bluuebunny/crossref_metadata_2025 huggingface dataset:
Intestinal HIF-2 to protect against radiation-induced gastrointestinal syndrome.
Authors: Taniguchi Cullen M , Wu Colleen , Atwood Todd , Maxim Peter , Giaccia Amato
Published: March 2020

10629

Background: Gastrointestinal (GI) toxicity accounts for significant morbidity during systemic chemotherapy or abdominopelvic radiation therapy. Unfortunately, there are no effective preventative treatments. Hypoxic signaling through hypoxia-inducible factor-1 (HIF-1) and -2 (HIF-2) is critical for intestinal homeostasis during inflammatory challenges and was posited to play a role in radioprotection. Methods: We stabilized both HIF-1 and HIF-2 pharmacologically with the prolyl hydroxylase inhibitor DMOG and with transgenic mice. Male C57/Bl6 mice eight weeks of age were pretreated with saline or 8mg DMOG 16hrs and 4hrs prior to being irradiated with a single fraction of 20Gy to the abdomen using a modified TLI jig that shields the upper body of the mouse to reduce hematopoietic toxicity. After XRT, the mice got daily doses of saline or DMOG for 5 days. Results: Mice treated with DMOG had a 1.5-fold enrichment of crypt regeneration in the colon as determined by microcolony assay (13.3±3.4 vs 21.2±1.7 crypts/section, saline vs DMOG, n=10/group, p=0.005). Death from GI radiotoxicity can result from compromised epithelial integrity. We tested epithelial and barrier function by gavaging irradiated mice with FITC-dextran, which undetectable in the blood unless the GI epithelia is compromised. Treatment with DMOG decreased FITC-dextran uptake by 4-fold over controls (52.6±14.7 vs 12.4±3.4 mcg/ml, n=6/group, p=0.02). These physiologic improvements translated to improved overall survival with DMOG treatment after being exposed to 20Gy of abdominal radiation (p=0.03). To determine if the radioprotective effect of DMOG was specific to HIF-1 or HIF-2, we overexpressed stabilized HIF1 or HIF2 in the intestinal epithelia using a lox-stop-lox (LSL) system and Villin-Cre. The overexpression of HIF1 had no effect on survival (p=0.22), while mice with intestinal-specific HIF2-overexpression had significantly improved survival after receiving 20Gy of abdominal radiation (p=0.001). Conclusions: Activation of HIF-2 is sufficient to protect mice from lethal doses of abdominal radiation may provide a novel class of treatments to protect the GI epithelium from the deleterious side effects of chemotherapy and radiation.
Molecular profiling of uveal melanoma patients.
Authors: Gatalica Zoran , Danenberg Kathleen D , McGinniss Matthew Jerome , Ghazalpour Anatole , Bender Ryan P , Ashfaq Raheela , Arguello David , Wright Brian , Griffin Nicole , Basu Gargi D.
Published: March 2020

10630

Background: Although uveal melanoma represents only 5% of all melanomas, it is the most common primary intraocular malignancy of the adult eye. Approximately 50% of patients will develop metastases which are resistant to medical interventions. There is a great need for improved therapy as the prognosis is poor for advanced stages. Our study was undertaken to investigate the presence of novel therapeutic targets. Methods: We analyzed 49 uveal melanoma patients with immunohistochemistry for 16 markers including cKIT, PDGFR, cMET, PTEN and IGF1R. Further, microarray analysis was performed on 29 samples using the Illumina platform. We also investigated amplification of EGFR and mutational analysis of cKIT, BRAF, KRAS and NRAS on a smaller patient subset. Results: Overexpression of KIT at the protein and RNA level was 74% (28 out of 38) and 45% (13 out of 29), respectively. Expression of cKIT did not correlate with gain-of-function cKIT mutations in any of the 34 samples tested. In our study, MET was overexpressed in 15 out of 17 cases at the RNA level and IGF1R was high in 4 out of 6 patients indicating poor prognosis. PTEN expression by IHC was present in 90% (36 out of 40) patients indicating the PI3K pathway is not activated in the majority of uveal melanoma patients. BRAF was wildtype in all 42 patients tested. Similarly, no KRAS or NRAS mutations were detected. Protein and RNA expression of PDGFR were low in our patients. MGMT was lost in 16 out of 40 patients at the protein level and 10 out of 29 patients at the RNA level. EGFR expression, copy number and protein levels were low in the patients tested. Conclusions: Our data on cKIT suggests that it is a promising target in uveal melanoma. Low expression of MGMT in about a third of our patients may indicate the likelihood of favorable response to dacarbazine and temozolomide. There are currently several clinical trials investigating various cKIT inhibitors, as well as temozolomide in advanced uveal melanoma patients. Our findings highlight the importance of molecular profiling uveal melanoma patients.
Accuracy of MRI, mammography (MG), and 2D and 3D ultrasound (2DUS/3DUS) in determining the pathologic tumor response after neoadjuvant chemotherapy (NACT) in breast cancer patients.
Authors: Hahn Markus , Siegmann Katja C. , Meisner Christoph , Steinhoff Ann-Katrin , Hattermann Valerie , Fehm Tanja N. , Hartkopf Andreas D. , Wallwiener Markus , Vogel Ulrich , Wallwiener Diethelm
Published: March 2020

