breast cancer is the most common malignancy among women worldwide. It is particularly important to provide precise therapies based on genomic alterations, especially for metastatic breast cancers (MBC), which exhibit a high tumor heterogeneity and dynamic changes during the course of disease progression. However, genomic sampling upon metastatic tissue biopsy frequently encountered difficulties due to its inherent invasive approach such as insufficient samples and clinical risks. Our study aims to assess the genomic alternation landscape of metastatic breast cancer detected by blood-based circulating tumor DNA (ctDNA) and evaluate the assay performance. Methods: We performed hybrid capture-based next-generation sequencing (NGS) of 150 genes on ctDNA from 203 female patients with MBC. The mean sequencing depth was more than 3000×. The results were compared with our internal tissue genomic database (297 female patients with MBC) tested by NGS and TCGA database (N=982) tested by whole exome sequencing. Genomic alterations including single nucleotide variation (SNV), insertions/deletions, copy number variations, gene rearrangement and fusions were assessed. Results: Genomic data from 203 female patients with metastatic breast cancer were analyzed via ctDNA [median age 53 years (range, 46–61 years)]. Evidence of ctDNA as estimated by the maximum somatic allele frequency (MSAF) was detected in 95.6% of the patients (median=7.1 alterations/patient), and 97.0% of the patients had at least one characterized altered gene. The most frequently mutated genes identified for SNV occurred in TP53 (47.8%), PIK3CA (36.0%), and ESR1 (16.3%) upon ctDNA analysis and TP53 (73.2%), PIK3CA (38.4%), and ESR1 (4.0%) from our internal tissue database. However, in TCGA cohort, where most patients were presented with early stage diseases, the most mutated gene in terms of SNV was PIK3CA (32.5%), followed by TP53 (30.7%) and TTN (16.0%). The status of ERBB2 amplifications had a high concordance among ctDNA (14.8%), tissue (14.9%), and TCGA database (13.5%). The MSAF level was significantly higher for the fusion-present cases (P=0.048) or amplification cases (p<0.0001) than non-fusion or non-amplification cases. Conclusions: Our study has suggested that ctDNA profiling is a feasible approach for the molecular analysis in metastatic breast cancer and may better capture the mutational landscape of MBC for further clinical implications.