bluuebunny/crossref_metadata_2025 huggingface dataset:
A phase III, randomized, double-blind, multicenter study comparing monotherapy with ipilimumab or gp100 peptide vaccine and the combination in patients with previously treated, unresectable stage III or IV melanoma.
Authors: O'Day S. , Hodi F. S. , McDermott D. F. , Weber R. W. , Sosman J. A. , Haanen J. B. , Zhu X. , Yellin M. J. , Hoos A. , Urba W. J.
Published: February 2017

4

Background: Ipilimumab, a fully human monoclonal antibody against cytotoxic T-lymphocyte antigen-4, demonstrated activity in advanced melanoma. Gp100 vaccine showed immunological and clinical responses, and enhanced clinical activity when combined with other immunotherapy. This phase III study compared efficacy and safety of ipilimumab or gp100 monotherapy and combination.

Methods: Eligible patients (HLA-A*0201+ previously treated adults with unresectable stage III/IV melanoma) were randomized 1:3:1 to ipilimumab (3 mg/kg q3w x 4 doses) + placebo (n=137), ipilimumab + gp100 (peptides 209-217[210M] and 280-288 [288V]; 1mg q3w x 4 doses; n=403), or gp100 + placebo (n=136). There was no maintenance phase. Primary endpoint was comparison of overall survival (OS) between patients who received combination versus gp100 alone; secondary endpoints were all other OS comparisons, best overall response rate (BORR), disease control rate (DCR) to W24, progression-free survival (PFS), and safety.

Results: The study demonstrated statistically significant results for all efficacy endpoints (below). Ipilimumab alone or combined with gp100 resulted in a significant improvement in OS with risk reduction of 32-34% compared to gp100. Significant differences in DCR, BORR, and PFS were observed. Adverse events with ipilimumab were consistent with prior studies: generally mild, immune-related, and medically manageable.

Conclusions: Ipilimumab is the first agent to improve median and long-term OS in a phase III study of previously treated patients with advanced melanoma. Addition of gp100 vaccine to ipilimumab did not improve outcome.

[Table: see text]

[Table: see text]
AVAGAST: A randomized, double-blind, placebo-controlled, phase III study of first-line capecitabine and cisplatin plus bevacizumab or placebo in patients with advanced gastric cancer (AGC).
Authors: Kang Y. , Ohtsu A. , Van Cutsem E. , Rha S. Y. , Sawaki A. , Park S. , Lim H. , Wu J. , Langer B. , Shah M. A.
Published: February 2017

LBA4007

Background: The median survival for patients (pts) with AGC in most phase III studies is less than 1 year. The addition of bevacizumab (bev) to chemotherapy (chemo) is supported by a strong preclinical rationale and by phase II evaluation. AVAGAST is the first randomized study to compare the efficacy and safety of bev + chemo vs placebo + chemo.

Methods: Pts with inoperable, locally advanced or metastatic stomach/gastroesophageal junction adenocarcinoma with no prior therapy were randomized 1:1 to capecitabine (cape, or 5-FU) + cisplatin (cis) and either bev (7.5 mg/kg iv) or placebo q3w. Stratification variables: geographical region, fluoropyrimidine treatment, disease status. Cis was given for 6 cycles; bev/placebo + cape/5-FU were given until disease progression or unmanageable toxicity. Primary objective: compare overall survival (OS); secondary objectives: compare progression-free survival (PFS), overall response rate (ORR), and safety (as overseen by an independent DSMB).

Results: From Sep 2007 to Dec 2008, 774 pts were enrolled. Treatment arms were balanced. Approx 95% of pts were metastatic. Two-thirds of pts were male, 49% of pts were from Asia/Pacific, 32% from Europe and 19% from the Americas. Median OS was 10.1 months with chemo + placebo and 12.1 months with chemo + bev in the intent-to-treat population (HR 0.87; p=0.1002). Median OS according to geographical region was 6.8 vs. 11.5 months (HR 0.63) in the Americas, 8.6 vs. 11.1 months (HR 0.85) in Europe and 12.1 vs. 13.9 months in Asia-Pacific (HR 0.97). Secondary endpoints and AEs of special interest for Bev are summarized below ( Table ).

Conclusions: While the primary endpoint was not met (median OS HR 0.87; p=0.1002), there was a significant improvement in PFS and ORR and an acceptable safety profile for bev + chemo in patients with AGC.

[Table: see text]

[Table: see text]
An open-label, randomized, phase III trial of zalutumumab, a human monoclonal EGF receptor (EGFr) antibody, versus best supportive care, in patients with noncurable squamous cell carcinoma (SCCHN) of the head and neck who have failed standard platinum-based chemotherapy (ZALUTE).
Authors: Machiels J. H. , Subramanian S. , Ruzsa A. , Repassy G. , Lifrenko I. , Flygare A. , Sorensen P. , Ehrnrooth E. , Baadsgaard O. , Clement P. M.
Published: February 2017

LBA5506

Background: Zalutumumab is a novel, fully human IgG1 mAb targeting the EGFr that has shown encouraging activity in SCCHN.

Methods: Patients with noncurable SCCHN with an ECOG PS of 0-2 and centrally documented radiographic progressive disease (PD) within 6 months after platinum-therapy were randomized between zalutumumab monotherapy and best supportive care (BSC) in a 2:1 ratio. Stratification parameter was ECOG PS. Methotrexate (MTX) was allowed in the BSC arm only. Individual dose-titration of zalutumumab was applied (max. exposure 16 mg/kg). The primary endpoint was overall survival (OS), with progression free survival (PFS) as the only secondary endpoint to be compared between groups, using log-rank test. 231 deaths were required to statistically differentiate OS between groups with 80% power.

