bluuebunny/crossref_metadata_2025 huggingface dataset:
CDK4/6 plus aromatase inhibitor-induced alopecia in breast cancer patients.
Authors: Chan Donald , Freites Martinez Azael David , Goldfarb Shari Beth , Modi Shanu , Gajria Devika , Lacouture Mario E.
Published: May 2019

e12537

Background: Cyclin-dependent kinase (CDK) 4 and 6 inhibitors are a novel therapy for metastatic breast cancer, and have shown to double the risk of alopecia. This study analyzed CDK4/6 plus aromatase inhibitor-induced alopecia (CDKIA), its impact on quality of life (QoL), and response to topical dermatologic therapy. Methods: The study analyzed a retrospective cohort of breast cancer patients diagnosed with CDKIA, evaluating clinical features, QoL, and response to therapy. CDKIA was also compared with endocrine-therapy induced alopecia (EIA). Results: 39 female CDKIA patients (median age 62 years [range 34-81]) were included, and 36 (92%) had standardized clinical images. CDKIA was most commonly attributed to a CDK inhibitor and letrozole in 23 patients (59%). CDKIA was similar to androgenetic alopecia (AGA) in every patient. Compared to EIA, CDKIA took less time to develop, was more severe, was associated with diffuse alopecia more frequently, and consisted of more vellus hairs on trichoscopy (Table). The Hairdex questionnaire, an alopecia-specific QoL survey, showed that CDKIA patients experienced worse QoL than EIA patients ( P < 0.05) and were most affected emotionally ( P < 0.01). There was a moderate to significant alopecia improvement in 11 of 13 CDKIA patients (85%) after treatment with topical minoxidil. Conclusions: CDKIA was clinically similar to AGA in association with diffuse alopecia. Patients with CDKIA had a negative emotional impact on appearance-based QoL. However, topical minoxidil may improve the severity of CDKIA. Baseline characteristics of CDKIA and EIA patients. [Table: see text]
Clinical value of Ki67 in risk-stratifying HR-positive breast cancer.
Authors: Bulbul Ajaz , Araujo-Mino Emilio Paul , Bautista Adriana , Rashad Sadaf , Khorsand-Sahbaie Masoud
Published: May 2019

e12540

Background: Oncotype DX (ODX) is a validated clinical tool requiring efficient utilization. Ki67 protein immunohistochemistry (IHC) may represent a screening approach correlating with the Recurrence score (RS) in resource limited setting. Methods: We retrospectively studied 242 patients (Jan. 1989 – Oct. 2017) across rural practices in NM. Median time to follow-up was 8.9 (0.03, 26.8) yrs. ODX candidates evaluated included node positive (NP), negative (NN), hormone receptor (HR) positive and HER2 negative cohort. Ki67 <20% (LKi-n=196) vs >20% (HKi-n=46) was compared to Low/Intermediate (LODX-n=202) vs High risk ODX (HODX-n=40). Descriptive statistics, Chi-square, Kaplan Meier survival and Cox proportional hazard models were used. Results: Median age was 64 ± 13.2. Stage I (54.1%), II (42.6 %), and III (3.3%); Grade 1 (24.2%), 2 (46.7%), 3 (24.9%). LKi in (196/242) 81%, HKi in (46/242) 19%. LODX in (202/242) 83.4%, HODX in 40/242 (16.5%). LKi was associated with stage I (87%), II (78%) vs. Stage III (25%) (p=0.015). LKi was associated with lower grades 1 (100%), 2 (92%) vs grade 3 (40%) (p=<0.001). LKi was associated with LODX (190/242) 94% and HKi with HODX (34/40) 85% (p <0.001). ODX recategorized 3% (6/196) LKi into HODX and 26% (12/46) HKi to LODX. LKi vs HKi 10-year FFP was 0.97 + 0.01 vs 0.73 + 0.08 HR 8.31 (3.12, 22.14)(p=<0.01) and 10-year OS was 0.87 + 0.03 vs 0.78 + 0.08 HR 1.77 (0.84, 3.78) (p=0.13), respectively. Ten-year OS in LKi was 0.98 + 0.02 vs 0.97 + 0.02 HR 0.42 (0.04, 3.62) (p= 0.43) with (n=46) or without (n=121) adjuvant chemotherapy respectively. Conclusions: LKi is predictive of excellent outcomes. It may have a role in risk stratification when access to ODX is limited. Lack of standardization of Ki67 reiterates the value of ODX. Prospective data are needed to confirm these findings.
Learning from every patient: Real-world clinical outcomes of patients with metastatic triple-negative breast cancer treated in the community oncology setting.
Authors: Khanna Anchit , Bowers Elani , Haiderali Amin , Slancar Michael Marian , Rainey Natalie Heather , Teo Lee Na , Collins Ian M. , Tafreshi Ali , Pokharel Khageshwor , Sabbah Ream , Bohensky Megan
Published: May 2019