1067

Background: The pathological tumor response in patients with locally advanced breast cancer to NACT is essential for survival and for surgical strategies. Therapy monitoring based on German recommendations is routinely performed by clinical examination, MG and 2DUS. The clinical value of MRI and 3DUS has not been established yet. The aim of the study was to determine the accuracy, sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) between the different imaging techniques in predicting postoperative histological tumor response after NACT. Methods: Patients with primary breast cancer (cT1-T4, cN0-1, M0) undergoing neoadjuvant chemotherapy between 2005 and 2010 were eligible for this prospective trial. The response was measured by MRI, MG, 2DUS and 3DUS for complete or partial remission versus stable disease after the last cycle of treatment and compared with the final pathological response. Patients with progressive disease were excluded from the study. Statistical analysis was done by calculating the accuracy of each imaging technique and the size difference between imaging and histological tumor size. Sensitivity, specificity, PPV and NPV were calculated for complete or partial pathological response. The study was approved by the local ethic committee (BCD001 194/2004). Results: 103 patients with the mean age of 47.7 (range 24.5 – 71.4) years were evaluated. The accuracy was 0.680 (95%CI: 0.580 -0.768) for MRI, 0.563 (95%CI: 0.453-0.669) for MG, 0.724 (95%CI: 0.618 -0.815) for 2DUS and 0.710 (95%CI: 0.588-0.813) for 3DUS. Sensitivity, specificity, PPV and NPV were 78%, 47%, 75% and 52% for MRI, 61%, 45%, 69% and 36% for MG, 93%, 23%, 74% and 60% for 2DUS, 94%, 19%, 73% and 57% for 3DUS. The mean (standard deviation) size difference was -1.8 mm (14.8) on MRI, 1.5 mm (26.0) on MG, -9.1mm (19.1) on 2DUS and for the volume difference -6916mm3 (15831) on 3DUS. Conclusions: The data suggest that 2DUS is sufficient in predicting tumor response between NACT treatment. MRI and MG are more accurate the 2DUS in predicting the tumor size for surgical planning.
Prognostic impact of weight change during chemotherapy.
Authors: Kasprowicz Nikola S. , Hepp Philip Gm , Andergassen Ulrich , Scholz Christoph , Annecke Katja , Wischnik Arthur , Simon Wolfgang , Forstbauer Helmut , Augustin Doris , Zwingers Thomas , Harbeck Nadia , Sommer Harald Leo , Friese Klaus , Kiechle Marion , Janni Wolfgang , Rack Brigitte Kathrin
Published: March 2020

1072

Background: Besides established prognostic factors such as tumor size or nodal status, individual host factors of the patient such as obesity, physical activity and diet seem to modulate the course of breast cancer (BC) as well. However, the specific impact of weight change during adjuvant chemotherapy remains unclear. The aim of this analysis was to evaluate the influence of weight change during chemotherapy on BC survival in a large, multi-center prospectively randomized trial. Methods: The ADEBAR trial compares two anthracycline based adjuvant chemotherapy regimen in patients (pts) with lymph node positive ( > 3 positive) early BC: 4 x epirubicin (E) 90 mg/m2 + cyclophosphamide (C) 600 mg/m2 q3w followed by 4 x docetaxel 100 mg/m2 q3w versus 6 x E 60 mg/m2 + 5-FU 500 mg/m2 d1+d8 and C 75 mg/m2 d1-14 q4w. Weight was measured before each cycle. The weight before the 1st and the 6th cycle was assessed. Significant weight change was defined as increase or decrease of > 5% of the initial weight. Overall survival (OS), disease free survival (DFS), and BC specific survival (BCSS) were assessed by Kaplan-Meier analysis. Results: In total, 1502 pts were included in the study. 1177 of them completed 6 cycles of chemotherapy. Out of the 350 pts (29.7%) who changed weight 142 pts (12.1%) lost and 208 pts (17.7 %) gained weight. There was a significant correlation between weight change and menopausal status (p<0.0001), indicating that more premenopausal pts gained and postmenopausal pts lost weight. All other tumor characteristics were similarly distributed across the groups. Pts with weight change > 5% showed a significantly worse outcome with respect to OS (p = 0.0028) and BCSS (p = 0.0258). A difference in DFS was not observed (p = 0.1917). The difference in OS was limited to pts who lost weight (p = 0.0008), whereas pts with weight gain have no significant different OS (p = 0.1246) in comparison to pts with constant weight. Conclusions: Our results suggest that weight loss during anthracycline-based treatment of early stage BC is associated with poorer OS. While weight normalization has shown beneficial effects in lifestyle intervention trials, patients should be advised not to lose weight during chemotherapy.
Phase III trial of first-line treatment with gemcitabine plus docetaxel versus gemcitabine plus paclitaxel in women with metastatic breast cancer (MBC): A comparison of different schedules and treatment.
Authors: Del Mastro Lucia , Fabi Alessandra , Mansutti Mauro , De Laurentiis Michele , Durando Antonio , Colantuoni Giuseppe , Zaniboni Alberto , Barni Sandro , Merlo Domenico Franco , Bruzzi Paolo , La Torre Ignazia , Ceccarelli Matteo , Kazeem Gbenga , Marchi Paolo , Boy Davide , Venturini Marco , De Placido Sabino , Cognetti Francesco
Published: March 2020