Results: 286 patients (34F, 252M) were randomized. The median age was 57 years (range 18-78), 65% had distant metastasis and 17% were ECOG PS 2, all similar between groups. 78% of patients in BSC arm received MTX. Although a median OS of 6.7 months was observed in the zalutumumab group compared to 5.2 in the BSC group, this was not statistically significant (p=0.065). A clear improvement in PFS (P=0.001) was demonstrated. Zalutumumab showed a safety profile as expected within this drug class.

Conclusions: This is the first controlled study to demonstrate that an EGFr-targeted antibody given as monotherapy induces a clinically meaningful improvement in PFS in patients with SSCHN who have failed platinum-based chemotherapy.

[Table: see text]

[Table: see text]
Dasatinib compared to imatinib (IM) in patients (pts) with newly diagnosed chronic-phase chronic myelogenous leukemia in chronic phase (CML-CP): Twelve-month efficacy and safety from the phase III DASISION study.
Authors: Kantarjian H. , Shah N. P. , Hochhaus A. , Cortes J. E. , Shah S. , Ayala M. , Moiraghi B. , Bradley-Garelik M. , Zhu C. , Baccarani M.
Published: February 2017

LBA6500

Background: Dasatinib is a highly potent BCR-ABL kinase inhibitor. Once daily dasatinib demonstrated high rates of durable complete cytogenetic response (CCyR) with 73% progression-free survival and 87% overall survival at 3 yrs in pts with CML-CP post IM failure. DASISION compares efficacy and safety of dasatinib and IM as initial treatment of CML-CP.

Methods: 519 pts with Ph(+) newly diagnosed CML-CP stratified by Hasford risk were randomized to dasatinib 100 mg QD (n = 259) or IM 400 mg QD (n = 260). The primary endpoint was 12-mo rate of confirmed CCyR (cCCyR; CCyR on 2 consecutive analyses; any # of metaphases). Other endpoints were rates of and times to CCyR and major molecular response (MMR).

Results: Pts characteristics were well balanced. Minimum follow-up was 12 mos; median treatment duration was 14 mos. 85% of dasatinib and 81% of IM pts remained on study. Median dose intensity was 99 mg/d for dasatinib and 400 mg/d for IM. cCCyR rate was superior for dasatinib vs IM (77% vs 66%, P = 0.0067). 12-mo CCyR and MMR rates ( Table ) were higher for dasatinib vs IM (CCyR: 83% vs 72%; MMR: 46% vs. 28%). MMR was obtained significantly faster with dasatinib (HR 2.0, P < 0.0001) as was CCyR (HR 1.5, P < 0.0001). Rates of transformation to AP/BC were 1.9% for dasatinib and 3.5% for IM. Grade 3/4 anemia (10% vs 7%) and neutropenia (21% vs 20%) were similar across arms; thrombocytopenia was more common for dasatinib (19% vs. 10%). Non-hematologic adverse drug reactions (all grades) in ≥10% of pts (dasatinib vs. IM) were fluid retention (19% vs 42%; including pleural effusion, all grade 1 or 2, 10% vs. 0%), nausea (8% vs. 20%), vomiting (5% vs. 10%), myalgia (6% vs.12%), muscle inflammation (4% vs. 17%) and rash (11% vs. 17%).

Conclusions: Dasatinib showed significantly higher and faster rates of CCyR and MMR vs IM. Given the predictive value of 12-mo CCyR and MMR and the favorable tolerability of dasatinib, dasatinib may improve long-term outcomes in pts with newly diagnosed CML-CP.

[Table: see text]

[Table: see text]
Adjuvant therapy with pegylated interferon alfa-2b (36 months) versus low-dose interferon alfa-2b (18 months) in melanoma patients without macro-metastatic nodes: EADO trial.
Authors: Grob J. J. , Jouary T. , Dreno B. , Gutzmer R. , Hauschild A. , Leccia M. T. , Landthaler M. , Asselineau J. , Garbe C. , Pehamberger H. E.
Published: February 2017

LBA8506

Background: Adjuvant therapy with low-dose adjuvant interferon alfa-2b (IFN) as well as with pegylated interferon alfa-2b (PEG-IFN) were both shown to be superior to observation in melanoma (M) patients (pts) without macro-metastatic nodes. However, the two strategies have never been assessed head to head. Weekly injection of PEG-IFN facilitates a longer duration of treatment which may be critical for benefit. We thus compared adjuvant therapy of flat low-dose PEG-IFN (36 months) versus low-dose IFN (18 months) in intermediate-risk M pts without macro-metastatic nodes.

Methods: In this multicenter, open-label, prospective randomized phase III trial, pts with resected M ≥ 1.5 mm in thickness and without clinically detectable nodes were randomized either to IFN (3 MU subcutaneously [sc] 3 times a week for 18 months) or to PEG-IFN (100 mcg sc once weekly for 36 months). Sentinel node procedure (SNP) was not a standard in 2003 and thus was optional. Approach was consistent by center. Randomization was stratified for centers and SNP procedure. Primary endpoint was relapse-free survival (RFS), and secondary were distant metastasis-free survival (DMFS), overall survival (OS), and grade 3-4 severe adverse events (SAE). Sample size (890 pts) was calculated to detect a 10% difference (power >80%, type I error of 5%, 2-sided) for RFS. Analysis describes 5-year probability of survival. Comparisons were done by intent-to-treat using Cox proportional models.

Results: Of 898 pts enrolled, 896 (443 PEG vs 453 IFN) were eligible for evaluation after a median follow-up of 4.7 years. SLNB was performed in 68.2% of pts. Neither RFS (PEG-IFN 66.2% vs IFN 64.8%, p=0.43; HR, 0.91; 95% CI, 0.73 to 1.15) nor DMFS (71.3% vs 72.6%, p=0.86; HR, 1.02; 95% CI, 0.80 to 1.32) or OS (77.0% vs 78.4%, p=0.55; HR, 1.09; 95% CI, 0.82 to 1.45) showed statistical difference. There was an excess of SAE grade 3-4 in PEG-IFN arm (44.6% vs 26.6% in the first 18 months) which impacted on median duration of treatment (17.8 months in IFN arm; 19.2 in PEG-IFN arm, with only 28% completing 36 months treatment).