e12554

Background: Triple-negative breast cancer is a biologically aggressive disease that accounts for 15% of all breast cancers, of which around 4-5% are metastatic (mTNBC) at diagnosis. Notably, there is no standard of care for mTNBC in the first line (1L) setting. This, in addition to higher relapse rates and poor long-term survival, warrants evaluation of real-world treatment patterns, especially in the 1L setting, to better inform on clinical outcomes. Methods: This observational, retrospective, chart review study included a cohort of twenty-six mTNBC patients from six different sites Australia, who commenced 1L treatment between July 1, 2012 and June 30, 2015. Medical records of eligible patients were abstracted using electronic case report forms after gaining relevant ethics approvals. Data on treatment patterns and clinical outcomes in the 1L setting were then collected from the index date until the end of data abstraction or death. The index date is defined as the date of initiation of 1L systemic therapy for mTNBC. Results: In the 1L setting, patients that received combination (52%) chemotherapy was slightly higher than single-agent (48%) chemotherapy. The commonest combination used was Carboplatin-Gemcitabine (12%), and the most common monotherapy was Nab-Paclitaxel (24%). The overall response rate and disease control rate were estimated to be 32% and 60% in the 1L setting. The median duration of treatment and the median time to next line of therapy were calculated to be 98 days and 12.45 (95% CI 2.79, 20.30) months respectively. Importantly, the median progression free survival (sensitivity analysis) and the median overall survival were estimated to be 3.17 (95% CI 1.91, 5.09) and 10.41 (95% CI 5.36, 16.53) months respectively. Conclusions: Chemotherapy is currently the mainstay of treatment for mTNBC. However, disease progression and chemo-related toxicities warrant stratified use of more efficacious and tolerable treatment options, especially in the 1L setting. Results from this study could be useful in comparing the efficacy and cost effectiveness of these emerging targeted and immuno-therapies outside the clinical trial setting.
Real-world data regarding the efficacy of neoadjuvant carboplatin-paclitaxel followed by dose-dense adriamycin-cyclophosphamide for triple-negative early breast cancer.
Authors: Bhojwani Ajay Ashok , Flint Helen , Hall Benjamin James , Wong Helen , Innes Helen , Cliff Joanne , Ahmed Eliyaz , Malik Zaf , O'Hagen Julie , Tolan Shaun , Hall Allison , Hayat Khizar , Errington Douglas , Alam Farida , Thorp Nicky , O'Reilly Susan , Law Andrea , Cicconi Silvia , Jackson Richard , Palmieri Carlo
Published: May 2019

e12559

Background: Platinum based regimens in the neoadjuvant (NA) setting for triple negative breast cancer (TNBC) have resulted in a significant increase in the pathological response (pCR) rate but at the cost of worse hematological toxicities. Despite these data such NA regimens are not widely used as yet for TNBC. Currently, no real world evidence exist regarding the efficacy and toxicity of this treatment regimen. Methods: Patients treated with neoadjuvant carbo-pac-ddAC between December 2015 and May 2018 at Clatterbridge Cancer Centre NHS Foundation Trust were identified via pharmacy records. Clinical records were reviewed, and clinico-pathological information and toxicity data were recorded. Data lock was January 16, 2019. Results: 53 female patients were identified with a median age of 48 years (IQR: 40.0-55.5). At presentation: Median tumour size 29mm (IQR: 20.0-40.0), 45% (24/53) were LN +, 8% (4/53) were ER+. Of 30 patients tested for germ line susceptibility, 23% (7/30) were found to have a BRCA mutation (full details to be presented). Delivery of planned CT : 4% (2/53) discontinued early for progressive disease or patient choice; of the remaining patients there were a total of 36 deferrals and 8 dose reductions. Surgical details: Breast: 42% (22/53) mastectomy & 58% (31/53) WLE, Ax management: 37% (19/51) Ax clearance & 63% (32/51) sentinel node biopsy (2 patients underwent previous axillary treatment for prior BC). Of 24 patients LN+ at presentation 58% (14/24) underwent Ax clearance; of these 64% (9/14) had no Ax involvement. pCR rate (ypT0/is, N0) (cases with prior ipsilateral Ax surgery excluded) was 53% (27/51) & pCR breast alone: 60% (31/52). Radiotherapy: 90% (47/52) received radiotherapy post-surgery. Outcome: At a median follow up 42.4 wks (IQR: 34.2-54.4), 6% (3/52) patients had disease recurrence resulting in 2 deaths. Conclusions: These initial real world data confirm the efficacy of NA therapy with carbo-pac-ddAC, with pCR rates consistent with literature. These results support the use of platinum based chemotherapy in the NA management of TNBC. Updated outcomes will be presented based on pCR versus no pCR; and BRCA status.
Somatic mutations in triple-negative breast carcinoma and high-grade serous ovarian carcinoma from young women.
Authors: Serio Pedro Adolpho MP , Pereira Glaucia Fernanda Lima , Katayama Maria Lucia Hirata , Maistro Simone , Lopez Rossana Veronica Mendoza , Roela Rosimeire Aparecida , Rodrigues Livia Munhoz , Koike Folgueira Maria A. A.
Published: May 2019

e12561

Background: High grade serous ovarian carcinoma (HGSOvCa) and triple negative breast cancer (TNBC) share characteristics, such as poor prognosis, BRCA1 germline mutations and TP53 somatic mutations. Our aim was to analyze somatic mutations from HGS-OvCa and TNBC from young patients aged ≤ 40 years. Methods: Whole genome or exome sequencing data for TNBC (n = 83) or HGS-OvCa (n = 21) was recovered from COSMIC or cBioPortal. Data was searched for cancer driver genes catalogued in Cancer Gene Census (CGC) or Candidate Cancer Gene Database rank A or B (CCGD) and for DNA repair genes. Results: TNBC mainly consisted of ductal carcinomas (78/83). A median of two cancer causing genes was affected in both TNBC and HGS-OvCa and TP53 was mutated in at least 2/3 of the samples. Only 7/83 and 2/19 of TNBC and HGS-OvCa samples, respectively, did not present variants in known cancer causing genes. C > T substitutions were the most frequent events in both TNBC and HGS-OvCa, however transversions were more frequently detected in TNBC. Besides TP53, another 33 genes were mutated in both tumor types, including PIK3CA, RYR2, TARBP1, CSMD3, DNAH11, MYO3A, NF1, TNRC6A, CACNA1E, HCMN1, PRKDC. Conclusions: Although many similarities were detected, TNBC in young patients presents a higher number of transversions and almost 25% of HGSOvCa present somatic mutations in HR genes. [Table: see text]
Longitudinal treatment patterns and adverse events (AEs) in younger patients (Pts) with metastatic triple-negative breast cancer (mTNBC): A real-world landscape analysis.
Authors: Kuderer Nicole Maria , Varghese Della , Hill Kala , Lyman Gary H. , Botteman Marc
Published: May 2019