1073

Background: Weekly (W) administration of Gemcitabine+Docetaxel (G+D) or Gemcitabine+Paclitaxel (G+P) at low doses may be associated with greater efficacy and/or lower toxicity compared to the standard 3-weekly (3W) schedule. Methods: Patients (pts) (360) with MBC, that relapsed after one adjuvant/neoadjuvant regimen containing an anthracycline (unless contraindicated) that was completed for at least 12 months, were to be randomized equally to a) D 75mg/m2 on Day1 + G 1000mg/m2 on Days1/8 q3W ; b) P 175mg/m2 on Day1 + G 1250mg/m2 on Days1/8 q3W ; c) D 30mg/m2 + G 800mg/m2 on Days1/8/15 qW; or d) P 80mg/m2 + G 800mg/m2 on Days1/8/15 qW. Primary endpoint was time to progression (TTP). Secondary endpoints were overall survival (OS), overall response rate (ORR) and overall toxicity (T). Results: Due to slow accrual rate, a futility analysis was performed to evaluate the chance of observing a significant result in favour of the alternative hypothesis. The results from this led to early study termination. 241 pts [median age (range) 57.0(31-77) years] were enrolled and randomized to: 3W G+D 60(24.9%); 3W G+P 64(26.6%); W G+D 58(24.1%); W G+P 59(24.5%), of which 18(30.0%), 24(37.5%), 14(24.1%) and 19(32.2%) pts respectively completed the study protocol (i.e. received 6 cycles, extended up to 10 for partial/complete responders). Median TTP [months(95%CIs)] was 8.33 (6.19-10.16) in W and 7.51 (5.93-8.33) in 3W, with 86.3% of pts progressed in each schedule. OS did not significantly differ between treatments and schedules. ORR was comparable between D and P, while it was higher in W than in 3W (50.4% vs. 33.1%; odds ratio 0.44 [95%CI: 0.26-0.75], p=0.003). Grade 3/4 Ts were 69.2% and 71.9% of pts in D and P and showed a higher trend in 3W (75.2%) than in W (65.8%). Neutropenia was the most frequent grade 3/4 T (51.7% and 44.7% in D and P; 39.3% and 56.5% in W and 3W). Conclusions: No substantial differences between treatments were observed in safety and efficacy. W might be associated with lower grade 3/4 Ts and possibly with a better tumour response compared to 3W. These results should be interpreted with caution due to early termination of the study.
Baseline comprehensive geriatric assessment to predict for toxicity of single-agent chemotherapy in elderly metastatic breast cancer patients: Results from the OMEGA study of the Dutch Breast Cancer Trialists’ Group.
Authors: Hamaker Marije , Seynaeve Caroline M. , Wymenga Machteld , van Tinteren Harm , Nortier J. W. R. , Maartense Eduard , de Groot Steffen , Smorenburg Carolien H.
Published: March 2020

1080

Background: A comprehensive geriatric assessment (CGA) systematically appraises the somatic, psychosocial and functional health status of elderly patients. If CGA can predict toxicity of chemotherapy in elderly cancer patients, this assessment could be useful in deciding on optimal treatment. In this analysis, we evaluated the association between frailty on CGA or Groningen Frailty Index (GFI), and grade 3/4 toxicity in metastatic breast cancer (MBC) patients treated with first-line chemotherapy. Methods: In the OMEGA study, MBC patients (≥ 65 years) were randomized between PEGdoxo 45mg/m2every 4 weeks or capecitabine 2000 mg/m2 on days 1-14 every 3 weeks. Baseline geriatric assessment included functional status (ECOG performance status (PS), IADL), cognition (MMSE), mood (GDS), comorbidity (Charlson), polypharmacy and undernutrition (BMI) and GFI. Frailty on CGA was defined as one or more of the following: IADL≤13, MMSE ≤23, GDS ≥5, BMI ≤20, ≥5 medications or Charlson ≥2. GFI score for frailty was ≥4. Results: In total, 78 patients were randomized (PEGdoxo 38, capecitabine 40), median age 75 years (range 65-86). ECOG PS was 0-1 in 78% of patients and 2-3 in 22%. So far, 72 patients were evaluable for toxicity and baseline CGA. Overall, 50 patients (70%) were frail on CGA, and 40 (55%) according to GFI. Grade 3/4 toxicity related to chemotherapy was reported in 30 patients (42%) and 50% of CGA-frail patients experienced grade 3/4 toxicity, compared to 20% of CGA-fit patients (p=0.02). Grade 3/4 toxicity was experienced by 44% of GFI-frail patients, compared to 38% of GFI-fit patients (p=0.39). After correcting for type of chemotherapy and age, toxicity was associated with CGA-frailty (odds ratio (OR) 4.00, 95% confidence interval (CI) 1.77-13.59, p=0.03) while GFI-frailty was not associated with toxicity (OR 1.11, 95% CI 0.85-1.46, p=0.43). Conclusions: In this randomized study on first-line single-agent chemotherapy in elderly MBC patients, baseline CGA demonstrated a good predictive value for grade 3/4 toxicity of chemotherapy but GFI did not.
Circulating tumor cells in metastatic breast cancer: Are they a strong and independent predictor of poor progression-free and overall survival?
Authors: Wallwiener Markus , Schneeweiss Andreas , Baccelli Irene , Riethdorf Sabine , Pantel Klaus , Marme Frederik , Schott Sarah , Trumpp Andreas , Taran Florin-Andrei , Hahn Markus , Schuetz Florian , Mueller Volkmar , Rack Brigitte Kathrin , Sohn Christof , Solomayer Erich-Franz , Janni Wolfgang , Hartkopf Andreas D. , Fehm Tanja N. ,   DETECT Study Group
Published: March 2020

1090

Background: Circulating tumor cells (CTCs) are detected in 30–60% of patients with metastatic breast cancer (MBC). The aim of this prospective multi-center study was to evaluate the impact of CTCs on progression free survival (PFS) and overall survival (OS) in a large cohort of 486 patients with progressive metastatic disease. Methods: CTC levels were determined for 486 patients at nine German University Breast Cancer Centers between 12/2007 and 06/2011. Samples of 7.5 ml blood were taken before initiation of a new line of therapy and CTCs were enumerated using the CellSearch System (Veridex LLC, Raritan, NJ, USA). CTC status (≥ 5 CTCs vs. < 5 CTCs per 7.5 ml blood) was assessed as a prognostic factor for PFS and OS using univariate (log-rank test) and multivariate (Cox regression model) statistical methods. Results: CTCs were detected in 205/486 (42%) patients. The median CTC count was 2 (range 0–6380) per 7.5 ml blood. The presence of ≥ 5 CTCs/7.5 ml blood did not correlate with any of the established clinicopathological factors except estrogen receptor status (p = 0.038). PFS and OS were both significantly shorter in patients with ≥ 5 CTCs/7.5 ml than in those with < 5 CTCs/7.5 ml blood. PFS was 5.0 [95% CI 4.1–5.8] months vs.7.6 [95% CI 5.9–9.3] months, p < 0.001; and OS was 15.0 [95% CI 13.5–16.5] months vs. 18.3 [95% CI 17.4–19.2] months, p < 0.001. In the multivariate analysis considering all clinicopathological factors and the CTC status, independent predictors of reduced OS and PFS were site of metastasis (visceral vs. bone), number of metastatic sites (multiple sites vs. one site), and CTC status. Conclusions: The presence of ≥ 5 CTCs/7.5 ml blood is a strong and independent predictor of poor PFS and OS in patients with MBC.
The relative value of anti-Müllerian hormone to predict premature menopause in patients receiving adjuvant chemotherapy for breast cancer: Results from the OPTION trial.
Authors: Leonard Robert C. F. , Adamson Douglas , Bertelli Gianfilippo , McLinden Michelle , Haiying Nan , Dunlop Joanna , Mansi Janine , Coleman Robert Edward , Thomas Gerry , Anderson Richard
Published: March 2020

