bluuebunny/crossref_metadata_2025 huggingface dataset:
Re-irradiation combined with chemotherapy after salvage surgery in head and neck carcinoma: A randomized trial from the GETTEC and GORTEC groups
Authors: Janot F. , De Raucourt D. , Castaing M. , Bardet E. , Dolivet G. , Bensadoun R. , Hamoir M. , Marandas P. , Mamelle G. , Bourhis J.
Published: March 2020

5508

Background: Full dose re-irradiation combined with chemotherapy has been shown to be feasible after salvage surgery with an “acceptable” toxicity (Cancer 2001; 91:2071–6). We performed a prospective, multicentric, randomized study to assess its carcinologic value. Methods: Between 1999 and 2005, 130 head and neck cancer patients were treated with salvage surgery and then randomly assigned either to full dose re-irradiation combined with chemotherapy (arm A) or absence of post-operative treatment (arm B). Patients eligibility criteria were: recurrence or second primary in a previously irradiated area to at least 45 Gy, absence of distant metastasis, salvage surgery with macroscopic complete resection; possibility of starting adjuvant treatment within 6 weeks after salvage surgery. Patients in arm A received 60 Gy in 12 weeks combined with concomitant 5FU, Hydroxyurea, as previously described (Ann Oncol 1996;7:913–8). Cox model was adjusted with stratification factors: tumor site, center, type of event (recurrence vs second primary). Results: 65 patients were randomized in each arm, including 71% of local and/or regional relapse and 29% of second primary. There was no imbalance in the distribution of age, sex, tumor site, T and N re-staging, and histological gravity signs (N+ with ECE and/or positive margin). The most important acute toxicity related to re-irradiation and chemotherapy was mucositis with ≥ grade 3 in 29% of patients. A moderate and acceptable increase in ≥ grade 3 RTOG late toxicity was observed in arm A (trismus, mucosa, fibrosis). Progression-free survival was significantly improved in Arm A with a hazard ratio of 1.6 (CI 95%, 1.1–2.4, p = 0.01), but overall survival was not statistically different. Conclusions: This is the first randomized trial to evaluate the effect of full dose re-irradiation combined with chemotherapy after salvage surgery. The results showed that re-irradiation and chemotherapy were able to significantly improve progression-free survival, with no significant impact on survival and acceptable toxicity. Supported by ARC.

No significant financial relationships to disclose.
A phase II trial of ZD6474 in patients with hereditary metastatic medullary thyroid cancer
Authors: Wells S. , You Y. N. , Lakhani V. , Hou J. , Langmuir P. , Headley D. , Skinner M. , Morse M. , Burch W. , Schlumberger M.
Published: March 2020

5533

Background: Medullary thyroid carcinoma (MTC) is the most common cause of death in patients with hereditary syndromes caused by specific mutations in the RET protooncogene. RET activation is the oncogenic event, which results in intrinsic RET receptor tyrosine kinase activity, but other pathways, such as VEGFR- and EGFR-dependent signaling, also participate in tumor growth and development. ZD6474 is a once-daily oral agent that selectively targets RET, VEGFR and EGFR tyrosine kinases. The clinical activity of ZD6474 was evaluated in patients with hereditary MTC. Methods: In this open-label Phase II study, patients with unresectable, measurable, locally advanced or metastatic hereditary MTC and a RET germline mutation received once-daily oral doses of ZD6474 300 mg. The primary objective was to assess the objective tumor response (RECIST). Secondary objectives included assessments of biochemical response (determined by changes in plasma levels of calcitonin [CTN]) and safety/tolerability of ZD6474. An exploratory objective was to measure plasma levels of carcinoembryonic antigen (CEA). Results: As of 30 November 2005, 16 patients (6 male/10 female; median age 50 years, range 22–77) had entered the study and received initial treatment with ZD6474 300mg. The median duration of treatment was 136 days (range 16–353). Fifteen patients were evaluable for tumor response, CTN, and CEA. Objective tumor assessments have demonstrated partial responses in 3 patients (n = 2 confirmed; n = 1 unconfirmed), stable disease in 10 patients (n = 8, ≥8 and <24 weeks; n = 2, ≥24 weeks) and progressive disease in 2 patients. A >50% decrease from baseline in plasma CTN levels has been maintained for at least 4 weeks in 12/15 patients; a decrease in plasma CEA levels of the same magnitude and duration has been observed in 6/15 patients. Common adverse events (AEs) were diarrhea (n = 12) and nausea, rash and fatigue (each n = 11). CTC grade 3 AEs attributable to ZD6474 were QTc interval prolongation (n = 3), and diarrhea, skin rash and hypertension (each n = 2). Conclusions: ZD6474 shows promising evidence of clinical activity in patients with hereditary MTC. These are preliminary data and patients are still being recruited to this ongoing study.