Conclusions: Flat low-dose PEG-IFN did not show superiority over conventional low dose IFN. Attempts to increase benefit by prolonging treatment with PEG-IFN over 3 years were hampered by a high rate of treatment discontinuation possibly linked to SAEs with PEG-IFN.

[Table: see text]
PARAMOUNT: Phase III study of maintenance pemetrexed (pem) plus best supportive care (BSC) versus placebo plus BSC immediately following induction treatment with pem plus cisplatin for advanced nonsquamous non-small cell lung cancer (NSCLC).
Authors: Paz-Ares L. G. , De Marinis F. , Dediu M. , Thomas M. , Pujol J. , Bidoli P. , Molinier O. , Sahoo T. P. , Laack E. , Reck M. , Corral J. , Melemed S. A. , John W. J. , Chouaki N. , Zimmerman A. , Visseren Grul C. M. , Gridelli C.
Published: February 2017

CRA7510

Background: The PARAMOUNT trial investigated whether pem continuation maintenance therapy improves progression-free survival (PFS) after pem-cisplatin induction therapy in patients (pts) with advanced nonsquamous NSCLC. Methods: In this double-blind, placebo-controlled trial, 939 pts participated in the induction phase, specified as four cycles of induction pem (500 mg/m2) and cisplatin (75 mg/m2) on day 1 of a 21-day cycle. Pts who had not progressed during pem-cisplatin induction and had an Eastern Cooperative Oncology Group performance status (PS) of 0/1 (n=539; 57.4%) were randomized (2:1, stratified for disease stage, PS, and induction response) to maintenance pem (500 mg/m2 on day 1 of a 21-day cycle) plus BSC (n=359) or placebo plus BSC (n=180) until disease progression. All pts received vitamin B12, folic acid, and dexamethasone. The primary endpoint was PFS (target: HR=0.65, two-sided alpha=0.05; 90% power with minimum of 238 events). Results: Pt characteristics were balanced between arms: median age=61 years; 58% male; 95% Caucasian; 32% PS 0; 91% stage IV; 87% adenocarcinoma; and 45% induction complete/partial response. Pem continuation maintenance resulted in a 36% reduction in the risk of progression (HR=0.64, 95% CI: 0.51-0.81; P=0.00025). The median independently reviewed PFS (472 pts, 297 events), measured from randomization, was 3.9 months (95% CI: 3.0-4.2) on the pem arm, and 2.6 months (95% CI: 2.2-2.9) on the placebo arm. The disease control rate (% pts with response/stable disease) was 71.8% on the pem arm, and 59.6% on the placebo arm (P=0.009). The drug-related serious adverse event (AE) rate was 8.9% on the pem arm, and 9.2% of pts had grade 3/4 laboratory Common Toxicity Criteria AEs. On the placebo arm, the rates were 2.8% and 0.6%, respectively. Discontinuations due to AEs were 5.3% on the pem arm, 3.3% on the placebo arm. Conclusions: PARAMOUNT met its primary endpoint and showed that pem continuation maintenance following pem-cisplatin induction is an effective and well tolerated treatment for pts with advanced nonsquamous NSCLC.
Barriers in providing breast and colorectal cancer survivorship care: Perceptions of U.S. primary care physicians (PCPs) and medical oncologists (MOs).
Authors: Virgo K. S. , Lerro C. C. , Klabunde C. N. , Earle C. , Ganz P. A.
Published: February 2017

CRA9006

Background: Increased coordination among clinicians in cancer survivorship care is needed yet the literature suggests barriers remain due to a fragmented healthcare system. This is the first nationwide study of barriers PCPs and MOs perceive regarding breast and colorectal cancer survivorship care. Methods: The Survey of Physician Attitudes Regarding the Care of Cancer Survivors (SPARCCS) was mailed to a nationally representative stratified sample (N=5,275) of eligible American Medical Association member PCPs and MOs (N=3,596) providing care to cancer survivors, to permit comparisons of views regarding follow-up testing, roles, knowledge self-confidence, and perceived barriers. We analyzed physician-based barriers using weighted multinomial logistic regression models adjusted for physician demographics, reimbursement, training, and practice characteristics. Results: 2,202 physicians (1,072 PCPs and 1,130 MOs) responded (57.6% response rate; 65.1% cooperation rate). In weighted univariate analyses, PCPs were significantly more likely to report often/always ordering tests or treatments as malpractice protection, being concerned about missed care, and lacking adequate training to manage patient problems. MOs were more likely to report (often/always and sometimes) concerns about duplicated care and about which physician provides general preventive health care. In multivariate regression models, physician specialty remained significant for 3 of 5 physician-based barriers. MOs were less likely to report inadequate training (OR: 0.33, 95% CI: 0.22-0.49), less likely to often/always order extra tests due to malpractice concerns (OR: 0.53, 95% CI: 0.34-0.84), and more likely to report being often/always (OR: 1.97, 95% CI: 1.13-3.43) and sometimes (OR: 2.16, 95% CI: 1.60-2.93) uncertain who is providing general preventive care, compared to PCPs. Conclusions: MOs perceived different physician-based barriers as problematic in cancer follow-up care compared to PCPs. Alleviation of inadequate training, malpractice-driven test ordering, and preventive care delivery barriers may require education and provision of survivorship care plans.
The evaluation of flaxseed for hot flashes: Results of a randomized, controlled trial, NCCTG study N08C7.
Authors: Pruthi S. , Qin R. , Terstriep S. A. , Liu H. , Loprinzi C. L. , Shah T. R. C. , Tucker K. F. , Dakhil S. R. , Bury M. J. , Carolla R. L. , Steen P. D. , Vuky J. , Barton D. L.
Published: February 2017