1094

Background: The OPTION trial in premenopausal women tested the ovarian protection effect of goserelin (G) given randomly before and during adjuvant chemotherapy for breast cancer. Methods: Using standard chemotherapy, women were randomised in 2 strata, under 40 yrs and over 40 yrs at diagnosis. 227 patients were recruited by end December 2009. 173 met the criteria for 1 year follow-up for this analysis; 140 patients of these had provided adequate data on menstrual bleeding; 87 patients were aged under 40 and 53 patients were aged over 40 at the time of chemotherapy. Cessation of menstruation during chemotherapy was defined as at least two consecutive cycles with no menstrual bleeding since the previous cycle and no return of menstrual bleeding prior to the final cycle of chemotherapy. Of those patients who had ceased periods during chemotherapy, those with no further menstrual bleeding at 12 months follow up were deemed to be menopausal. Patients were randomised to receive G or no G at start of chemotherapy. Primary endpoint was recovery of menses at 12 months from start of chemotherapy. AMH was measured in 117 women pre-treatment, and at 1 year after starting chemotherapy. Results: There were no differences in pretreatment AMH between control and goserelin-treated groups, thus further analyses were performed on all women grouped together. AMH was lower following chemotherapy (0.40±0.65 vs 1.38±1.82ng/ml; mean±SD; P<0.001)). Pre-treatment AMH was a significant predictor of post-treatment amenorrhoea (P=0.001). By multivariate logistic regression analysis with age and AMH, age remained significant (P=0.003) whereas AMH did not (P=0.07). Grouping pre-treatment and post-chemo AMH into quartiles showed that AMH became undetectable in 94% of women with lowest pre-treatment AMH vs 46.2% of women with the highest pretreatment AMH. We have previously demonstrated in a small cohort that pretreatment AMH can predict long-term (5 year) ovarian activity in women with breast cancer. Conclusions: The present data confirm the value of pretreatment AMH in assessing the likelihood of ongoing ovarian activity after chemotherapy for early breast cancer.
Neoadjuvant epirubicin, gemcitabine, and docetaxel for primary breast cancer: Survival and prognostic factors in two consecutive neoadjuvant phase I/II trials.
Authors: Marme Frederik , Bermejo Justo Lorenzo , Sinn Hans-Peter , Lichter Peter , Schuetz Florian , Rom Joachim , Aigner Julia , Sohn Christof , Schneeweiss Andreas
Published: March 2020

1096

Background: We previously reported primary end points of two consecutive phase I/II trials which evaluated two different schedules of neoadjuvant gemcitabine (G), epirubicin (E) and docetaxel (Doc) for primary breast cancer. Here we report mature survival data and evaluate prognostic factors for disease-free (DFS) and overall survival (OS). Methods: 151 patients were treated in two phase I/II trials of G, E and Doc as neoadjuvant chemotherapy (NAC) for T2-4 N0-2 M0 PBC between Feb. ’02 and Dec. ’04. Patients were treated with six cycles of GEDoc (G 800mg/m2 day (d) 1+8, E 60-90mg/m2 d 1, Doc 60-75mg/m2 d 1 every three weeks) or five cycles of G 1250mg/m2 plus E 90-100mg/m2 every two weeks followed sequentially by four cycles of Doc 80-100mg/m2 every two weeks (GEsDoc). Pathologic complete response (pCR), clinical/pathological factors were correlated with DFS and OS. Results: There was no significant difference in DFS or OS between patients in the GEDoc and GEsDoc trial (DFS: Hazard ratio (HR) 1.13, p=0.67; OS: HR 1.06, p=0.88) with a 5-year DFS and OS of 72 vs 74% and 85 vs 86%, respectively. In an univariate analysis pCR unexpectedly was associated with a worse OS (HR 3.11; p= 0.007). HR for DFS showed a similar but non-significant trend (HR 1.78; p=0.1). Molecular subtypes (OS: HR [lum B] 3.17; [triple negative] 5.81; [HER2] 11.5; p=0.002), negative estrogen receptor (ER) status (OS: HR 3.14; p=0.002) and Ki-67 >20% (OS: HR 5.41; p=0.001) were all significantly associated with DFS and OS. The recently published CPS-EG score (Mittendorf 2011) was also significantly correlated with OS (p=0.006) and DFS (p=0.0006). In a multivariate analysis high Ki-67 was the only significant predictor of OS (HR 10.4; p=0.0026) whereas molecular subtype (p=0.05) and Ki-67 (p=0.04) were significantly associated with DFS. Conclusions: These results raise caution on the reliability of pCR as a single surrogate marker for survival in trials with small sample sizes. Our results emphazise the role of additional factors, esp. Ki-67 and subtypes. Integrative scores based on clinical and pathologic stage as well as tumor biology, might be more reliable predictors of survival.
SPIO-enhanced MR imaging for axillary staging to avoid sentinel node biopsy in patients with breast cancer.
Authors: Motomura Kazuyoshi , Izumi Tetsuta , Tateishi Souichirou , Noguchi Atsushi , Sumino Hiroshi , Kumatani Youji , Ishitobi Makoto , Koyama Hiroki , Horinouchi Takashi , Nakanishi Katsuyuki
Published: March 2020