[Table: see text]
Significant clinical and biologic activity of RAF/VEGF-R kinase inhibitor BAY 43–9006 in patients with metastatic papillary thyroid carcinoma (PTC): Updated results of a phase II study
Authors: Kloos R. , Ringel M. , Knopp M. , Heverhagen J. , Rittenberry J. , Weldy L. , Arbogast D. , Collamore M. , King M. , Young D. , Shah M.
Published: March 2020

5534

Purpose: Oncogenic defects in the genes involving RAS-RAF-MAPK signaling pathway (RAS, BRAF, or RET/PTC) occur in ∼60% of PTC. VEGF also plays a critical role in thyroid cancer progression. Due to lack of effective treatment, systemic therapy for iodine-refractory PTC is desperately needed. Methods: The primary endpoint of this phase II trial was to assess the objective response rates of BAY 43–9006 in pts with metastatic PTC. Secondary endpoints included clinical response correlation with 1) serum thyroglobulin (Tg) levels; 2) functional imaging including FDG-PET, and DCE-MRI; and 3) tumor genotype and degree of signaling inhibition in tumor biopsies. Using a minimax 2-stage design, 16 or 25 chemo-naïve pts with iodine-refractory PTC were to be enrolled in Arm A (accessible tumor for biopsy). An exploratory Arm B was designed with a plan to halt accrual as soon as Arm A was fully accrued. Eligible pts for Arm B had other subtypes of thyroid cancer or prior chemo, and did not require tumor biopsies. Pts received BAY 43–9006 at the dose of 400 mg PO BID. Response was assessed every 8 wks using RECIST. Results: A total of 58 pts (Arm A = 20, Arm B = 38) were enrolled from October 2004 to August 2005. Median duration of follow-up is 36 weeks (range, 16–60). Of 56 pts assessable for toxicity, serious adverse events (AEs) included aspergillus infection (gr 5, n = 1), secondary AML (gr 5, n = 1) and diverticular rupture (gr 3, n = 1). Common Gr 3 AEs were hand-foot syndrome (n = 9) and musculoskeletal pain (n = 10). Two confirmed partial responses (PRs) and 6 minor responses (23–29% decrease in sum of the longest diameter) were observed in 16 evaluable pts on Arm A. In 10 Tg-response evaluable pts on Arm A, median decrease in Tg was 70% (range, 45–90). Significant decreases in tumor perfusion and SUVs were noted in such pts. In addition, one PR and one minor response (27% decrease in sum of longest diameter; 85% reduction in Tg) have been observed among 20 pts with PTC on Arm B. Data for functional imaging and tissue correlative studies will be presented. Conclusions: BAY 43–9006 is a well-tolerated targeted therapy that has significant clinical and biologic anti-tumor activity in pts with iodine-refractory metastatic PTC.

No significant financial relationships to disclose.
Evaluation of patterns of failure and subjective salivary function in patients treated with intensity modulated radiotherapy for head and neck squamous cell carcinomas
Authors: Daly M. E. , Lieskovsky Y. , Pawlicki T. , Yau J. , Pinto H. , Kaplan M. , Koong A. , Goffinet D. R. , Xing L. , Le Q.
Published: March 2020

5536

Background: Conventional RT (CRT) for head and neck squamous cell carcinoma (HNSCC) is associated with severe late side effects which can worsen quality of life of surviving patients. Intensity-modulated radiotherapy (IMRT) allows the delivery of tumoricidal doses to the target volume while maintaining tolerable doses to critical organs. Several previous studies have demonstrated promising results for tumor control and disease free survival for HNSCC treated with IMRT. In this study, we correlated patterns of failure with target volume delineations in HNSCC treated with IMRT at our instittuion and evaluated subjective xerostomia outcomes after IMRT as compared to CRT. Material and Methods: Between 1/00 and 4/05, 69 patients with newly diagnosed non-metastatic HNSCC underwent curative parotid sparing IMRT at Stanford University. Sites included were oropharynx (39), oral cavity (8), larynx (8), hypopharynx (8) and unknown primary (6). Forty-six patients received definitive IMRT (66 Gy, 2.2 Gy/fraction), and 23 patients received post-operative IMRT (60.2 Gy, 2.15 Gy/fraction). Fifty-one patients also received concomitant chemotherapy. Post-treatment salivary gland function was evaluated by a validated xerostomia questionnaire (XQ) in 29 IMRT and 75 matched non-IMRT patients > 6 months after completing RT. Results: At a median follow-up of 17 months for living patients (range 6.5–60), 7 locoregional failures were observed, 5 in the gross target volume (GTV), 1 in the clinical target volume (CTV), and 1 at the junction of the IMRT and supraclavicular fields. The 2-year Kaplan Meier estimates of locoregional control and overall survival were 92% and 80% for definitive IMRT and 85% and 85% for post-op IMRT patients, respectively. The mean total XQ score was significantly better for IMRT than for non-IMRT patients (p = 0.006). Conclusions: The predominant pattern of failure in IMRT treated patients is in the GTV. Parotid sparing with IMRT resulted in decreased subjective xerostomia and may improve quality of life in irradiated HNSCC patients.

No significant financial relationships to disclose.
Prognostic value of VEGFC, HER2 and HER3 gene expression in recurrent squamous cell head and neck tumors
Authors: Fountzilas G. , Angouridakis N. , Wirtz R. M. , Claas S. , Nikolaou A. , Kalogeras K. T.
Published: March 2020