e12562

Background: While no uniform standard of care exists for mTNBC, conventional chemotherapy remains the treatment mainstay. This retrospective analysis of U.S. commercial claims data was conducted to characterize real-world longitudinal chemotherapy treatment patterns and predictors of AEs in mTNBC. Methods: We assessed all pts with mTNBC aged 18-60 years starting first-line (1L) chemotherapy from 01/01/2011 to 12/31/2015 in the IMS LifeLink database, which does not report on investigational therapies. Longitudinal treatment patterns, treatment duration, and AEs were characterized by line-of-therapy (LOT). The primary and secondary endpoints were any AE and treatment duration. Multivariable logistic and Cox regression analyses were used to identify clinical risk factors for AEs and predictors of longer treatment duration, respectively. Results: 1,447 mTNBC pts receiving ≥1 LOT were identified (median [range] age, 51 [24-60] years), of which 54% received ≥2 and 8% ≥3 LOT. Combination therapy (combi-Tx) was used as 1L for 73%, second-line (2L) for 22%, and third-line (3L) for 32% of pts. The most common combi-Tx was cyclophosphamide/doxorubicin (1L: 40%; 2L: 5%), and carboplatin/gemcitabine in 3L (17%). The most common 1L and 2L monotherapies (mono-Tx) were taxanes (10% and 66%), and 3L capecitabine (13%). Median treatment duration for 1L to 3L was 56-58 days, and for combi- vs mono-Tx in 1L, 50 vs 71 days. The proportion of pts experiencing any AE was 34% during 1L, 38% during 2L, and 56% during 3L therapy. After adjusting for key confounders including Charlson comorbidity index, independent risk factors for AEs were later LOT, 3L vs 1L (OR = 3.20, 95%CI: 2.13-4.79), and younger age groups vs age 55-60 (OR = 1.94, 95%CI: 1.48-2.55). Additional analysis will assess independent predictors of treatment duration. Conclusions: This real-world study reveals considerable treatment heterogeneity and short treatment durations even with conventional combination chemotherapies. Among non-Medicare mTNBC pts, younger age is a risk factor for AEs possibly due to more aggressive therapies. More treatment options are needed for pts with mTNBC.
Chronobiological assessment of triple-negative breast cancer.
Authors: Revazishvili Pati , Tavartkiladze Alexandre , Tavartkiladze Levan , Sordia Teimuraz , Gvajaia Ani
Published: May 2019

e12564

Background: Triple Negative Breast Cancer (ER-, PR-, Her2/neu-., TNBC) constitutes 15-18 per cent of all malignant breast cancers. It is characterized by aggressive course and high lethality. Methods: We assessed chronobiological features of 19 patients with TNBC (medium age group 34-71). We used data of Melatonin and Cortisol circadian secretions for assessment parameters. During the month, we took blood from patients on every third day, from 02:00-04:00 pm to 02:00-04:00 a.m time intervals. The control group was composed of 14 patients with breast cancer, histological type: ER/PR+ and Her2/neu-. Results: As the result of the research, meaningful differences have been revealed between the investigated and control group. In patients with TNBC, the medium day-time concentration of Melatonin during the day was 1.1 pg/ml (normal range - up to 20 pg/ml), while at night its level increased by 4.2 pg/ml. In the control group, the average day-time level was 5.7 pg/ml, and at night - 12.5 pg/ml. Regarding Cortisol, in the investigated group, in day-time hours its average concentration in blood was 2.1 μg/dl (normal tange - 2.5 - 11.9 μg/dl, at afternoon), while at night - 0.7 μg/dl (normal range < 1.8 μg/dl, at night). In the control group, at day-time, the average cortisol concentration was 4.095 μg/dl (normal range - 2.5 - 11.9 μg/dl, at afternoon), at night - 0.94 μg/dl (normal nange < 1.8 μg/dl, Night). Conclusions: The study results have showed significant biochemical differences between ER/PR+/ Her2/neu- and TNBC- patients. Reduction of circadian secretion of Melatonin, as a major biochemical marker, directly correlates with the degree of cancer aggression, as it is seen fom the study. Furthermore, in patients whose Melatonin concentration was critically low, ductal (CK5/6+ and/or EGFR+) and metaplastic (epidermal: CK5/6+, EGFR+, Ck14+, p63+) forms were histochemically detected, which are extremely aggressive subtypes of TNBC. Regarding Cortisol levels in patients with critically Melatonin level, the Cortisol concentration was at critically low margin as well, that is considered to be the additional chronobiological marker for the aggressive course and rapid progression of cancer.
Efficacy of platinum-based regimens as the first-line therapy in Chinese patients with advanced TNBC and deleterious BRCA1/2 mutations.
Authors: Wang Nan , Li Kun , Kong Wei-Yao , Liu Xiao-Ran , Tan Meng-Yao , Jiang Han-Fang , Song Guo-Hong , Di Lijun , Wang Quanren , Wang Amy , Yu Jianjun , Jia Shidong , Li Huiping
Published: May 2019