1103

Background: We previously demonstrated the usefulness of SPIO-enhanced MR imaging for the detection of metastases in sentinel nodes localized by computed tomography (CT) lymphography (CT-LG) in patients with breast cancer (Ann Surg Oncol, 2011). These techniques have evolved and we report our most recent results of axillary staging using them. Methods: Previously unreported 87 consecutive patients with breast cancer and clinically negative nodes were enrolled in this study. Sentinel nodes identified by CT-LG were evaluated prospectively using SPIO-enhanced MR imaging. A node was considered non-metastatic if it showed a homogenous low signal intensity and metastatic if the entire node or a focal area did not show a low signal intensity on MR imaging. Sentinel nodes located by CT-LG were removed, and imaging results and histopathological findings were compared. Results: The mean patient age was 54.9 years (range, 34-77). Sentinel nodes were identified by CT-LG and removed successfully in all patients. The mean number of sentinel nodes identified by CT-LG was 1.16 (range, 1-2). Twenty of 22 patients with positive sentinel nodes definitively diagnosed by pathology demonstrated metastases on SPIO-enhanced MR imaging. Fifty-eight of 65 patients with negative sentinel nodes definitively diagnosed by pathology were non-metastatic on imaging studies. The sensitivity, specificity and accuracy of MR imaging for the diagnosis of sentinel node metastases were 91%, 89%, and 90%, respectively. Two patients whose metastases were not detected had micrometastases. No adverse events were associated with either CT or MR imaging. Conclusions: SPIO-enhanced MR imaging provided accurate axillary staging, and therefore sentinel node biopsy may not be necessary for most patients with breast cancer.
Prognosis of early breast cancer patients treated with sentinel node biopsy: A prospective study from the Japanese society for sentinel node navigation surgery.
Authors: Imoto Shigeru , Aikou Takashi , Takei Hiroyuki , Wada Noriaki , Aihara Tomohiko , Inaba Masaaki , Motomura Kazuyoshi , Masuda Norikazu , Nagashima Takeshi , Jinno Hiromitsu , Miura Daishu , Saito Mari , Morita Satoshi , Sakamoto Junichi , Kitajima Masaki
Published: March 2020

1106

Background: Sentinel node biopsy (SNB) is a new standard of care for clinically node-negative breast cancer patients. Our society conducted a prospective study on SNB for early breast cancer patients from Jul 2004 to Oct 2005 (UMIN000006126). A preliminary result regarding with success rates of multiple mapping methods and the adverse events was presented at the 2007 ASCO. We observed patient’s outcome for 5 years. Methods: Of the 1,411 cases registered, the objects were 1,107 cases excluding cases with bilateral breast cancer, non-invasive breast cancer, past history of other malignancy or failure of SNB and cases treated with primary chemotherapy or endocrine therapy. Adjuvant therapy and breast irradiation were decided by physician’s discretion and patient’s preference. To evaluate the risk of isolated tumor cells or micrometastases in sentinel lymph nodes (SLN), clinicopathological factors were analyzed using the Cox regression model. Results: After a median follow-up of 62 months, there were 85 recurrences and 14 deaths. 5-year Kaplan-Meire estimates for disease-free survival and overall survival (OS) were 92.6% and 97.5% in 848 cases with pN0(sn), 96.2% and 100% in 26 with pN0(i+)(sn), 89.3% and 95.3% in 68 with pN1mi(sn) and 82.8% and 92.0% in 165 with pN1(sn) or greater nodal metastases. No axillary lymph node dissection (ALND) was performed in 809 cases (95.4%), 18 (69.2%), 38 (55.9%), and 24 (14.5%), respectively. Regional node recurrence was found in 8 cases (0.9%), 0 (0%), 2 (2.9%) and 2 (1.2%), respectively. Univariate analysis showed that pN1(sn) or greater nodal metastases, pT2-4, nuclear grade 3, lymphovascular invasion, negative hormone receptor status, SNB followed by ALND, chemotherapy therapy were significant risk factors for OS. However, from multivariate analysis, nuclear grade 3, lymphovascular invasion and SNB followed by ALND were independent unfavorable prognostic factors (hazard ratio: 3.21, 2.61 and 3.93). Conclusions: Although a non-randomized prospective study, isolated tumor cells and micrometastases in SLN did not affect patient’s survival. ALND should be omitted for early breast patients with those metastases.
Role of breast surgery in T1-T3 breast cancer patients with synchronous bone metastases.
Authors: Botteri Edoardo , Munzone Elisabetta , Bagnardi Vincenzo , Intra Mattia , Rotmensz Nicole , Bazolli Barbara , Montanari Bruno , Aurilio Gaetano , Sciandivasci Angela , Esposito Angela , Pagani Gianmatteo , Adamoli Laura , Nole Franco , Goldhirsch Aron
Published: March 2020