5538

Background: The main prognostic variables of head and neck squamous cell carcinoma (HNSCC) are the location and size of the tumor and the presence of cervical lymph node metastases. Differential gene expression of members of the HER and VEGF families is a common feature in HNSCC. To elucidate the prognostic value and the interrelation of these factors we performed a detailed gene expression analysis within HNSCC tissue samples Methods: We analyzed fresh frozen tissue from 48 recurrent HNSCC tumors stored at -80oC. RNA was isolated with the RNeasy kit (Qiagen, Inc.), followed by kinetic one-step RT-PCR for the expression of 8 candidate genes (EGFR, HER2, HER3, HER4, VEGFA, VEGFB, VEGFC and VEGFD). Raw data (Ct values) were normalized to RPL37A expression (housekeeper gene) and candidate gene expression between patient groups with differential clinical outcomes was analyzed by using Genedata Expressionist and GraphPad Prism 4 software packages. Median patient follow-up from initial diagnosis was 27 months. Results: Overexpression of VEGFA and EGFR was prominent in most tumors, but did not appear to have any prognostic value. However, VEGFC expression was significantly higher (p = 0.0002) in the tumors of patients with poor overall survival (< 27 months). Interestingly, these tumors were further characterized by significantly lower expression levels of HER2 and HER3. Median survival of patients with tumor VEGFC expression levels of >600 was calculated to be 42 months from initial diagnosis (Kaplan-Meier Survival Analysis), compared to 182 months in the rest of the patients. Conclusions: We have found that elevated VEGFC expression and low expression of HER2 and HER3 correlate with poor outcome in recurrent HNSCC patients. VEGFC preferably binds to the VEGFR3, which is predominantly expressed on lymphatic vessels. Overexpression of VEGFC may therefore result in the establishment of intratumoral lymphatic vessels, which have been shown to facilitate the dissemination of tumor cells into lymph nodes and the formation of distant metastases. We conclude that the determination of VEGFC, HER2 and HER3 expression may be of high prognostic value in HNSCC patients and that it may serve in the early identification of aggressive HNSCC subtypes.

No significant financial relationships to disclose.
Concurrent chemotherapy practice patterns for head and neck cancer: What is standard of care?
Authors: Wong S. J. , Agha Z. , Milligan S.
Published: March 2020

5542

Background: The superiority of concurrent high dose cisplatin and radiation (RT) compared to RT alone for pts with locally advanced squamous cell cancer of the head and neck (SCCHN) has been demonstrated in large prospective phase III clinical trials. However, little is known regarding general prescribing patterns for chemotherapy (CT) utilization in combined modality treatment (CMT) for SCCHN. We conducted the present study to gain insight as to whether results from pivotal phase III trials affect utilization of concurrent CT in academic and community centers. Methods: We analyzed individual data from 326 SCCHN pts treated with concurrent CT and RT between 03/2003 and 12/2004 from 53 centers (43 community-based, 7 academic, and 3 VA or military) using electronically captured data from IntelliDose, a chemotherapy order software program. Results: Of 326 total pts, 123 pts (38%) received single agent cisplatin. From this group, 71 (58%) received low dose cisplatin (<74 mg/m2, mean initial dose 67 mg), while 52 patients (42%) received high dose cisplatin (≥ 74 mg/m2, mean initial dose 189 mg). 72 pts (22%) received carboplatin/paclitaxel, 60 pts (18%) received cisplatin /5FU, 18 pts (5.5%) received single agent carboplatin, while 6 pts (1.8%) received cetuximab either alone or in combination with cisplatin. Other infrequently used regimens (each < 5%) cumulatively accounted for 14% of pts treated. Comparison of chemotherapy utilization between academic and community-based practice centers showed no statistical difference with respect to use of high dose cisplatin versus low dose cisplatin, or single agent cisplatin versus non-cisplatin regimens. Conclusions: Despite evidence from phase III studies that concurrent high dose cisplatin is the standard of care for CMT of locally advanced SCCHN, utilization of other regimens, such as weekly low dose cisplatin, are commonly utilized.

[Table: see text]
Preliminary results of concurrent chemotherapy with intensity-modulated radiation therapy (IMRT) for advanced cancer of the larynx/hypopharynx
Authors: Lee N. , Chan K. , Zhung J. , Wolden S. , Su Y. B. , Kraus D. , Singh B. , Shaha A. , Shah J. , Pfister D. G.
Published: March 2020

5544

Purpose: Retrospective review of an institution’s IMRT experience in treating advanced laryngeal/hypopharyngeal carcinoma with concurrent chemotherapy. Methods: Between 1/02–6/05, 31 patients with advanced laryngeal/hypopharyngeal carcinoma (74% T3/T4 disease;71% stage IV) underwent combined modality treatment. There were 20 laryngeal and 11 hypopharyngeal carcinomas. All patients received definitive IMRT with a median RT dose of 70 Gy. Concurrent chemotherapy was also given to all patients [cis-platinum (100mg/m2/cycle) or carboplatin/5-fluorouracil (J Clin Oncol 2004;22:69) every 3 weeks for 2–3 planned cycles; 3 patients received a weekly paclitaxel/carboplatin program]. Prophylactic feeding tubes (PEG) were placed in all patients. Acute toxicity and late xerostomia were scored using the RTOG radiation morbidity scale. The 2-year estimates for local progression-free rate (LPF), regional progression-free rate (RPF), distant metastases-free rate (DMF), and overall survival (OS) were calculated using the Kaplan-Meier method. Results: With a median follow-up of 17 months (range: 7–48), 2-year estimates of LPF, RPF, DMF, and OS rates were 76%, 94%, 96%, 87%, respectively. All patients with local failure of laryngeal carcinoma had persistent disease at the end of treatment. Grade ≥2 mucositis was experienced by 68% of the patients during treatment. Xerostomia continued to decrease over time from the end of RT and only 4 still complained of Grade 2 xerostomia. A greater proportion of patients with hypopharynx than larynx cancer were still PEG-dependent (55% versus 25%) after combined modality treatment at the time of this analysis. One patient developed laryngeal necrosis. Conclusions: These preliminary results show that IMRT, in combination with chemotherapy, achieved encouraging local control rates in patients with advanced laryngeal/hypopharyngeal carcinoma. Xerostomia improved over time. Pharyngoesophageal stricture with PEG dependency remains a problem especially in patients with hypopharyngeal carcinoma. Strategies using the ability of IMRT to limit the dose delivered to the esophagus and inferior constrictor musculature may be useful to further minimize this late complication.