e12565

Background: Platinum-based therapy remains an effective treatment for triple-negative breast cancer (TNBC), however, the usage is largely limited due to its side effect and rapidly developed drug resistance. High prevalence of BRCA1/2 mutations are reported in TNBC. Here we explored efficacy of platinum-based regimens as the first-line treatment for Chinese patients (pts) with advanced TNBC, and analyzed its association with mutations of germline BRCA1/2 (gBRCA). Methods: We retrospectively analyze 220 patients diagnosed as advanced TNBC who were treated at the Dept. of Breast Oncology, Peking University Cancer Hospital in 2013-2018, and routinely evaluated by RECIST 1.1. Statistical analysis is performed in R 3.5.1. Cox proportional-hazard models are used for survival analysis. Results: 129 pts received non-platinum chemotherapy (NPCT) as the first-line therapy, and 91 pts received platinum-based chemotherapy (PBCT). The clinical benefit rate (CBR) and median PFS were not statistically different between NPCT and PBCT groups The median OS was 30.0 and 22.5 months for PBCT and NPCT group respectively (P = 0.09, HR = 0.70). Among them, 114 pts had BRCA gene tested, of which 14 had deleterious gBRCA mutations, 7 in each group. In PBCT group, the CBR was 85.7% and 35.1% for pts with and without deleterious gBRCA mutations respectively (P = 0.04). The median PFS, OS were 14.9 months and 5.3months (P = 0.001), 26.5 and 15.5 months (P = 0.16) for pts with and without the gBRCA mutations. No significant difference was observed between NPCT pts with and without gBRCA mutations as regards the CBR, PFS and OS. PBCT Pts had significantly more grade 3-4 anaemia (5.5% vs 0%) and thrombocytopenia (8.8% vs 0%) while higher percentage of palmar-plantar erythrodysesthesia (PPE) (12.4% vs 0%) and peripheral neuropathy (8.6% vs 1.1%) were observed in NPCT pts. Conclusions: The efficacy of platinum-based regimens as the first-line treatment of advanced TNBC insignificantly differs from that of non-platinum therapy. However, they are more effective for patients with deleterious gBRCA mutations, suggesting a BRCA1/2 genetic testing may be warranted for such patients.
Phase II study of eribulin mesylate for treatment of CNS metastases (mets) in metastatic breast cancer (mBC).
Authors: Nelson Ariel Ann , Manjappa Shivaprasad , Choudhary Yuvraj , Thompson Cheryl L. , Agler Jeanine , Lawrence Bethany , Ahluwalia Manmeet Singh , Silverman Paula
Published: May 2019

e12571

Background: There is no approved drug therapy for CNS mets from mBC. Eribulin mesylate (eribulin) is a microtubule inhibitor approved for treatment of mBC patients (pts) who have received at least 2 prior chemotherapy regimens. Previously reported cases have demonstrated significant CNS responses in mBC pts treated with eribulin. This study evaluates the CNS response in pts with mBC treated with eribulin. Methods: CASE7113 was a prospective phase II single-arm study to evaluate the 12-week CNS progression free survival (12-wk CNS-PFS) of pts with mBC and CNS mets treated with eribulin. 20 pts were to be enrolled to demonstrate a 40% 12-wk CNS-PFS (95% CI, 8.5% - 61.5%). All pts had radiologically confirmed mBC CNS lesions with at least one lesion that did not receive prior radiation or surgical resection. Eribulin was administered at standard dose of 1.4mg/m2 IV on days 1 and 8 of a 21 day-cycle. Pts underwent baseline and 12-week brain MRI. The study was closed due to slow accrual; an analysis of enrolled pts was performed. Results: 9 female pts were enrolled; median age was 56 (32-82) years. 55% and 67% had ER+ and/or PR+ and Her2+ mBC respectfully. 1 pt had triple negative breast cancer (TNBC). Median number of prior therapies was 3 (0-12). The 12-wk CNS-PFS (95% CI) was 88.9% (51.8% - 99.7%), the median PFS (95% CI) was 22.6 (4.3 - 31.9) weeks, the median OS (95% CI) was 15.7 (4.0 - 27.3) months. 4 pts achieved stable disease and 1 pt had a partial response. There were no unexpected toxicities. Conclusions: For mBCa pts with CNS mets, this estimate of 12-wk CNS-PFS suggests activity of eribulin and merits further investigation in this population in the context of clinical trials. Clinical trial information: NCT02581839.
Detection of brain metastasis by metabolomics methods in metastatic breast cancer patients.
Authors: Özer Özge , Nemutlu Emirhan , Eylem Cemil Can , Kır Sedef , Reçber Tuba , Aktas Burak Yasin , Kars Ayse , Aksoy Sercan
Published: May 2019

e12572

Background: The aim of this study was to identify markers for the early diagnosis of brain metastasis by metabolomic methods in breast cancer patients. Methods: A total of 88 breast cancer patients with distant metastases were included the study. The patients were divided into two groups according to their metastasis status as patients with brain metastases and patients with distant metastases without any brain metastases. For metabolomic analyses, liquid chromatography quadrupole time-of-flight mass spectrometry (LC-qTOF-MS) and gas chromatography mass spectrometry (GC-MS) analysis methods were used. Results: 88 patients were included the study. 33 of the 88 patients had brain metastasis group and 55 patients had distant metastases without brain metastasis. A total of 79 metabolites were identified by the GC-MS analysis. Of these, 11 of them (alanine, sphingosine, fructose, fumaric acid, glycine, lactic acid, phenylalanine, pyroglutamic acid, serine, threonine, and valine) were found at statistically significantly higher levels in the patient group with brain metastases (p < 0.05). In LC-qTOF-MS analysis 47 metabolites were identified with statistically significant results between the two groups. Predictive accuriecies for idendification of the brain metastasis with 5 and 10 metobolites models were 94.6% and 95.2%, respectively.Amino acyl tRNA biosynthesis, arginine and proline metabolism, nitrogen metabolism, cyanaminoacid metabolism, nicontic and nicotinicamide metabolism, glycine, serine and threonine metabolism pathways have been involved more significantly in patients with brain metastasis (p < 0.05). Conclusions: Although these results need to be confirmatory prospective studies, these data promising for early detection of the brain metastasis by markers in sera.
Chronobiological features of melatonin receptors (MT1) expression in breast cancer cells.
Authors: Tavartkiladze Alexandre , Gvajaia Ani , Revazishvili Pati
Published: May 2019