CRA9015

Background: Hot flashes are a common symptom during the menopause transition or following breast cancer treatment that can negatively impact the quality of life for many women. Preliminary data have suggested that flaxseed, a rich source of dietary lignans, may be a potentially effective treatment for hot flashes. Methods: A phase III randomized, placebo controlled trial was conducted to evaluate the efficacy of flaxseed in reducing hot flashes. Postmenopausal women were randomly assigned to a flaxseed bar (providing 410 mg of lignans) for 6 weeks vs a placebo bar. Participants completed daily prospective, self report hot flash diaries during the baseline week and then began eating one study bar per day for 6 weeks, while continuing to record their daily hot flashes. The intra-patient difference in hot flash activity between baseline and the last treatment week was the primary endpoint. Side effects of the bars were evaluated through self report and CTC assessment. Results: Between October and December 2009, 188 women were enrolled onto this trial. Mean hot flash scores were reduced by 4.9 units in the flaxseed group and 3.5 in the placebo group (p=0.29). In both groups, a little over a third of the women received a 50% reduction in their hot flash scores. Only one side effect was significantly different between groups, that being grade 1 pruritis, which was more common (7%) in the placebo group versus 1% in the flaxseed group. Both groups reported increased abdominal distension, flatulence, diarrhea and nausea. Adherence and ability to detect treatment assignment did not differ between groups. Conclusions: The results of this trial do not support the use of 410 mg of flaxseed lignans for the reduction of hot flashes. The gastrointestinal side effects seen in both groups were likely due to the fiber content in the flaxseed and placebo bars.
RTOG 0525: Molecular correlates from a randomized phase III trial of newly diagnosed glioblastoma.
Authors: Aldape K. D. , Wang M. , Sulman E. P. , Hegi M. , Colman H. , Jones G. , Chakravarti A. , Mehta M. P. , Andrews D. W. , Long L. , Diefes K. , Heathcock L. , Jenkins R. , Schultz C. J. , Gilbert M. R. ,   Radiation Therapy Oncology Group
Published: February 2017

LBA2000

Background: Formalin-fixed, paraffin embedded GBM tumor tissue, adequate for conventional MGMT methylation analyses, was required for entry onto the RTOG 0525 clinical trial. Methods: Four prognostic biomarkers were evaluated on a training set of 220 retrospectively obtained GBM samples, consisting of IDH1 mutation, the glioma-CpG island methylator phenotype (G-CIMP), a microarray-based mRNA panel and a novel MGMT promoter methylation assay. For each biomarker, 2 (IDH1 and mRNA) or 3 subgroups (G-CIMP and MGMT) were defined based on associations with overall survival. All combinations (36 possible) of each of the 4 biomarker-derived subgroups were then defined and compared with survival data and then consolidated into 4 risk groups. Once created in the training set, this model was applied to the RTOG 0525 samples (n=763) for external validation. Results: Application of the molecular risk classification to RTOG 0525 samples (left table) showed a highly significant survival association (p<0.001). When compared to the recursive partitioning analysis (RPA, table on right), this composite molecular classifier better identified patients with long term survival and appears to improve resolution by revealing an additional distinct risk group. The molecular classifier was prognostic in each of the treatment arms individually. Conclusions: Four distinct biomarkers or biomarker panels were tested in GBM. These biomarkers were compared with clinical outcome in a training set to optimize a method to combine them into a classifier. This classifier was then validated on a large sample set from a large phase III clinical trial. This composite panel may represent an improvement over the existing RPA with respect to risk stratification of patients for GBM. Additionally, it has the potential to impact future clinical trial designs and provide enhanced opportunities for personalization of therapy for GBM. Support: NCI U10 CA2121661, U10 CA37422, P50 CA127001.

[Table: see text]
Exemestane for primary prevention of breast cancer in postmenopausal women: NCIC CTG MAP.3—A randomized, placebo-controlled clinical trial.
Authors: Goss P. E. , Ingle J. N. , Ales-Martinez J. , Cheung A. , Chlebowski R. T. , Wactawski-Wende J. , McTiernan A. , Robbins J. , Johnson K. , Martin L. , Winquist E. , Sarto G. , Garber J. E. , Fabian C. J. , Pujol P. , Maunsell E. , Farmer P. , Gelmon K. A. , Tu D. , Richardson H.
Published: February 2017

LBA504

Background: Limited efficacy and serious toxicities have limited uptake of tamoxifen or raloxifene as preventatives of breast cancer. Aromatase inhibitors (AIs) prevent contralateral breast cancers more than tamoxifen in adjuvant trials and have fewer serious side effects. This is the first report of an AI used in primary prevention. Methods: NCIC CTG MAP.3 is a randomized trial designed to detect a 65% reduction in annual incidence of invasive breast cancer (IBC) on exemestane (E) versus placebo (P). Eligible postmenopausal women had ≥ one of the following risk factors: Gail score >1.66%, prior ADH, ALH, LCIS or DCIS with mastectomy, age over 60. Health-related and menopause-specific quality of life (QOL) were assessed by SF-36 and MENQOL questionnaires. Results: From 2004-2010, 4,560 women were randomized: age 62.5 yrs (37-90); Gail Score 2.3 % (0.6-21); BMI 28.0 kg/m2 (15.9-65.4). Risk factors included: age >60 yrs (49%); Gail score >1.66 (40%); and prior ADH, ALH, LCIS or DCIS with mastectomy (11%). At median follow-up of 35 months there were 11 IBCs on E and 32 on P (annual incidence 0.19% vs 0.55%; HR= 0.35, 95% CI 0.18-0.70, p = 0.002); ductal (10E/27P), lobular (1E/5P). Most tumors were ER positive (7E/27P); Her2/neu negative (10E/26P); TNM stage T1 (8E/28P), N0 (7E/22P), M0 (11E/30P). E was superior in all subgroups: by Gail score, age, BMI, prior LCIS and DCIS. The annual incidence rate of IBC or DCIS was 0.35% E and 0.77% P (HR=0.47;95% CI 0.27-0.79; p = 0.004) based on 64 IBCs or DCISs (20E/44P). Clinical bone fractures, osteoporosis, hypercholesterolemia or cardiovascular events were equal in both arms. No clinically meaningful differences in QOL were detected. Conclusions: Exemestane significantly reduced invasive and pre-invasive breast cancers in postmenopausal women at increased risk for breast cancer with no serious toxicities. Exemestane should be considered a new option for primary prevention of breast cancer. Supported by the Canadian Cancer Society; Pfizer Inc. PEG supported in part by Avon Foundation.
Clinical presentation of breast cancer: Age, stage, and treatment modalities in a contemporary cohort of Michigan women.
Authors: Smith D. R. , Caughran J. , Kreinbrink J. L. , Parish G. K. , Silver S. M. , Breslin T. M. , Pettinga J. E. , Mehringer A. M. , Wesen C. A. , Yin H. , Share D. , Davis A. T. , Pleban F. T. , Bacon-Baguley T. A.
Published: February 2017