No significant financial relationships to disclose.
A phase II study of lapatinib in recurrent or metastatic EGFR and/or ErbB2 expressing adenoid cystic (ACC) and non-ACC malignant tumors of the salivary glands (MSGT)
Authors: Agulnik M. , Cohen E. E. , Cohen R. B. , Chen E. X. , Hotte S. J. , Winquist E. , Laurie S. , Hayes D. N. , Dancey J. E. , Siu L. L.
Published: March 2020

5566

Background: The limited therapeutic index of chemotherapy in recurrent or metastatic MSGT provides a strong rationale for the evaluation of molecularly targeted agents in this disease. Lapatinib is a dual inhibitor of EGFR and ErbB2 tyrosine kinase activity. Expression of ErbB2 and EGFR has been associated with biological aggressiveness and poor prognosis in MSGT, respectively. We conducted a phase II study to determine the antitumor activity of lapatinib in MSGT. Methods: The main study has a two-stage design in which patients (pts) with progressive, recurrent or metastatic ACC, and immunohistochemically expressing at least 1+ EGFR and/or 2+ ErbB2, were treated with lapatinib 1500 mg PO daily. Each cycle consists of 4 weeks of continuous dosing. Pts with non-ACC MSGT of other histologies, meeting identical eligibility criteria, were treated in this trial as a single-stage, separate cohort. Results: Of 57 pts screened for this study, 29/33 (88%) ACC and 22/24 (92%) non-ACC pts expressed EGFR and/or ErbB2. Thirty-eight pts have been accrued to the study to date (20 ACC/18 non-ACC). The remaining 13 pts who were screened positive either declined entry or were ineligible for other reasons. Baseline data on 34 pts are: M:F = 25:9, median age 56 (range 38–80), PS 0:1:2 = 16:17:1, prior radiation:chemotherapy = 30:18. After 92 cycles of therapy, the most frequent adverse events experienced (as % of cycles) were diarrhea (54%), pain (52%), fatigue (52%), lymphopenia (39%), anemia (38%), hyperglycemia (38%) and dyspnea (34%). No grade 4 adverse events have occurred and only 8 pts experienced a grade 3 adverse event, primarily pain and dyspnea. No significant cardiac toxicity has been observed. Among 14 ACC pts evaluable for response so far: 9 have SD (range 2–9 cycles), 3 PD, and 2 died prior to cycle 2. For 12 evaluable non-ACC pts: 8 have SD (range 2–9 cycles), and 4 PD. No pts have had an objective response. Conclusions: Although there are no objective responses to date, lapatinib is well tolerated, with tumor stabilization achieved by 64% of pts and 24/38 pts remain on treatment at present. Trial accrual of ACC pts into the first stage has been completed, the second stage will open if an objective response is seen.

No significant financial relationships to disclose.
Radiosensitization with a COX2 inhibitor with chemoradiation for head and neck cancer
Authors: Prellop P. , Peters G. , Carroll W. , Nabell L. , Spencer S. , Ove R.
Published: March 2020

5582

Background: Cyclo-oxygenase 2 (COX2) inhibitors have shown promise as radio- and chemosensitizers. We conducted a phase IB/II study to evaluate the toxicity and efficacy of celecoxib, a selective COX2 inhibitor, administered concurrently with carboplatin, paclitaxel, and radiation for locally advanced or recurrent head and neck cancer. Methods: Patients with stage III/IV or recurrent squamous cell carcinoma of the oropharynx, oral cavity, hypopharynx, or larynx were eligible. Primary endpoints were toxicity, local control and survival. Patients were treated with weekly carboplatin (AUC = 2.0), paclitaxel (30 mg/m2) and concurrent radiation (70 Gy). Celecoxib (400 mg bid) was started 1 week prior to the initiation of radiotherapy and was given for a total of 2 years. In 12/04, the study closed due to concerns of cardiotoxicity with COX-2 inhibitors. Celecoxib was discontinued in all patients. The study restarted in 5/06 with the modification that celecoxib would be given only during radiation. Results: Between 12/02 and 1/06, a total of 28 patients were enrolled: 89% were male, median age was 56.5, 3 with recurrent cancer and 25 treated definitively. Five patients have been treated on the modified study. Grade 3/4 toxicities include: mucositis (35% G3), dermatitis (18% G3; 7% G4), febrile neutropenia (21% G3; 3% G4), dysphagia (57% G3), nausea/vomiting (29% G3). Thirty percent did not complete prescribed chemotherapy due to myelosuppression. Acturarial 2 year outcomes in the 20 evaluable, definitively treated patients: 65% survival, 76% local control. Conclusions: Compared to published data using carbo/taxol and RT, an unexpectantly high incident of febrile neutropenia was observed but no increase in radiation dermatitis or mucositis. Two year survival data is comparable to published data.