e12581

Background: According to WHO data, Breast Cancer is the most prevalent malignancy in women. The biological role of Melatonin in the etiology and pathogenesis of the tumour disease has already been approved by a number of research studies. The purpose of our investigation was the assessment of features of Melatonin receptor circadian expression in circulating tumour cells of breast cancer (CTCs). Methods: We observed 34 patients (aged 36-68) with breast cancer (various immunophenotypes). CTCs were separated from patients’ venous blood every third day, in 02:00-04:00 pm and in 02:00-04:00 am intervals. The cells were taken from each patient 4 times. On CTCs, MT1 – receptor expression was assessed using immunocytochemical method. Results: Results of the study revealed that Melatonin receptor expression in breast cancer patients is characterised by the noticable circadian rhythmics. MT1–receptor expression peak by CTCs was detected at 02:00-04:00 am i.e. at night. The less aggressive tumor the higher is the extent of the receptor expression (density). Respectively, in hormone dependent and Her2/neu (negative) tumors the highest expression of the MT1–receptor occurs in hormone dependent and Her2/neu(positive) tumors–medium expression and in triple negative breast Cancer (TNBC) cells–the lowest expression, while in some TNBC–circulating tumor cells MT1 receptor expression has not been detected at all. Conclusions: Hence, based on our the results, we can conclude that Melatonin as the expression of main biochemical marker receptors of bio-rhythms in breast cancer cells, has highly expressed chronobiological nature and directly correlates with histological types of tumor, that provides conditions for the development of new chronotherapeutic strategies in breast cancer treatment.
Tracking the tumor evolution of patients with recurrence of ipsilateral breast tumor.
Authors: Song Yane , Peng Li , Zhou Wei , Niu Yiru , Yang Wanning , Mao Beibei , Guo Xianchao , Han Wenbo , Zhang Henghui , Chen Weizhi , Mao Feng
Published: May 2019

e12582

Background: After primary surgical resection, quite a proportion of breast cancer survivors would experience local recurrence within 5 years. Whether local recurrent tumors arise independently or from the primary tumors, which is critical for diagnosis and appropriate treatment, remains a clinical dilemma. Phylogenetic analysis between the primary and recurrent tumor provides a new strategy helpful for determining the origin of the local recurrent tumor. Methods: DNA was extracted from FFPE samples of the primary and recurrent tumors from 12 patients with recurrence of ipsilateral breast tumor. Phylogenetic analysis between the primary and recurrent tumors in the same individual was performed based on whole exome sequencing. PyClone and SciClone were employed to detect subclones. Results: The median time to recurrence of the 12 patients was 15 months (9 to 52 months). 9 (75%) of the 12 patients recurred within 2 years. Each patient had one shared somatic mutation clone between the primary and recurrent tumor, with shared somatic mutation number ranging from 5 to 59. This observation suggests that the recurrent tumor maybe originate from the primary tumor. Conclusions: The shared somatic mutation clone indicates the primary and recurrent tumor could be of the same origin and the recurrent tumor was metastasis from primary lesion. This may provide some information to help selecting the most appropriate treatment for patients.
The landscape of palliative systemic therapy and overall survival of 2,063 advanced breast cancer patients in the China National Cancer Center.
Authors: Guan Xiuwen , Xu Binghe , Ma Fei , Li Qing , Zhang Pin , Yuan Peng , Wang Jiayu , Luo Yang , Cai Ruigang , Li Qiao , Mo Hongnan , Li Yiqun , Lin Shaoyan , Chen Yimeng , Wang Zijing
Published: May 2019

e12583

Background: Despite novel therapeutic options evolved rapidly, advanced breast cancer (ABC) remains an incurable disease with a median overall survival (OS) of 24-30 months. However, real-world data on the treatment and outcome of ABC in routine practice was rare, especially in Chinese cohort. Methods: We summarized the clinicopathological characteristics, therapeutic regimens and survival outcome of 2063 females with ABC who were hospitalized between January 2003 and December 2013 from the Database in China National Cancer Center. Results: The median OS of enrolled population was 42.6 months (95% CI 39.6 to 45.5). Significantly prolonged OS was observed since 2011 ( P= 0.041), with a median OS of 41.0 months (95% CI 37.5 to 44.4) in patients diagnosed with ABC in 2003-2010 and 44.6 months (95% CI 37.9 to 51.2) in 2011-2013, respectively. Between these two periods, Luminal-like, HER2-positive, and Triple-negative patients had an improved median OS of 45.9 to 56.2 months ( P= 0.001), 38.3 to 43.1 months ( P= 0.414), and 28.6 to 28.7 months ( P= 0.364), respectively. As for the analysis of therapeutic mode alteration, the proportion of multidisciplinary care for recurrent disease raised significantly over the years (χ2= 8.2, P= 0.004), from 39.6% in 2003-2010 to 47.7% in 2011-2013. In Luminal-like patients, the application of endocrine therapy increased significantly from 64.4% in 2003-2010 to 77.6% in 2011-2013 during the palliative systemic therapy (χ2= 17.7, P < 0.001). Among HER2-positive patients, significantly increased application of HER2-targeted therapy were observed in both adjuvant therapy (χ2= 4.7, P= 0.030) and palliative therapy (χ2= 10.3, P= 0.001) between these two periods. For patients receiving the first-line chemotherapy, the use of maintenance treatment ascended dramatically from 37.1% in 2003-2010 to 58.8% in 2011-2013 (χ2= 50.5, P < 0.001). The percentage of participating clinical trials was 14.3%, slightly increased in 2011-2013, when compared with the proportion of 11.6% in 2003-2010 (χ2= 2.0, P= 0.160). Conclusions: Real-world data revealed that significantly prolonged OS in China was achieved since 2011 due to the increased use of multidisciplinary care, endocrine therapy, HER2-targeted therapy and maintenance treatment.
Nab-paсlitaxel (Nab-P) in patients with metastatic breast cancer (mBC) with visceral crisis (VC): Efficacy and tolerability.
Authors: Novoselova Kristina A. , Vladimirova Liubov Yu , Abramova Natalia A , Storozhakova Anna E , Popova Irina L. , Tikhanovskaya Natalia M. , Ryadinskaya Ludmila A. , Lyanova Aza A. , Salamov Georgy , Teplyakova Maria , Prikhodko Ekaterina , Tishina Anna V.
Published: May 2019