1

Background: The U.S. Preventative Services Task Force (USPSTF) revised their breast cancer screening recommendations in 2009 changing their stance on age and frequency of mammography screening to biannual exams starting at age 50. The purpose of this study is to analyze data from a statewide breast cancer registry managed by the Michigan Breast Oncology Quality Initiative (MiBOQI) to determine the impact of these new recommendations on diagnosing and treating breast cancer.

Methods: De-identified data were collected on women participating in the MiBOQI registry at seventeen statewide institutions from 2006-2009. Data included method of detection, cancer stage, age at detection, treatment type, and patient demographics. Participants were stratified based on age, and data analyzed using NCSS software (chi-square and t-tests).

Results:5903 women with breast cancer with an average age at diagnosis of 59.4 years were included. 65.5% of breast cancers were detected via mammography, 29.8% by palpation, and 4.7% by other methods. In women under 50 years of age, cancers were detected by mammography in 48.3% (69.3% >50yr) and by palpation in 46.1% (24.1% >50yr). Patients with palpable presentations were younger (55.8 yr vs. 61.2 yr; p <0.001). Cancers with a palpable presentation were diagnosed at higher stages (50.0% stage II) than with mammography (52.5% stage I; p<0.001). Breast conservation surgery occurred more frequently than mastectomy (palpation 54.2%; mammography 72.9%, p<0.001) but cancers detected through palpation were more likely to undergo mastectomy procedures.

Conclusions: Results of this study validate the importance of annual screening mammography in women older than 50 years, and women aged 40 to 49 years recently omitted from screening guidelines. There was an increased prevalence of palpation for the method of detection in women less than 50 years of age. If screening mammography is omitted in this group, cancers when detected may be of a more advanced stage and result in more mastectomies. This study also supports the use of palpation as a method of detection despite recent recommendations against teaching self breast exams by USPSTF.
The impact of lymph node status on clinical outcomes following accelerated partial breast irradiation.
Authors: Shah C. , Wilkinson J. B. , Wallace M. , Vicini F. A.
Published: February 2017

107

Background: Currently, node-positive patients are considered unsuitable for APBI per the ASTRO guidelines with limited data on outcomes of node-positive patients following APBI.

Methods: 510 patients with early-stage breast cancer received accelerated partial breast irradiation (APBI) between April 1993 and November 2010. Of these, 39 were lymph node positive with 10 patients having N1mi disease (median size of mets = 0.82 mm) and 29 patients having N1 disease (61.5% had 1 node positive [median size of mets = 2.5 mm], 30.8% had 2 nodes positive [median size of mets = 8.0 mm], and 7.7% had 3 nodes positive [median size of mets = 20 mm]). Patient, clinical, and pathologic factors were analyzed and compared for the node-negative (N0) and node-positive (N+) cohorts including age, tumor size, receptor status, margin status, adjuvant hormone therapy, adjuvant chemotherapy, and length of follow-up.

Results: N+ patients were younger (p=0.04), had larger tumors (p<0.001), and were more likely to receive chemotherapy (p<0.001). Median follow-up was 5.3 years for N0 patients and 5.9 years for N+ patients (p=0.06). At 5 years, no differences were seen in the 5-year actuarial rates of LR (2.2% v. 2.6%, p=0.86), AR (0% v. 0%, p=0.69), DFS (90.0% v. 88.0%, p=0.79), CSS (98.0% v. 90.0%, p=0.06), or OS (91.0 v. 84.0%, p=0.65) while higher rates of RR (0% v. 6.1%, p<0.001) and DM (2.2% v. 8.9%, p=0.005) were noted in N+ patients. A total of 10 LRs occurred in the N0 patients and 1 LR in the N+ patients at a median of 2.6 and 1.5 years respectively. Both RR that developed in N+ patients were within the supraclavicular fossa at a median of 2.8 years. Univariate analysis of LR was performed and age (p=0.31), tumor size (p=0.48), ER status (p=0.13), PR status (p=0.34), T-stage (p=0.48), chemotherapy (p=0.41), APBI technique (p=0.80), and nodal status (p=0.86) were not associated with LR while there was a trend for the association of LR with close/positive margins (p=0.07), and failure to receive adjuvant hormonal therapy (p=0.06). No variables were associated with any type of AR.

Conclusions: No difference was seen in the rates of local recurrence or axillary failure between node-negative and node-positive following APBI with 5-years of follow-up.
Use of clinical and treatment factors to predict survival outcome in nonmetastatic metaplastic breast cancer.
Authors: Lai L. L. , Luu T. H. , Nelson R. A.
Published: February 2017

11

Background: Although metaplastic breast cancer (MBC) represents < 1% of breast cancer, stem cell research has stimulated interest in the genetics and biology of MBC. Because prognostic clinical and treatment factors remain ill-defined for this rare breast cancer subtype, we queried a public cancer data registry to identify factors predictive of overall survival (OS) in MBC.