No significant financial relationships to disclose.
Effect of the third generation selective estrogen receptor modulator arzoxifene on mammographic breast density
Authors: Kimler B. F. , Ursin G. , Fabian C. J. , Anderson J. R. , Chamberlain C. , Mayo M. S. , O’Shaughnessy J. A. , Lynch H. T. , Johnson K. A. , Browne D.
Published: March 2020

562

Background: Arzoxifene (ARZ) is currently being studied for treatment of breast cancer patients in a Phase II trial because of tamoxifen-like efficacy but lack of uterine agonist effect. We conducted a Phase II chemoprevention trial in women at high risk for development of breast cancer on the basis of personal or family history. Methods: Potential subjects had multiple biomarkers assessed, including random periareolar fine needle aspiration (RPFNA) with breast epithelial cells processed for cytomorphology and immunocytochemistry. Women who exhibited cytologic hyperplasia ± atypia were eligible for enrollment. Subjects were stratified on the basis of atypia, estrogen receptor expression, menopause status, germline BrCa1/2 mutation status, and accrual site. Subjects were randomized (double-blind) between placebo and ARZ (LY353381.HCI, 20 mg daily) for 6 mo, with an option to continue on study for another 6 mo while receiving open-label ARZ. Assessments conducted at baseline, 6 mo, and 12 mo included mammographic breast density. Mammograms were digitized to image files which were cropped to remove labels and dates, and then identified by a study subject ID number and a random coding for baseline, 6 or 12 mo. This allowed the reader (GU) to view the three files for a subject, but to remain blinded as to the sequence of the films or the study agent. The files were assessed for mammographic density using the Madena computer-assisted system. Results: Of 199 subjects enrolled on the study, 52% were pre-menopausal; with 101 women randomized to placebo and 98 to ARZ. At baseline, mean values were comparable for placebo and ARZ groups for breast area (∼244 cm2), total dense area (∼100 cm2), and the percent of the breast at increased density (41.3% vs 46.2%). After 6 mo, there were minimal changes in total breast area (P=0.13); but statistically significant decreases (P<0.001) for the comparison of placebo vs ARZ (2-sided T-test) for change in both dense area (+3.8 vs −12.9 cm2) and percent breast density (+0.8% vs −4.6%). Conclusions: The 3rd generation SERM arzoxifene administered for 6 mo produces statistically significant decreases in mammographic breast density relative to placebo in women at high risk for development of breast cancer.

No significant financial relationships to disclose.
Analysis of fracture risk factors from the ’Arimidex’, Tamoxifen, Alone or in Combination (ATAC) trial: 5-year data
Authors: Howell A.
Published: March 2020

563

Background: The Completed Treatment Analysis of the ATAC trial at 68 months’ median follow-up confirmed that initial adjuvant treatment with anastrozole has significant efficacy and tolerability advantages compared with tamoxifen (ATAC Trialists’ Group. Lancet 2005; 365: 60–2). In the ATAC trial, the rate of all fracture types for anastrozole was higher than with tamoxifen. To better understand the impact of fracture risk factors on actual fracture rates, we undertook an analysis of the risk factors for all reported fractures in the ATAC trial up to 5 years. Methods: The analysis followed a time-to-event approach, using the Cox model with forward selection of prognostic covariates, together with the likelihood ratio test at the 5% significance level. Considered risk factors were age, body mass index (by tertile), previous hormone replacement therapy, concomitant medications (vitamin D, calcium, thiazides, statins, corticosteroids, thyroid hormones, bisphosphonates, antiepileptics, anxiolytics), geographical region (very high, high, or moderate and low hip fracture risk areas) (Kanis et al. J Bone Miner Res 2002; 17: 1237–44), smoking, and trial therapy (anastrozole or tamoxifen). Hazard ratios and associated 95% confidence intervals were obtained from the final model, which contained all statistically significant factors. Results: Of 6186 women, 524 (8.5%) had a fracture. Statistically significant predictors of fracture were age, region, and trial therapy ( Table ). A significant decrease in fracture risk was also observed in statin users although this decrease may not have been due to statin use, but rather to related factors. Conclusions: It is essential that individuals at high risk of fracture be identified so that they can receive appropriate evaluation and treatment. Profiling of risk as described here could enable the development of risk scores that would allow the identification and close observation of patients at high risk of fracture prior to commencing adjuvant therapy.

[Table: see text]

[Table: see text]
Confirmation of double-peaked time distribution of mortality for breast cancer in a population-based study
Authors: Wong N. S. , Gao F. , Tan S. B. , Machin D. , Ng E. H.
Published: March 2020

593

Background: Double-peaked time distributions of mortality hazard function have been reported for breast cancer patients from Western populations treated with mastectomy alone and is thought to reflect accelerated tumor growth at metastatic sites mediated by angiogenesis after primary tumor removal. Similar data is not available for Asian populations. We sought to investigate if differences exist in the pattern of mortality hazard function between Western breast cancer patients and Asian patients in Singapore treated with mastectomy alone which may suggest underlying differences in tumor biology between the two populations. Methods: We performed a retrospective cohort study of 3809 female unilateral breast cancer patients registered in the Singapore Breast Cancer Registry between October 1994 to June 1999. Data regarding patient demographics, tumor characteristics and death data were available. Overall survival curves were calculated using the Kaplan-Meier method and compared by the log-rank test. Death-specific hazard rate was calculated as the conditional probability of dying in a time interval, given that the patient was alive at the beginning of the interval. The life table method was used to calculate the yearly hazard rates. All tests were two-sided and significant at the 5% level. Results: In this cohort, 1169 patients (45.9%) had mastectomy alone without further adjuvant therapy. Demographics were: median age 55; 87.4% Chinese; 62.9% postmenopausal; 51.6% hormone receptor positive; 70.3% node negative; 22.8% high histological grade; 76.9% stage I or II. A double-peaked mortality hazard pattern, with a first major mortality rise reaching the maximum at the 2nd - 4th year after diagnosis and a second small mortality rise near the 9th year was observed. Analyses by subgroups showed a similar pattern in node positive or high grade tumors but not in node negative or well to moderately differentiated tumors. A double peaked pattern was seen regardless of menopausal status. The double-peaked pattern observed in our patients was quantitatively and qualitatively similar to that reported by Western series. Conclusions: Our study confirms a double-peaked process in Asian patients and gives further support to the tumor dormancy hypothesis.