1115

Background: The role of breast surgery in advanced breast cancer (ABC) is controversial. The main potential advantage of removing the primary tumor is to eliminate the source of further metastatic spread. While previous studies addressed the question in very heterogeneous populations (e.g. patients with any local and distant extension), we have focused on a homogeneous series of ABC patients. Methods: From our institutional Tumor Registry we selected 191 consecutive women diagnosed between 2000 and 2008 with locally operable (T1-T3) ABC, synchronous bone metastases and no other distant sites involved. The progression free survival (PFS) was calculated from diagnosis to the date of progression, defined as either a new site of metastatic disease or clinical/radiographic evidence of increasing tumor burden at a previously known bone metastatic site. Results: Median age was 51 years and 92% of the women had an endocrine-responsive tumor. One-hundred and thirty patients out of 191 (68%) underwent surgery at the time of diagnosis, while 61 (32%) did not. Twenty-six of the operated patients (20%) had previously undergone neoadjuvant chemotherapy; 15 (12%) had positive or undetermined surgical margins. Operated and non-operated patients were similar with respect to age, tumor size, nodal involvement, estrogen and progesterone receptor status, HER2 overexpression and Ki-67, but differed in terms of number of bone metastatic sites: a single metastasis was detected in 34 (26%) operated and 7 (11%) non-operated cases (P=0.02). First-line treatment strategies with endocrine therapy, chemotherapy and Trastuzumab were similarly distributed between the two groups. The 5-year PFS was 22.0% and 10.4% in operated and non-operated patients, respectively. The multi-adjusted hazard ratio was 0.62 (95% confidence interval 0.39-0.98) in favor of surgery. The exclusion of the patients who had received neoadjuvant chemotherapy and patients with positive or undetermined surgical margins did not alter the results. Conclusions: In this large and homogeneous series of ABC patients with synchronous bone metastases, the role of breast surgery had a favorable impact on the progression of the disease, indicating a potential survival benefit.
The APC I1307K polymorphism as a significant risk factor for CRC in average-risk Ashkenazi Jews.
Authors: Boursi Ben , Sella Tal , Liberman Eliezer , Geva Ravit , Shmueli Einat , Sagiv Eyal , Kazanov Dina , Kraus Sarah , Arber Nadir
Published: March 2020

1507

Background: The I1307K adenomatous polyposis coli gene variant, prevalent among Ashkenazi Jews, may increase risk for colorectal neoplasia. We studied the clinical importance of screening for this polymorphism in 3305 Israelis undergoing colonoscopic assessment. Methods: Blood samples and risk factor information were collected from individuals undergoing colonoscopic examination at our medical center. Germline genetic analysis for the APC I1307K variant was performed using real-time PCR for DNA extracted from peripheral mononuclear cells. Results: The overall prevalence of the I1307K polymorphism was 8.0% (10.1% among Ashkenazi while only 2.7% among Sephardic Jews, p<0.001). The overall adjusted odds ratio (OR) for CR neoplasia among carriers was 1.51(95% CI, 1.16 –1.98). Among average risk Ashkenazi Jews, the OR was 1.76 (95% CI 1.26-2.45). On the contrary, among Sephardi subjects the OR was 0.996 (95% CI, 0.51-1.93). A multiplicative interaction was identified between Ashkenazi ethnicity and APC I1307K carrier status (PINTERACTION=0.055). The histopathological features of adenomas and cancers did not differ between carriers and non-carriers. Conclusions: The APC I1307K gene variant is an important risk factor for CRC in average risk Ashkenazi jews and should be considered for screening in this population.
MEN1 gene mutations with different phenotypic presentations in two families: Is it a time to grade MEN1 mutations as high-risk and low-risk?
Authors: Shifrin Alexander L. , Bale Allen E , Dykas Dan , Fay Angela Musial , Belitsis Kenneth , Fomin Svetalna , Lann Danielle , Villanueva Ronald , Zheng Min , Govil Sushama , Erler Brian , Matulewicz Theodore , Topilow Arthur , Krasna Mark , Vernick Jerome
Published: March 2020

1540

Background: MEN1 syndrome results from MEN1 gene mutations and is characterized by primary hyperparathyroidism (PHPT), pancreatic endocrine tumors (PET), pituitary adenomas, thymic and other tumors. About 600 different mutations have been reported on Human Gene Mutation Database and 30 of them presented as Familial Isolated Hyperparathyroidism (FIHP); however, no genotype-phenotype correlations have been identified. Methods: We characterized 2 independent families with newly diagnosed MEN1. Mutation analyses were performed in Dept of Genetics Yale University. Diagnostic tests, surgical treatment were implemented. Results: Family 1 has 21 members. 5 presented with early onset of PHPT and no other tumors. 3 ½ parathyroidectomies were performed. A proband had direct sequencing that showed a mutation in Exon 7, consisting of single base insertion in codon 319 (TAC to TTAC)(c1065_1066insT). There were no deaths in the family. Family 2 has 20 members. 7 were tested and showed a mutation in Exon 2, consisting of single base deletion in codon 103 (CTG to _TG)(c417delC). One 1st generation member died from PET at age 79, three 3rd generation members had multifocal metatstatic malignant gastrinomas (ages 32, 39, 41). The proband had total pancreatectomy at age 32. Five members had PHPT, angiofibromas. Three 2nd generation members had thymic carcinomas (ages 20, 54, 60). Conclusions: Phenotypic presentation of MEN1 syndrome may vary with the same mutation suggesting a lack of genotype-phenotype correlation and the effect of modifying factors. On the other hand, these two families—one with a mutation predicted to truncate the menin protein close to its terminus and the other with a truncating mutation early in the coding sequence—have dramatically different severity of the syndrome. Our findings suggest that the exon 7 mutation has a milder effect on protein function resulting in FIHP. The management may be heavily influenced by the predicted clinical phenotype, we are proposing the development of a grading system for MEN1 gene mutations as low-risk and high-risk and to attempt to identify other modifying genetic and environmental factors to improve screening and timing for surgery.
Genetic testing referral, uptake, and results in a program for women age 40 or younger with breast cancer.
Authors: Ali Asma , Warner Ellen , Hill Kimberley
Published: March 2020