e12589

Background: Better efficiency and safety of Nab-P is known to be due to the advantages of pharmacokinetics and pharmacodynamics of the drug. The fraction of unbound paclitaxel in plasma is 2.6-fold higher with Nab-P than with P. The purpose of the study was to assess efficacy and safety of Nab-P in ≥2nd lines of chemotherapy (CT) in patients (pts) with mBC with VC. Methods: Inclusion criteria: mBC with VC, ≥ 2 line of CT, HR+, HER2neu+ or triple negative type (TN), normal liver and renal function. Pts received Nab-P 260 mg/m2 q 21 days. Pts with Her2/Neu + received trastuzumab 6 mg/kg q 21 days. Results: 32 mBC pts, mean age 51.34 years (CI 35-76) were included. Among 32 pts Her2/Neu + had 5 (15.6%), TN – 9 (28.1%), HR+ 18(56.3%). 13(40.6%) pts received Nab-P as 2 line of CT, 13 (40.6%) pts, as 3-4 lines, 7(21.9%) as ≥5 lines. Pts were divided into 2 groups: group A - pts with VC 17(53.1%), group B - without VC 15(46.9%). Groups were comparable by age, number of previous CT lines, immunohistochemical types of BC. Group A had 2.47±0.32 CT lines (CV51.83%), including 8(47%) pts, who had received paclitaxel (P) in previous CT lines. Group B had on average 2±0.27 CT lines (CV53.03%). The objective response rate (ORR) was 37.5%(12 pts). In the group A ORR was 35.3% (6 pts). Out of 8 pts with VC, who had received P in previous lines, ORR was achieved in 3 pts (37.5%). In the group B ORR was 33.34%(5 pts). TTP was 6.8 mos (95% CI 6.1-13.7) for all pts, in the group A – 5.7 mos (95% CI 5.9-10.2), in the group B 6 mos (95% CI 6.5-13.7) (p = 0.046). Median 3-year OS of pts in group A was 18.9 mos (95% CI 4.3-22.4), in group B - 22.5 mos (95% CI 8.2-26.7) (p = 0.038). Toxicity did not differ significantly in pts in groups A and B and was manageable. Pts, who previously received P, had no new or severe toxicity. Conclusions: The data obtained confirms the possibility of Nab-P application in pts with VC. The use of Nab-P in pts treated with taxanes in previous lines is supposed for further study.
An EGFR extracellular domain mutation data in the East Asian non-small cell lung cancer populations and response to icotinib: A multicenter study.
Authors: Wang Wen xian , Xu Chunwei , Chen Yu , Cai Xiuyu , Fang Yong , Zhang Quxia , Zhu You-cai , Yu Zongyang , Chen Gang , Wang Hong , Zhuang Wu , Chen Xiaohui , Huang Yun-jian , Shen Hong , Zheng Song , Zhou Ji'an , Ye Junhui , Fang Meiyu , Lv Tangfeng , Song Yong
Published: May 2019

e13000

Background: “Pan-negative” non-small cell lung cancer (NSCLC) patient specimens that lack mutations in known targetable genes. EGFR extracellular domain mutations (ECD) as novel oncogenic mutations are found in colorectal cancer, glioma, and neuroblastoma cases and has not yet reported in NSCLC. No enough evidence between icotinib treatment and ECD has been reported in NSCLC. Methods: Comprehensive mutational analyses were performed on 3279 NSCLC specimens. In this cohort of patients, common lung cancer oncogenic driver mutations were firstly detected in EGFR, as well as the KRAS, BRAF, ALK, ROS1 and RET genes by next generation sequencing tumor DNA (ctDNA) and apply icotinib for treatment for EGFR ECD. Results: Of this entire cohort, sixteen (0.49%) patients (3279 cases) were identified with EGFR ECD, including p.L62R (2), p.R98Q (1), p.I213M (1), p.A237F (1), p.A289V (1), p.A289T (1), p.T302H (1), p.T354K (1), p.T363N (1), p.D368Y (1), p.T430S (1), p.A508V (1), p.N528D (1), p.K593Q (1) and G598V (1). During the treatment by icotinib, two cases (p.A289V, p.A289T) had partial response to icotinib for four and six months, which suggested that icotinib conferred sensitivity to A289X mutation. EGFR A289X mutations were sensitive to icotinib treatment in BaF3 cell lines and in xenograft models. These results paralleled those seen with the well-described EGFR oncogenic driver mutation, L858R, suggesting similar mechanistic underpinnings for the mutations. Conclusions: Here, a new EGFR driver mutation, A289X, was identified in the ECD of two NSCLC specimens. NGS may expand the EGFR mutations spectrum for icotinib treatment in NSCLC, however, it needs to be confirmed in more patients with NSCLC in East Asian and other populations.
Real-world large-scale study of ERBB2 gene fusions and its response to afatinib in Chinese non-small cell lung cancer (NSCLC): A multicenter study.
Authors: Xu Chunwei , Wang Wen xian , Zhang Quxia , Chen Yu , Cai Xiuyu , Fang Yong , Zhu You-cai , Huang Yun-jian , Wang Hong , Zhuang Wu , Zhang Yinbin , Wang Liping , Jiang Xiaofang , Cai Shangli , Huang Jianhui , Feng Shuitu , Fang Meiyu , Chen Gang , Lv Tangfeng , Song Yong
Published: May 2019