Methods: Patients diagnosed with breast cancer from 2001-2008 were identified using the Surveillance, Epidemiology, and End Results (SEER) database. We included only patients with infiltrating ductal carcinoma (IDC) and MBC who had non-metastatic disease. Patients were evaluated by standard demographic, clinicopathologic, and treatment factors including age, race/ethnicity, extent of disease, tumor marker expression and treatment received. Differences between IDC and MBC were assessed using Chi-Square methods. OS across groups was measured using the Kaplan-Meier method and compared using the log-rank test. Cox proportional hazard and stepwise models were used to identify prognostic variables and to adjust for covariates. Median follow-up was 31 months.

Results: Of the total 508,071 breast cancer cases, there were 1,246 (0.25%) patients with MBC and 392,809 (77%) with IDC. 5-yr OS for locoregional MBC and IDC was 67% and 84%, respectively (p<0.0001). When compared with IDC, MBC patients were older, had larger ER/PR negative cancers, and were more likely to have nodal disease. Factors predictive of worse OS in MBC on multivariate analysis are listed below. Tumor grade, ER/PR expression, and type of surgery (partial v. total mastectomy) did not impact OS. Of the treatment factors, only radiation affected OS (p=0.0002).

Conclusions: To our knowledge this is the largest report of clinical and treatment factors predictive of outcomes in patients with MBC. Studies integrating clinical factors with molecular data may advance therapy that is more specific for this rare breast cancer subtype.

[Table: see text]
A prospective study of cancer-related fatigue in women undergoing radiotherapy for breast cancer.
Authors: Torres M. A. , Liu T. , Chen H. , Godette K. D. , Stapleford L. J. , Mister D. , Pace T. , Miller A. H.
Published: February 2017

110

Background: To investigate potential risk factors for cancer-related fatigue in women with breast cancer undergoing whole-breast radiotherapy (RT), we assessed the contribution of chemotherapy (CTX), RT-induced epidermal thickening, and inflammatory mediators to post RT fatigue.

Methods: Following lumpectomy, 30 women received whole breast RT (50 Gy plus a 10 Gy boost). Prior to RT, at week 6 of RT, and 6 weeks post RT, subjects completed a validated questionnaire assessing fatigue (Multidimensional Fatigue Inventory [MFI-20]). At the above visits, patients underwent blood sampling for inflammatory mediators. In addition, breast epidermal thickness was measured using ultrasound tissue characterization.

Results: Fatigue scores in the sample as a whole did not increase during RT. Independent multivariate analyses of clinical and demographic factors revealed that prior CTX (p<.001) and age <50 (p=.03) were significant predictors of higher post RT fatigue scores. Before, during, and after RT, CTX-treated patients had significantly higher mean fatigue scores than non-CTX-treated subjects. For example, mean MFI scores post RT in patients previously treated with CTX (n=15) were 28 points higher than patients not treated with CTX (mean 61 vs. 33, p<.001), with a clinically meaningful difference being 10 points. Race, cancer stage, and epidermal thickening (defined as a 50% increase over baseline during or after RT, n=17) did not predict higher post RT fatigue scores. Of the inflammatory mediators, plasma IL-6 prior to RT was the strongest predictor of post RT fatigue (p=.02). In addition, plasma IL-6 concentrations prior to RT were significantly higher in patients who received CTX versus those who did not (mean 5.0 vs. 2.5, p=.01). IL-6 prior to RT was also significantly correlated with RT-induced epidermal thickening (p=.04).

Conclusions: Our study suggests that CTX-induced inflammation, measured by plasma IL-6, is independently associated with the development of fatigue as well as epidermal thickening in women undergoing breast RT. Treatments targeting inflammation before RT may reduce both fatigue and epidermal thickening post RT, particularly in patients who have been previously been treated with CTX.
Preoperative radiotherapy in patients with locally advanced breast cancer: Tumor response and patient outcome after 26 years of median follow-up.
Authors: Santos M. , Heymann S. , Fayard F. , Dunant A. , Arriagada R. , Marsiglia H. , Bourgier C.
Published: February 2017

113

Background: Preoperative radiotherapy (PreopRT) in locally advanced breast cancer patients (LABC) has been rarely reported. The purpose of this study was to determine if pathological response to PreopRT could have prognostic value on locoregional control and survival.

Methods: From 1970 to 1984, 203 LABC patients were treated by PreopRT, delivering 45Gy in 25 fractions to the breast, supraclavicular fossa, axilla and ipsilateral internal mammary chain. After a median interval of 38 days (range: 5-121 days), radical mastectomy and axillary dissection was performed independently of radiation response. Chemotherapy or endocrine therapy was prescribed according to physician discretion in 28% and 11% of patients, respectively. Premenopausal patients underwent ovarian ablation. Median follow-up was 26 years. Locoregional control (LRC), disease-free survival (DFS), and overall survival (OS) were estimated using the Kaplan-Meier method, the comparison of survival between groups was performed using the log-rank test, multivariate analysis was performed using the Cox model.

Results: Thirty-three patients (16.2%) had a pathologic complete response (pCR) in the breast. The 10- and 20-year Kaplan-Meier LC were 90% (95% confidence interval CI: 85-94%) and 84% (95% CI: 77-89%), respectively. The 10 and 20-years DFS were 49% (CI: 42-55%) and 35% (CI: 29-42%), and the 10 and 20-years OS, 56% (CI: 49-63%) and 41% (CI: 35-48%), in that order. Patients with pCR tended to have better DFS (p=0.06) and OS (p=0.07) when compared to patients with partial response or stable/progressive disease. Having a pCR did not significantly influenced LRC (p=0.44). Multivariate analysis showed that a lower number of positive nodes on axillary dissection and younger age were associated with better DFS (p<0.0001 and p=0.02) and OS (p<0.0001 and p=0.007).