1542

Background: PYNK: Breast Cancer Program for Young Woman is a novel program started in 2008 at our center to optimize management and promote research for women ≤ age 40 newly diagnosed with breast cancer. Clinical and epidemiological data including cancer family history (FH) is prospectively collected on each consenting patient. As Toronto’s population is uniquely multiethnic we sought to determine BRCA testing eligibility, uptake and results for PYNK patients. Methods: Of the 145 consecutive patients, data were available for 109, of whom 2 had testing prior to diagnosis. Our provincial BRCA testing criteria are age < 35 at diagnosis; suspicious FH; or Ashkenazi Jewish (AJ) and age < 50 at diagnosis. Results: Of the 107 previously untested patients, 40 were < 35 at diagnosis. In 5 of the other 67 testing eligibility could not be assessed. 66 of the 102 (65%) were eligible and of those 65 (98%) were offered referral for counseling. One declined counseling, 9 were not yet seen, 2 declined testing, and 53 were tested. Test results are available for 47 as follows: 30 (64%) no mutation, 4 (8%) variant of uncertain significance (VUS), 7(15%) BRCA1 mutations and 6 (13%) BRCA2 mutations including 1 of the 4 AJ women. Ethnicity of the other 12 mutation carriers was: 1 Hispanic, 2 European, 2 African, 4 Asians, 1 mix, 1 unknown and 1 not recorded. Two (15%) of the mutation carriers had no FH of breast or ovarian cancer. Four additional women opted for counseling and testing despite ineligibility and none had mutations. Conclusions: A specialized program for young women facilitates appropriate referral for genetic testing and encourages high testing uptake, which is important given the high prevalence of mutations (28% of tested women). Further research is necessary to assess the psychological and management impact of having a VUS on young women compared to their older counterparts.
Predictors of contralateral prophylactic mastectomy among patients with ductal carcinoma in situ (DCIS) who underwent evaluation for BRCA genetic testing.
Authors: Elsayegh Nisreen , Gutierrez-Barrera Angelica M. , Muse Kimberly I. , Lin Heather , Turco Diana L. , Litton Jennifer Keating , Kuerer Henry Mark , Arun Banu
Published: March 2020

1549

Background: Patients with DCIS are at increased risk for developing contralateral breast cancer (CBC). Therefore, an increasing number of women with DCIS are electing for contralateral prophylactic mastectomy (CPM). In a previous study involving 2072 women with DCIS, 13.5% chose CPM. In this study, we aimed to evaluate factors associated with CPM in patients with DCIS who underwent genetic counseling for BRCA. Methods: 165 women with pure DCIS, who underwent genetic counseling, were included in the study. Patients’ characteristics were obtained from a prospectively maintained research database at UT M.D. Anderson Cancer Center. Univariate and multivaraite logistic regression analysis were used to determine predictive factors associated with CPM. Patients’ characteristics included age, marital and educational status, tumor markers, nuclear grade, family history with breast (BC) and ovarian cancer (OC), race, Ashkenazi Jewish ancestry, and BRCA genetic test results. Results: Out of 165 patients, 17(10.3%) were found to have a BRCA deleterious mutation. 44(26.7%) underwent CPM. Younger patients (median ≤ 45 yr) were more likely to elect for CPM than older patients (p= 0.0098). Patients who tested positive for a BRCA mutation were more likely to elect for CPM than those who tested negative or were not tested (p= 0.0001). Patients who had a family history of OC (15 (57.7%) were more likely to choose CPM than those who did not (p= 0.0004). These three factors remained significant in the multivariate model (p <0.008). Marital and educational status, tumor markers, nuclear grade, and family history of breast cancer were not significant predictors of CPM. Conclusions: The rate of CPM in patients with DCIS is high. Factors associated with increased likelihood of undergoing CPM include family history of OC, age, and BRCA positivity. Further studies are needed to evaluate patients perception of CBC risk, and if this may play a role in the high number of CPM.
Breast cancer prognosis in BRCA1/2 mutation carriers: A case control study.
Authors: Arpino Grazia , Pensabene Matilde , Forestieri Valeria , Condello Caterina , Sarno Maria Anna , Ruocco Raffaella , Cerillo Ivana , De Angelis Carmine , Lauria Rossella , Crispo Anna , De Placido Sabino
Published: March 2020

1554

Background: We evaluated the clinical impact of germ-line BRCA1/2 mutations and variants of unknown clinical significance (VUS) for BRCA1/2 in patients (pts) with early breast cancer (BC). Methods: Twenty-eight BRCA-positive (BRCA+) BC pts with germ-line BRCA1 /2 mutations and 16 VUS BC pts were selected from our database and matched (1:3) with 154 nonhereditary BC controls (sporadic controls, SC, defined by no associated personal history of breast cancer and no family history of breast and ovarian cancer or an uninformative BRCA mutation test) for stage, histologic subtype, age, and year of diagnosis. Clinical characteristics, recurrence (rec) pattern, disease free survival (DFS) and overall survival (OS) were analyzed. Results: Compared with VUS and SC, BRCA+ pts were less likely to express estrogen receptor (64% vs. 89% vs. 54% respectively p<.005) and progesterone receptor (64% vs. 86% vs. 59% respectively p<.005) but more likely to be triple negative (0 vs. 3.4% vs 47.4% respectively p<.005). Compared with VUS and SC, BRCA+ pts were more likely treated by radical mastectomy (37.5% vs. 26.4% vs. 59.3% % respectively p<.005). Pattern of rec was also different. Compared with VUS and SC, BRAC+ pts developed more second tumors (11% vs. 6.3% vs. 1.9% respectively p<.0001) but less local or distant rec (31% vs. 2.6 vs. 0% for local rec and 12% vs. 16% vs. 11% for distant rec respectively p<.0001). Controlateral BC was more frequent in VUS compared to the BRAC+ and SC pts (12% vs. 7% vs. 1% respectively, p<.0001). At a median follow up of 88 months, at univariate analysis, BRAC+ but not VUS pts had worse OS compared to SC (p=.006). No difference in DFS was observed for VUS or BRAC+ when compared to SC pts. After adjustment for age, stage, grade, nodal status, hormone receptors, adjuvant therapy and year of diagnosis, BRCA+ pts continued to have and increased risk of death compared to SC (HR 5.9, 95% CI 1.9-18.1, p<.002). Most of the deaths observed in BRAC+ pts were not cancer related. Conclusions: Despite decrease incidence of local or distant recs, BRAC+ pts seems to be more likely to die compared to SC. Development of second cancers and unknown effects of BRCA1/2 mutations on nonneoplastic diseases that cause death may account for this findings.
Sun exposure profile in the French population: Results of the EDIFICE melanoma survey.
Authors: Sassolas Bruno , Grange Florent , Touboul Chantal , Lebbe Celeste , Saiag Philippe , Mortier Laurent , Lhomel Christine , Robert Caroline
Published: March 2020