No significant financial relationships to disclose.
Local-regional relapse and distant metastasis in conservatively managed triple negative early stage breast cancer
Authors: Haffty B. G. , Yang Q. , Reiss M. , Kearney T. , Hait W. , Toppmeyer D.
Published: March 2020

594

Background: Triple negative (TN) basal-like breast cancers (Negative for ER,PR,HER2/neu) represent an aggressive phenotype, with unique clinical and pathologic features. The purpose of this study was to determine the prognostic significance of this classification with respect to local-regional relapse and distant metastasis in a cohort of conservatively managed breast cancer patients. Methods: A large data base of conservatively managed breast cancer patients with long term follow-up, in which all three immunhistochemical markers, ER,PR and HER2/neu were available was reviewed. Patients were classified as TN if they tested negative for all three markers. Of 442 patients in the data base with all three markers available, 100 were classified as TN. All clinical, pathologic, outcomes and molecular marker data were entered into a computerized database. Results: As of September 2005, with a median follow-up of 7 years, of the 442 patients in the study there have been 50 in-breast relapses, 10 nodal relapses, 68 distant relapses and 62 deaths. Compared with the other subtypes, the TN cohort had a poorer overall survival (67% vs 75%, p = .096), poorer distant metastasis-free rate (61% vs 75%, p = .002), poorer cause-specific survival (67% vs 78%, p = .03), and poorer nodal relapse-free rate (93% vs 99%, p = .021). In a multivariate Cox regression analysis, TN subtype was an independent predictor of distant metastasis (HR=2.6, CI 1.53–4.35, p = .004) and cause- specific survival (HR= 2.36, CI 1.28–4.38, p= .006). There was no significant difference in local (in-breast) control between the TN and other subtypes. BRCA testing was performed on 85 patients in this cohort, of whom 8 had deleterious mutations in BRCA1 and 6 had deleterious mutations in BRCA2. Of 8 BRCA1 mutant patients 7 were classified as TN, while only 1 of 6 BRCA2 patients were TN (p < .001). Conclusions: Patients classified as TN have a poor prognosis with respect to overall, disease free and cause specific survival. However there was no evidence that these patients are at higher risk for local relapse following conservative surgery and radiation. BRCA1 mutant patients develop predominantly TN tumors.

No significant financial relationships to disclose.
Bimodal breast cancer incidence patterns provide support for a dualistic model of mammary carcinogenesis
Authors: Anderson W. F. , Pfeiffer R. M. , Dores G. M. , Sherman M. E.
Published: March 2020

595

Background: Although breast cancers are extremely heterogeneous with respect to clinical presentation, histopathological appearance, and molecular alterations; breast cancer is often viewed as a single biologic entity with common etiology and unified pathogenesis. Accumulating data has challenged this view, demonstrating that the stratification of tumors by gene expression profiles, immunohistochemical (IHC) staining patterns, and other techniques may permit the categorization of breast cancers into two main pathways of mammary carcinogenesis. Based upon cellular origin and/or estrogen receptor (ER) expression there are 1) tumors from stem cells committed to luminal differentiation and ER expression and 2) neoplasms from stem cells programmed to display basal differentiation and lacking ER expression. If confirmed, these observations may form the basis for revised conceptual frameworks. Methods:: We applied age-at-diagnosis density plots and a two component statistical mixture model to breast cancer cases overall (n=270,124) in the SEER program. These age distributions were reevaluated after stratification by histopathologic type, race, and ER. Results: A bimodal distribution provided a better fit for the age distribution patterns than a single distribution for breast cancers overall and for all histologic types, except medullary carcinoma. However, the proportion of early-onset and late-onset tumors varied: ductal and tubular carcinomas demonstrated relatively equal proportions; lobular, papillary and mucinous tumors were associated with late-onset populations; and inflammatory and medullary tumors were more related to early-onset disease. Medullary carcinomas were exceptional in showing a single distribution irrespective of race and/or ER status. Of note, medullary breast carcinomas are rare tumors that are associated with germline mutations in BRCA1. Conclusion: Most histopathologic types of breast carcinomas demonstrated a bimodal mixture of early- and late-onset cancer populations, possibly representing two major age-related causal pathways. These population-based results seem consistent with emerging molecular data, showing two main classes of breast cancer based upon cellular origin and ER expression.