e13002

Background: ERBB2 mutation has been found to be an oncogenic driver gene in non-small cell lung cancers (NSCLC) and ERBB2-directed therapies have shown promising results in this unique population, while little is known about ERBB2 fusion association with outcomes of afatinib. The aim of this study was to investigate the efficacy of afatinib in patients with advanced ERBB2 fusion NSCLC. Methods: A multicenter study in China was initiated from February 2014, and NSCLC patients have been enrolled as of December 2018. To determine the frequency of the ERBB2 fusions in NSCLC and other tumors, we analyzed data from 2743 clinical NSCLC cases, each of which had results from next-generation sequencing (NGS)-based 381 genes panel assay, analogous to the index patient. Results: Of this entire cohort, eight (0.29%) patients were identified with an ERBB2 fusion, including TNS4-ERBB2 (1), ERBB2-CD79B (1), IGFBP4-ERBB2 (1), ERBB2-PSMD3 (1), SEZ6-ERBB2 (1), ERBB2-PGAP3 (1), ARL5C-ERBB2 (1) and B3GNTL1-ERBB2 (1). The genes most frequently co-altered in patients with ERBB2 fusions were TP53 (37.50%), CDKN2A (25.00%), RB1 (25.00%) and RBM10 (25.00%). Overall TMB in the ERBB2 fusions was low (median 2.97 mut/Mb). For treatments, 25.00% patients chose afatinib, another patients chose chemotherapy or chemoradiotherapy, and case examples of advanced ERBB2 fusion driven NSCLC patients responding to afatinib were actively being sought thru our database. Conclusions: Patients with advanced ERBB2 fusion NSCLC showed a good outcome of afatinib compared to those with ALK/ ROS1 fusion which response to crizotinib, which strengthen the need for effective ERBB2-targeted drugs in clinical practice.
Improving access to genetic counseling services in an adolescent and young adult (AYA) clinic.
Authors: Ross Jessica , Bell Donna , Yarbrough Angela R. , Peterson Susan K. , Makhnoon Sukh , Arun Banu , Livingston J Andrew , Roth Michael
Published: May 2019

e13009

Background: Numerous studies have explored genetic testing access and benefits in adult and pediatric cancer patients, however little is known about the use of these services in adolescents and young adult (AYA) cancer patients. Routine genetic counseling may be particularly important for AYAs who are survivors of childhood cancer, as 8.5% of children with cancer have an inherited pathogenic germline variant. Genetic testing also helps reduce cancer morbidity and mortality in adolescents, as well as helps to guide cancer prevention strategies in family members. This study describes an innovative approach to fostering AYA patients’ access to genetic counseling services. Methods: AYA patients (ages 15-29) with a new or prior cancer diagnosis were referred to MD Anderson Cancer Center’s AYA multi-disciplinary clinic. Prior to their clinic visits, a genetic counselor reviewed relevant medical and family history information for patients seen from 7/12/18 through 1/11/19. For those at risk for a hereditary cancer syndrome, a recommendation for a genetic counseling referral was given to the AYA medical provider based on established guidelines, professional consensus, and clinical judgement guided by thorough literature reviews. Results: In total, 254 AYA patients’ charts were reviewed and 70 (27.6%) patients had histories that warranted a genetic counseling referral. Of these 70 patients, 53 (75.7%) were not previously seen by genetics. Of the 53 patients newly recommended to be referred, 29 (54.7%) had referrals placed. Of the 24 patients not referred, 17 did not attend their AYA visit, 5 refused the referral, and 2 were not referred for undetermined reasons. Of those referred, 10 completed genetic counseling, 14 are scheduled for counseling, 3 did not attend their appointment, and 2 had counseling at another institution. This process led to a 41.3% absolute increase in referrals to genetic counseling for those at risk for hereditary cancer syndromes. Conclusions: The described clinic workflow identified gaps in genetic referrals and showed an innovative approach to fostering AYA access to genetic services. This approach may be useful for other institutions interested in increasing access to genetic services for AYAs.
Pathogenic germline mutation hotspots in east Asian cancer genomes.
Authors: Shi Xiaoshun , Chen Allen Menglin , Huang Kailing , Zheng Zhouxia , Chen Zhuona , Young Sylvia , Zhang Jiexia , Dong Xiaoying , Liu Xiguang , Lu Di , Feng Siyang , Morahan Grant , Cai Kaican
Published: May 2019

e13011

Background: To summarise the prevalence of pathogenic germline variants in East Asian cancer genomes and to develop an online resource and reference for genetic analysis of cancer susceptible germline mutation hotspots. Methods: We performed the most extensive investigation of germline mutations in East Asian cancer population based on publicly available data collected from multiple institutions over 1,600 patients with 15 cancer types. The pathogenic cancer susceptibility gene mutations were called by analyzing whole exome sequencing data generated from the normal control samples from the cancer patients deposited on the SRA database. Results: Compared with 9,435 East Asian controls in the gnomAD dataset, we identified pathogenic recurrent germline mutations based on our MaGiC analysis pipeline including quality controlled, filtration and annotation. More than 150 variants were found, and the top 3 hotspot mutations are TP53 in 5 types of cancer, BRCA2 in 3 types of cancer and PIK3CA in 4 types of cancer. The hotspot variants(same cancer predisposition gene set, but different pathogenic mutations) were of population difference in comparison with Caucasian population. Conclusions: Our work is the first comprehensive analysis of East Asian cancer predisposition germline mutations. It provides informative references for cancer genetic consulting and early prevention in more than 20% of world population. The update of our database covering larger populations and more cancer types is needed and still ongoing.
Integrated genomics-based approach to identify new therapeutic targets and cancer biomarkers for lung cancer.
Authors: Daigo Yataro , Takano Atsushi , Nakamura Yusuke
Published: May 2019