1566

Background: The main environmental risk factor for melanoma is related to UV-exposure. Our objective was to evaluate in a survey the profile of sun exposition in the French population as well as the level of knowledge about UV risk and UV protection. Methods: “Edifice Melanoma” a nationwide observational survey was conducted in France via phone interviews among a representative sample of 1502 subjects aged ≥ 18, using the quota method. The survey took place shortly after the summer (September 28th to October 20th, 2011). Results: From the total population of 1502 subjects, 330 (22%) denied any sun exposition. Among those declaring being exposed to the sun (1172), 62% affirmed using a photoprotection method (clothes, sun protective cream). The opportunities for sun exposure arose during holidays (85%), sport (79%) or professional activities (23%), with an annual average exposure of 113 days. 902 subjects (77%) declared avoiding sun exposure between 12 and 4 PM. The main sociodemographic characteristics of subjects exposed to the sun, compared to non-exposed ones are as followed (p<0,05): men, aged <40, with no children or with children aged <15, from high social and occupational group, with at least a 2-years university degree. The analysis of sociodemographic characteristics of subjects declaring to use sun protective measures are (p<0,05): women from high social and occupational group, with at least a 2-years university degree, with high income levels. We explored additional risk behavior in the population studied. Subjects who declared having sun exposure were more likely (p<0,05) to be : smokers, alcohol users and/or alcoholic, tanning bed users before the age of 30, and have a high number of nevi (>50). On the other hand, prior history of cancer was associated with a non-exposure behavior. Conclusions: These data provide important new information about sun behavior in the French population and might give important clues in the field of public health and education to increase the effectiveness of melanoma primary prevention campaigns. A better knowledge of the target to improve would provide better results for public health benefit.
The effect of family history on adherence to breast cancer screening guidelines.
Authors: Hibler Lauren Marie , Chagpar Anees B.
Published: March 2020

1571

Background: A family history of breast cancer increases the risk of developing this disease. We sought to determine the effect of a family history of a first degree relative with breast cancer (FDFHx) on adherence to mammography (MMG) and clinical breast examination (CBE) guidelines. Methods: The National Health Interview Survey (NHIS), conducted annually by the Centers for Disease Control, is designed to be representative of the US population. The 2010 NHIS data was used to evaluate the effect of FDFHx on the likelihood that women aged ≥ 30 had MMG and/or CBE within the past year. Results: Of the 12,320 women aged ≥ 30, 1276 (10.7%) had a FDFHx; 1263 (99.0%) of female breast cancer and 13 (1.0%) of male breast cancer. Overall, 4573 (38.4%) of women reported having had MMG within the past year; 5377 (46.3%) had CBE within the past year. FDFHx was associated with use of MMG and CBE within the past year (58.0% vs. 36.0%, p<0.001, and 57.5% vs. 45.0%, p<0.001, respectively). Women with a FDFHx of male breast cancer were no more likely to have MMG (72.5% vs. 57.9%, p=0.313) nor CBE (66.8% vs. 57.4%, p=0.518) within the past year than those with a FDFHx of female breast cancer. On multivariate analysis controlling for age, race, personal history of breast cancer (PHx), income, insurance, education and region, FDFHx was associated with a higher likelihood of having MMG (OR=1.75; 95% CI: 1.48-2.06, p<0.001) and CBE (OR=1.48; 95% CI: 1.26-1.74, p<0.001) within the past year. Region was not associated with adherence to either MMG or CBE screening guidelines. Conclusions: FDFHx, along with age, race, PHx, income, insurance, and education, is an independent predictor of adherence to screening MMG and CBE guidelines. Still, only 58% of women with a FDFHx had MMG and CBE in the past year. Further efforts are warranted to improve screening in this population at increased risk. [Table: see text]
Incidence of bone metastases among children with cancer in Denmark.
Authors: Hernandez Rohini Khorana , Ehrenstein Vera , Mægbæk Merete Lund , Liede Alexander , Sørensen Henrik Toft
Published: March 2020

1579

Background: There are no published population-based studies on the incidence of bone metastases (BM) among children with cancer. The current literature is limited to small case series or case reports. Methods: We used the Danish Cancer Registry (DCR) to identify children <18 years old diagnosed with cancer between 1/1/1994 and 12/31/2009. Patients were followed from cancer diagnosis to BM, emigration, death, or end of study (1/1/2011). DCR data were linked to (1) Danish Civil Registration System to obtain information on death and emigration, and (2) Danish National Registry of Patients to identify ICD-10 codes for BM. We estimated incidence rates (IRs) of BM and mortality rates overall and stratified by gender, calendar year, age, and primary tumor type. Results: During the study period, 2,652 children were identified with a first-time diagnosis of cancer, of whom 35 (1.3%) developed BM (mean follow-up of 7.0 years). The IR of BM was 1.9 per 1,000 person-years (95% CI: 1.4 – 2.6); the highest rates occurred in children aged 12 – 17 years and among those with osteosarcoma (Table). Twenty-one (60%) children with BM died during follow-up, yielding a mortality rate of 192 per 1,000 person-years (95% CI: 125 – 295). The median time from cancer diagnosis to BM was 221 days and from BM to death was 283 days. Conclusions: This study represents the first comprehensive examination of BM in children and reveals that BM is a rare event, with median survival of less than one year from diagnosis. [Table: see text]