Conclusions: LCR achieved by PreopRT followed by radical mastectomy in LABC was excellent in this study, despite few patients having adjuvant systemic therapy. Complete pathologic response defined a subgroup of women with a trend toward better DFS and OS. Older patients and those with a higher number of involved axillary nodes had a worse prognosis.
Role of HER2 status in the treatment of brain metastases arising from breast cancer by stereotactic radiosurgery.
Authors: Novik Y. , Kunnakkat S. , Donahue B. , Rush S. , Golfinos J. , Parker E. , Narayana A.
Published: February 2017

117

Background: Overexpression of human epidermal growth factor receptor-2 (HER2) in breast cancer has been shown to be an independent risk factor of development of brain metastases (BM). However, the role of HER2 on the radiosensitivity of BM remains controversial. We investigated the efficacy of single fraction stereotactic radiosurgery (SRS) in the treatment of limited BM from breast cancer, based on the HER2 status.

Methods: From 2004 to 2010, 57 patients with limited BM were treated with SRS using Leksell Gamma-Knife to a median dose of 20 Gy (range 12-20 Gy) prescribed to the 50% isodose line. The median number of lesions treated were 2 (range 1-7) and the median tumor volume was 92.8 mm3 (range 3.4 -793.7 mm3). There were 27 HER2 positive patients, with 32 ER positive and 22 PR positive patients. Six patients were triple negative. ER/PR information was not available for 4 patients. Overexpression of HER2 was defined as HER2 +++ by immunohistochemistry using the DAKO HercepTest or fluorescent in situ hybridization (FISH) analysis. Time to local recurrence, time to development of new brain metastases, progression-free survival (PFS), and overall survival (OS) were assessed from the date of SRS.

Results: With a median follow-up of 11 months (range 1-66 months), 12 patients developed recurrence at the previously treated site (9 HER2 positive patients) and 30 developed new brain metastases (16 HER2 positive patients) The median PFS and OS for all patients were 8 and 16 months respectively. The median PFS for HER2 positive patients compared to HER2 negative patients were 7 and 11 months, respectively (p=0.352). HER2 positive patients had a median OS of 20 months, compared to 14 months in HER2 negative patients (p=0.086). Five patients went on to develop leptomeningeal disease, all of whom were HER2 positive.

Conclusions: HER2 overexpression does not increase the risk of recurrence at the site of treatment or appearance of new BM. It does not affect PFS or OS following SRS. However, it remains a risk factor for the development of leptomeningeal disease.
Prognosis by breast cancer subtypes in patients treated with adjuvant chemotherapy in a clinical trial.
Authors: Ali A. M. G. , Provenzano E. , Abraham J. , Bartlett J. M. , Poole C. J. , Hiller L. , Dunn J. , Twelves C. , Earl H. M. , Caldas C. , Pharoah P.
Published: February 2017

12

Background: Breast cancer can be classified into molecular subtypes that have distinct survival patterns. The purpose of this study was i) to evaluate the prognostic significance of breast cancer subtypes in a cohort of women taking part in the NEAT and BR9601 clinical trials comparing CMF with ECMF, and ii) to evaluate whether the subtypes were predictive of the added benefit of epirubicin in these trials.

Methods: Tumor tissue microarrays were stained and scored for ER, PR, HER2, EGFR and CK5/6. These were used to classify the tumors into six intrinsic subtypes (1). We used Cox regression to compare overall survival (OS), breast cancer specific survival (BSS) and relapse free survival (RFS) in the different subgroups. We also compared the effect of ECMF with CMF by subgroup.

Results: IHC data were available for 1725 cases of whom 805 were Luminal 1-basal negative, 153 were Luminal 1-basal positive, 174 were Luminal 2, 192 were HER2-like, 230 were core basal phenotype and 171 were 5-negative phenotype. Median follow-up time was 7 years. The prognostic effects of the subtypes were similar to those reported for unselected breast cancer cases irrespective of adjuvant therapy (Blows FM, et al. PLoS Med 2010;75:e1000279.). In particular, the luminal 1-basal negative tumors were associated with the best prognosis in five years after surgery and the HER2-like tumors were associated with the poorest prognosis. ECMF has previously shown to be associated with a 33% relative risk reduction for OS compared to CMF (Poole CJ et al. N Engl J Med 2006;35518:1851-62.). There was little evidence for significant heterogeneity of effect by tumor subtype for any end point (OS P= 0.40, BSS P=0.53 RFS P=0.50). However, there was an observed trend towards the largest additional benefit from ECMF being in women with tumors of the 5-negative phenotype (OS HR=0.39 95% CI 0.21-0.73) and the smallest being in Luminal 1-basal negative tumors (OS HR=0.86 95% CI 0.64-1.16).

Conclusions: In a clinical trial in which all patients received chemotherapy, we confirmed that breast cancer subtypes show distinct behaviour with differences in short and long term survival. The benefit of ECMF over CMF was statistically similar in all disease subtypes.
Stereotactic radiosurgery for early-stage breast cancer: A new paradigm.
Authors: Yu C. X. , Regine W. , Zheng M. , Zhang J. , Feigenberg S. J.
Published: February 2017

120

Background: Stereotactic radiosurgery (SRS) has not been widely used for breast cancer partly due to: 1) the lack of a suitable immobilization device; and 2) the lack of a delivery system that can concentrate a high radiation dose noninvasively. We have developed a SRS system that effectively addresses these obstacles and demonstrated the dosimetric feasibility of simultaneously ablating the intact tumor and sterilizing the tumor bed.

Methods: A breast immobilization device consists of a solid outer cup with embedded stereotactic frame and a porous inner cup; the two cups join at the chest wall side by a soft goggle-like lip for comfort. A negative pressure is applied to the space between the two cups to immobilize the breast tissues. 15 patients with surgical clips in their breast underwent a geometric reproducibility trial, in which the patients received two CT scans spaced 10-60 minutes while wearing the cup. A SRS delivery system uses 36 Co-60 sources that rotate around a focal point to produce 36 non-coplanar arcs. The breast cup is locked on the treatment couch with the patient in prone position. The couch moves dynamically during treatment, allowing the focal spots to “paint” the desired 3D dose distribution.