e13019

Background: Because the number of lung cancer patients who show good response to standard therapies is still limited, development of new anti-cancer agents with minimum risk of adverse effects and highly sensitive molecular biomarkers is urgently required. Methods: We have been screening novel therapeutic targets and their companion biomarkers for lung cancer as follows; i) To identify up-regulated genes in lung cancers by the gene microarray analysis, ii) To verify the candidate genes for their low expression in normal organs, iii) To validate the clinicopathological significance of their protein expression by tissue microarray covering hundreds of lung cancers, and iv) To verify their function for the growth of lung cancer cells by siRNAs. Results: We identified dozens of candidate oncoproteins and selected a serine/threonine kinase LASK2 (lung cancer-associated kinase 2). Immunohistochemical analysis showed that strong LASK2 positivity was an independent prognostic factor for non-small cell lung cancer patients (P < 0.0001). Suppression of LASK2 expression by its siRNAs inhibited proliferation of lung cancer cells. Introduction of LASK2 in mammalian cells also enhanced cellular growth in vitro and in mice model. Induction of LASK2 appeared to increase the levels of phosphorylation of oncogenic signal proteins for lung cancer. The data indicate that LASK2 is a prognostic biomarker and therapeutic target for lung cancers. Conclusions: Integrated genomics-based approach could facilitate the development of new cancer biomarkers as well as therapeutic targets for small molecules, monoclonal antibodies, nucleic acid drugs, and immunotherapies.
Confirmation of germline variants identified by tumor testing: A population-based study.
Authors: Pender Alexandra , Karsan Aly , Yip Stephen , Bosdet Ian , Young Sean , Tucker Tracy , Schrader Kasmintan A , Sun Sophie
Published: May 2019

e13021

Background: Multi-gene panel tumour testing (TT) has been available in British Columbia since mid-2016 for metastatic non-small cell lung cancer (NSCLC), colorectal cancer (CRC), melanoma (MEL), low-grade glioma (LGG), and gastro-intestinal stromal tumours (GIST). TT can detect somatic driver mutations and potential pathogenic germline variants (pPGVs) associated with hereditary cancer susceptibility. We reviewed the frequency of pPGVs identified by TT and examined referral rates to the Hereditary Cancer Program (HCP) for confirmatory germline testing (GT) and therapeutic implications of PGV findings. Methods: All patients (pts) undergoing TT testing from October 1, 2016 to December 31, 2018 were identified. Diagnosis, age, gender, family history and treatment data were obtained. TT was performed by next-generation sequencing for all/selected regions of the following genes: AKT1, ALK, BRAF, BRCA1, BRCA2, CCND1, CCND3, CIC, EGFR, ERBB2, ERBB3, FUBP1, HRAS, IDH1, IDH2, KIT, KRAS, MAP2K1, MET, NRAS, PDGFRA, PIK3CA, PTEN, ROS1, SDHA, SDHB, SDHC, SDHD. Results: Among 2937 TTs, pPGVs were identified in 83 pts (2.8%) [Table 1]. 50 pts (57%) were referred to HCP, 41 had germline testing, and 14 PGV were confirmed. PGVs were most commonly identified in BRCA1/2 and SDHA and these findings did not influence oncologic treatments. Conclusions: TT detected pPGVs in 2.8% of unselected pts with metastatic cancers. Among 41 pts undergoing germline testing, 34% who would not have otherwise met testing criteria, had a confirmed PGV. Referral rates were low due to lack of patient and clinician awareness and poor health status. Although PGV findings did not directly impact treatment, TT identified 14 new families with hereditary cancer who can benefit from early detection and screening. Future directions include expansion of TT to include additional hereditary cancer susceptibility genes and development of digital tools for pts and clinicians. [Table: see text]
Discussion on several problems between tumor-associated venous thrombosis and driving genes status.
Authors: Zhang Xue , Jiang Da , Yang Haiying , Zuo Jing , Jin Hui , Huang Fang
Published: May 2019

e13022

Background: The study aimed to explore clinical correlation between venous thrombosis and driving genes status in cancer patients (pts). Methods: The clinical data of cancer pts from 2014 to 2018 in our hospital were collected to calculate the overall thrombosis rate, driving gene mutation rate, and thrombosis rate in pts with mutated driving genes. Pts were divided into mutation group and non-mutation group based on the driving gene mutation status. Khorana model was used to divide each group into three subgroups and the thrombosis rate of each subgroup was calculated. The diagnostic value of the Khorana model was calculated in the whole patient set and each group. The correlation between driving gene mutation status and thrombus status was also analyzed. Results: A total of 2049 pts were enrolled, with 4.44% overall thrombosis rate and 72.13% driving gene mutation rate. The thrombosis rates in pts with EGFR, c-Met, ALK, HER-2, KRAS or ROS1 mutations were, in turn, 5.34%, 4.33%, 3.92%, 3.73%, 3.45% and 2.74%, however, there was no statistical difference in thrombosis rates between pts with or without the above gene mutations (EGFR, p = 0.90; c-Met, p = 0.23; ALK, p = 0.85; HER-2, p = 0.28; KRAS, p = 1.00; ROS1, p = 0.58). In the correlation analysis between the driving gene status and the thrombus status, the Spearman correlation coefficient was -0.024, and no statistically significant difference was observed (p = 0.69). Based on the Khorana model, the thrombosis rates of the low-, intermediate- and high-risk subgroups in the mutation group and non- mutation group were 0% vs 0%, 10.23 vs 8.33%, and 6.67% vs 12.50% respectively, which didn’t show statistically significant differences (low- risk, p = 1.00; intermediate-risk, p = 0.85; high-risk, p = 0.59). For the whole patient set, mutation group and non-mutation group, the Khorana model predicted venous thrombosis with the sensitivities of 13.33%, 10.00% and 20.00%, as well as the specificities of 92.02%, 92.55% and 90.67%; and the area under the ROC curve were 0.706 (p = 0.007), 0.719 (p = 0.02) and 0.681 (p = 0.18), respectively. Conclusions: The Khorana model has a moderate diagnostic value, and there is no correlation between the driving gene status of cancer pts and venous thrombosis.