No significant financial relationships to disclose.
Race as a risk factor for developing osteonecrosis of the jaw after long term bisphosphonate therapy in patients with metastatic breast cancer
Authors: Aiti T. , McDunn S. , Hussein L. , Ashkenazi I. , Jajeh A. , Wang Y. , Zaren H. A.
Published: March 2020

596

Background: Association between osteonecrosis of the jaw (ONJ) and bisphosphonate treatment has been increasingly reported in the literature. Methods: This is a retrospective review of a single institution’s experience with patients diagnosed with bone metastasis secondary to breast cancer, who developed ONJ while treated with bisphosphonates (Zoledronic acid - Zometa; Pamidronate - Aredia), between 1.1.2001 and 10.30.2005. Presentation, age, race, and outcome were reviewed. Logistic Regression was used to test for statistical significance. Results: 161 patients with bone metastasis secondary to breast cancer treated with bisphosphonates were reviewed (82 African American, 29 Caucasians, 26 Hispanic, 15 Asian and 9 others.). ONJ developed in 6 (3.7%) patients, 5 of which were Caucasians. Logistic regression adjusting for dose shows that the odds ratio for developing ONJ comparing Caucasians with non-Caucasians is 45.7 (p=0.016). Age did not impact occurrence of ONJ. All 6 patients developed ONJ after a minimum of 31 months of treatment. Two patients had a history of previous tooth extraction. In four other patients, ONJ appeared spontaneously. One patient, who presented with an abscess, developed sepsis which resulted in the patient’s death. Two patients were treated with debridement and antibiotics and their lesions healed. Three other patients ended up suffering from a chronically exposed bone. Conclusion: ONJ is a serious complication of bisphosphonate therapy and it affected a significant proportion of our patients. Our data suggests that Caucasians may be more susceptible. Since sample size is small, determining if race is a risk factor for the development of ONJ, while on bisphosphonate therapy, will require further investigation.

No significant financial relationships to disclose.
Initial biopsy procedure for breast cancer diagnosis influences number of surgical procedures and cost of care
Authors: Al-Refaie W. B. , Cormier J. N. , Xing Y. , Hunt K. K. , Fearmonti G. , Ghandi R. , Kuerer H. M. , Meric-Bernstam F. , Bedrosian I. , Lucci A.
Published: March 2020

598

Background: Excisional biopsy (ExB) and percutaneous needle biopsy (PB) are both accurate methods for diagnosing breast cancer. However, comprehensive breast cancer staging requires surgical assessment of the primary tumor and regional nodes. This study was designed to examine surgical and financial implications for breast cancer patients undergoing either ExB or PB. Methods: We evaluated 2,459 women with invasive breast cancer enrolled in a comprehensive database from 2000 to 2005. Clinical and treatment factors were compared for patients who had ExB versus PB. Total costs, facility fees (operating rooms, radiology suites, and pathology processing), and professional fees were estimated. A multivariate logistic regression was performed to determine factors associated with biopsy type. Results: PB was utilized in 1817 (74%) patients and ExB in 642 (26%). Of ExB patients, 86% were performed prior to referral. Patients undergoing ExB required a greater number of surgical procedures for margin control and lymph node assessment compared to PB (median 2.0 vs. 1.0, respectively). ExB exacted a cost increase 1.7 times that of PB, with a difference of >$3400 at our institution. After adjusting for age, tumor size and year of diagnosis, ExB was significantly associated with an increased number of surgical procedures required for definitive treatment compared to PB (OR = 166.7, p < 0.001). Conclusions: Excisional biopsy for breast cancer diagnosis results in an increased need for return trips to the operating room and higher cost of care. Percutaneous biopsy should be considered as the preferred approach in the diagnosis of breast cancer.

No significant financial relationships to disclose.
Comparative analysis of MRI vs mammography in evaluation of size, number of lesions and nodal status of breast cancer
Authors: Saha S. , Chitneni S. , Sehgal R. , Arora M. , Desouza B. , David S. , Singh T.
Published: March 2020

600

Background: Breast MRI is thought to be better in evaluating patients (pts) with BrCa. Our study was to compare MRI vs mam to predict leisons and LNS in BrCa. Methods: A retrospective study of 100 consecutive pts with pathologically proven BrCa was done. All had preoperative MRI and mam. Findings were compared to the final pathologic size, used as gold standard. MRI and was done at same center and single surgeon did all surgeries. Results: Of 100 pts,MRI reported 124 lesions. MRI reported size in 107 and mam reported size in 63 lesions. In MRI detected sizes 8% had same size as pathological size, 66% were overestimated by a mean of 0.64cm and 26% were underestimated by a mean of 0.48cm. For mam lesions, 10% had same size, 34% were overestimated by a mean of 1.10cm, 57% were underestimated by a mean of 0.78 cm. Total of 25 additional lesions were found in 23 pts in same and 6 leisons in 6 pts in contralateral breast by MRI. MRI also detected enlarged axillary and intramammary LN in 15% pts, 40% were true positives(+ve) and 60% were false +ve. One pt had metastatic LN in the contralateral axilla detected by MRI and confirmed by lymphoscintogram and pathology. 3% pts had neo-adjuvant chemotherapy Conclusion: In our study mam underestimated the breast lesion size in pts significantly more than MRI, but MRI overestimated BrCa lesion size in more number of pts. The mean difference in size on MRI when compared to the pathological size is less than 1 cm, while mam overestimated by a mean of greater than 1cm. This might be particularly important for T1 and T2 lesions, where size is the most important criterion for the T-stage classification. The identification of additional lesions and enlarged LN on MRI further validates the utility of MRI.