Results: The reproducibility of the 42 available clips was 1.83 mm ± 1.08 mm (2 std) and patients reported good comfort. 8 treatment plans simultaneously delivering an ablative dose of 18Gy to an intact tumor plus a 3mm margin (CTV1) and 10Gy to the tumor bed (CTV2 = CTV1+1cm) have been developed and verified with measurements. The dose-volume histograms showed very uniform dose coverage with 98% of CTV1 receiving 18Gy and 100% of tumor bed receiving 10Gy. On average, only 21% of the normal breast receives greater than 5Gy, safe to deliver 3 fractions of such doses.

Conclusions: A breast-specific SRS system has been developed. Dosimetric studies illustrated the feasibility of managing early-stage breast cancer with SRS. Clinical studies that will identify patients in whom current forms of surgery and postoperative radiation may be eliminated are planned, allowing completion of local therapies noninvasively within a few days rather than months.
MammoSite partial breast irradiation following breast-conserving surgery for early-stage breast cancer.
Authors: Shokek O. , Yacoub S. , Bauer T. L. , Bell T. , Fortier G. A. , Grim R. , Hempling R. E. , Johnson D. E. , Kassas B. , Lasher D. , Mudge K. , Pandelidis S. , Pramanik R. , Watson M. , Wojcicka J. , Shah A.
Published: February 2017

122

Background: Partial breast irradiation (PBI) remains investigational until comparisons to whole-breast external beam radiotherapy (EBRT) confirm noninferiority.

Methods: From 2004 to 2010, 103 patients at York Cancer Center (Pennsylvania) who underwent margin-negative breast-conserving surgery for early-stage invasive or in situ breast carcinoma were enrolled on a prospective MammoSite PBI protocol. NSABP B39 stage and planning criteria were utilized, with unicentric tumors up to 3 cm and pN0-1 axillary staging for invasive carcinomas. PBI was prescribed to 1 cm from the applicator surface in 10 twice-daily fractions to 34 Gy.

Results: With a median follow-up of 27 months, three patients experienced recurrence: one with isolated local in-breast tumor recurrence (local IBTR), one with IBTR remote from the surgical cavity (non-local IBTR) plus regional and distant recurrence, and one with regional and distant recurrence only 3- and 5-year freedom from local IBTR are 100% and 96% (non-local IBTR: 100% and 95%). Physician-reported cosmesis evaluations are available for 25 patients at 2-3 years after treatment, with a median score of “excellent.” 26 additional patients on protocol underwent insertion of the MammoSite applicator but had it removed without treatment, most commonly due to unsatisfactory cavity conformance (24 patients), uncommonly due to infection or seroma (two patients). Their characteristics (invasive vs. in situ disease, T/N stage, negative vs. close margins, age) were not statistically different than the 103 MammoSite-treated patients. All except one received EBRT, and none experienced IBTR, which is not statistically different than the IBTR rates of the 103 MammoSite-treated patients (p=0.84).

Conclusions: MammoSite PBI in well-selected patients was associated with low rates of IBTR and not significantly different than a comparison cohort selected for MammoSite PBI but treated instead with EBRT. Randomized comparisons of PBI vs. EBRT are required to confirm PBI as standard.
Lymphedema and arm symptoms following three-dimensional conformal radiation therapy (3DCRT) for node-positive breast cancer (BC) patients.
Authors: Sparks I. , Prior P. , Xiang Q. , Li X. A. , Yen T. W. , White J. R.
Published: February 2017

130

Background: Regional nodal irradiation for lymph node (LN) positive BC after lumpectomy/mastectomy can be subject to controversy due to the potential for treatment morbidity particularly lymphedema. Little is known about lymphedema and other arm morbidity rates after 3DCRT approaches.

Methods: 172 LN positive BC cases treated from 2000 to 2007 using 3-DCRT and Dose Volume Histogram analyses were studied. All cases underwent axillary node dissection (AND). Axillary target volumes (ATV) were delineated on all treatment planning CT scans. Field arrangement and beam modifications were selected to deliver a min of 45 Gy to 90% of the ATV. Post-treatment bilateral arm circumference measurements (96%) and patient reported ipsilateral arm symptoms (thickness, heaviness, tingling, numbness) were recorded.

Results: Median follow-up was 83.7 months. Median (med) patient age was 50. 52% were premenopausal. 76/66% had positive estrogen/progesterone receptors and 16% were HER2+. 52% underwent lumpectomy and 46% mastectomy. Median number of LN removed was 17 (1-46), number +LN was 3 (1-29), and tumor size was 3.7 cm. For 79 patients with separate AND the mean resected axillary volume was 157.8 cc (med 171 cc, range 25-472 ). The mean contoured ATV was 69 cc (med 58cc, range 16-608). On average 95% of the ATV was covered by a med of 44.7 Gy. Local control was achieved in 94.7% regional LN control in 99.4%. 16.7% met criteria for lymphedema (> 2 cm difference in circumference). Arm symptoms were reported by 51 (30%) of these 20 (39%) had measured circumference change > 2 cm. Referral to physical therapy was documented for 15% for reduced ROM but at last follow-up noted in 2.3%. The measured lymphedema rate was higher in patients who had mastectomy – 22 v. 11% (p=0.042) and worse with increasing resected axillary dissection volumes (p=0.032), ATV volume (p=0.883), and RT dose inhomgeneity coefficient (p = 0.049).

Conclusions: Measured lymphedema rates following AND and 3-DCRT in this study were similar to those reported for AND in randomized studies compared to sentinel node. Careful attention to 3DCRT methods may help optimize lymphedema rates.