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No significant financial relationships to disclose.
Linked claims and medical records for case management of breast cancer diagnosis
Authors: Eberl M. , Broffman G. , Pomerantz J. , Watroba N. , Reinhardt M. , Mahoney M. C. , Fox C. , Edge S. B.
Published: March 2020

6000

Background: Real time linkage of medical records and administrative claims may assist physicians in managing cancer care. Failure to obtain requisite follow-up (f/u) of abnormal mammograms may delay cancer diagnosis and impact outcome with studies showing that up to 20% of women do not get recommened f/u. We tested the accuracy of claims data linked to medical records in identifying women who did not receive f/u for an abnormal mammogram (BI-RADS 0,3,4,5). Methods: Electronic medical records in a staff model practice affiliated with a single payer were scanned to identify the BI-RADS code for all mammograms performed by practice radiologists. For each woman covered by the payer with a BI-RADS 0,3,4 or 5 mammogram, claims were searched for f/u breast procedures (imaging, biopsy, surgery). For women with more than 1 abnormal mammogram in the study period, only f/u of the first abnormal mammogram was studied. Cases were censured if their insurance coverage with the payer terminated before the required period of follow-up. Medical records of cases defined by claims as not having recommended f/u were reviewed to determine the accuracy of claims analysis. Results: 17,329 women covered by the payer had at least one mammogram in the practice from 1/1/2001 to 12/31/2003. The BI-RADS was 0, 3, 4 or 5 in 1,319 (7.5%). Among 1,206 eligible for f/u, 189 (16%) did not receive the BI-RADS recommended f/u (see table ). Medical record review showed that the claims search accurately identified the follow-up care in 95% of these cases. Conclusions: Administrative claims accurately identify care for diagnostic management of abnormal mammograms. Real-time linkage of claims to mammogram BI-RADS data is being tested as a regional case management system to assist physicians in assuring approrpriate follow-up for abnormal mammograms.

[Table: see text]

No significant financial relationships to disclose.
Consistency in regional trends of aggressiveness in cancer care near the end of life for elderly Americans, 1991–2000
Authors: Earle C. C. , Landrum M. , Jeffrey S. , Neville B. , Weeks J. , Ayanian J.
Published: March 2020

6004

Background: We have previously developed and reported on performance measures assessing the aggressiveness of cancer treatment near the end of life for selected cancers during 1993–96. Methods: We compared the care delivered in the 77 Health Care Service Areas (HCSAs) monitored by the Surveillance, Epidemiology, and End Results (SEER) program to all Medicare-eligible patients aged 65 and over who died of cancer (any diagnosis) between 1991 and 2000. We used hierarchical regression models to estimate regional variation in both levels and trends of each indicator. We then ranked each region according to the model-estimated rate of each indicator and computed the correlation among relative ranks of each region over the ten-year study period. Results: 215,488 patients met eligibility criteria. Within this broader and more recent sample we confirmed previous observations of steadily and significantly increasing use of chemotherapy within 2 weeks of death, emergency room visits, and intensive care unit admissions in the last month of life, and, among those admitted to hospice, an increasing proportion of late admissions within 3 days of death. There was significant regional variation in all measures, but the relative rankings of health care service areas from one year to the next were stable, with correlations of ranks ranging from .91–.98 from 1991–1992, and .66–.84 over the 5-year span from 1991–1995. Because of significant regional variation in trends, we found only moderate correlations ranging from .40–.61 over the entire decade. Conclusions: Cancer treatment near the end of life continued to become increasingly aggressive over the 1990s, however, there was significant regional variation in trends. The stability of regional practice patterns supports the reliability of these measures for quality surveillance purposes.

[Table: see text]

No significant financial relationships to disclose.
Postive sentinel nodes after neoadjuvant chemotherapy: What factors predict additional disease in the axilla?
Authors: Jeruss J. S. , Ayers G. D. , Cristofanilli M. , Ross M. I. , Babiera G. , Meric-Bernstam F. , Kuerer H. M. , Feig B. W. , Yi M. , Hunt K. K.
Published: March 2020

602

Background: The predictive utility of sentinel lymph node biopsy (SLNB) after neoadjuvant chemotherapy is similar to that for patients treated initially with surgery. We hypothesized that patients with positive SLNs after chemotherapy would have unique clinical and pathologic factors predictive of additional non-SLN positivity. Methods: From 1993 - 2005, 104 patients were identified from a prospective database who responded to neoadjuvant therapy, had a positive SLNB, and underwent axillary dissection. At presentation, 66 patients had clinically negative nodes (CN) by ultrasound, and 38 patients had positive nodes by fine needle aspirate (Pos). Univariate and multivariate assessments of 17 predictive factors for additional non-SLN disease were performed using chi-square and logistical regression analysis with a bootstrapped backwards elimination procedure. Results: Patients with CN nodes (47%) were less likely to have additional non-SLNs positive when compared to patients with FNA Pos nodes at presentation (71%) (p=0.017). In additional univariate analysis, method of SLN metastasis detection, lymphovascular invasion (LVI), multicentricity, LN response to neoadjuvant therapy, nuclear grade, number of SLNs positive, and size of SLN metastasis were predictive for additional positive non-SLNs (p ≤ 0.05). In multivariate analysis, LVI, method of SLN metastasis detection, multicentricity, axillary node status at presentation, and pathologic tumor size retained grouped significance with a bootstrap adjusted AUC of 0.762. A nomogram for predicting non-SLN metastasis was created incorporating these variables. Multifocality, ER, nuclear grade, and number of negative or positive SLNs did not add statistical predictive power to our model. Conclusions: Patients treated with neoadjuvant therapy who have positive SLNs are at high risk of having additional non-SLN disease; use of a nomogram may help to risk-stratify this patient population. We have identified unique predictive variables for these patients, including multicentricity and nodal status at presentation, that indicate additional non-SLN disease when the SLN is positive. We plan to validate the predictive ability of the multivariate results for this patient population prospectively.

No significant financial relationships to disclose.