bluuebunny/crossref_metadata_2025 huggingface dataset:
Efficacy of concurrent cetuximab (C225) versus 5-fluorouracil/carboplatin (5FU/CBDCA) or cisplatin (CDDP) with intensity-modulated radiation therapy (IMRT) for locally advanced head and neck cancer (LAHNSCC).
Authors: Shapiro Lauren Quinn , Sherman Eric Jeffrey , Koutcher Lawrence , Setton Jeremy , Zhang Zhigang , Shi Weiji , Rao Shyam S. , Fury Matthew G. , Wolden Suzanne L. , Kraus Dennis , Pfister David G. , Lee Nancy Y.
Published: March 2020

5537

Background: We reported inferior outcomes for LAHNSCC patients (pts) that received concurrent C225 vs. high-dose CDDP with IMRT (IJROBP 2011; 81:915). Prior to FDA approval of C225 for LAHNSCC, non-CDDP candidates at our institution were treated with 5FU/CBDCA (JNCI 1999; 91:2081). The purpose of this study was to compare the outcomes of concurrent C225 vs. 5FU/CBDCA vs. CDDP with IMRT for LAHNSCC. Methods: Retrospective review of records was performed for pts treated at MSKCC with concurrent C225 (n=49) vs. 5FU/CBDCA (n=52) vs. high-dose CDDP (n=259) and IMRT from 11/02 to 04/08. Overall survival (OS), locoregional failure-free survival (LRFS), and late toxicity for all pts and oropharyngeal subset were obtained. Outcomes were analyzed using univariate/multivariate Cox proportional hazards model or competing-risks analysis. Multivariate OS analysis was confirmed by propensity score adjustment. Results: Pts were similar with regard to site, overall stage, and alcohol/tobacco history. Compared to pts treated with CDDP, those who received C225 or 5FU/CBDCA were older, with lower performance status, higher Charlson score, higher T stage, and worse renal function. With median follow-up of 53.1 months for survivors, the 4-year OS was 40.9% (95% CI 26.0-55.2%) for C225 vs. 70.2% (95% CI 55.5-80.9%) for 5FU/CBDCA vs. 86.9% (95% CI 82.0-90.6%) for CDDP. Compared with CDDP, C225 (hazard ratio [HR] 4.01, p<0.0001) but not 5FU/CBDCA (HR 1.54, p=0.15) was associated with worse OS on multivariate analysis. Propensity score analysis yielded a HR of 2.76 (p=0.01) for treatment with C225 vs. platinum-based chemotherapy. 4-year actuarial LRF for 5FU/CBDCA was similar to CDDP (9.7% vs. 6.3%, HR 1.51, p=0.42 by Gray’s method) and significantly lower than C225 (40.2%, HR 4.95, p=0.002). Late toxicity was as follows: C225 (6.1%) vs. CDDP (7.7%) vs. 5FU/CBDCA (21.2%). Conclusions: After adjusting for independent risk factors, there was no significant difference in OS or LRFS between 5FU/CBDCA and high-dose CDDP, but C225/RT resulted in significantly inferior OS and LRFS. Late toxicity was worst with 5FU/CBDCA.
Phase II trial of everolimus in patients with previously treated recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN).
Authors: Varadarajan Prakash , Kotsakis Athanasios Panayotis , Martin Daniel , Gutkind Jorge Silvio , Gibson Michael K. , Argiris Athanassios
Published: March 2020

5541

Background: The PI3K/Akt/mTOR pathway plays an important role in SCCHN pathogenesis and resistance to treatment. We conducted a phase II study of everolimus, an oral inhibitor of mTOR, in patients with refractory SCCHN. Methods: Patients with recurrent or metastatic SCCHN treated with at least 1 prior regimen, performance status (PS) 0-2, and adequate organ function, received everolimus 10 mg once daily orally. The primary endpoint was the disease control rate (DCR) defined as the proportion of patients with a complete response, a partial response, or stable disease. A two-stage design was followed. Cytokines were measured in plasma and serum at baseline and post treatment. Results: 9 patients were enrolled. Median age 63 years (range 51 - 82), Male/Female, 6/3, performance status 0/1/2, 2/5/1. Primary site: oropharynx (2), oral cavity (4), larynx (1), others (2). Median number of palliative therapies in the recurrent/metastatic setting prior to study was 1 (range 1- 4). Median number of cycles of everolimus delivered was 1 (range 1-5). No objective responses were seen. One patient had stable disease that lasted 6 months but all other patients had progression as best response. DCR was 11%. Median progression-free survival was 40 days. Four patients have died due to disease progression. Grade 3 adverse events were infrequent: pain (2 patients), anemia (2 patients), and 1 patient each with pruritus, hypertransaminasemia, hyponatremia, lymphopenia, and fatigue. No Grade 4 toxicities were reported. Biomarker analysis in 2 patients with available post treatment samples showed reduced plasma levels of VEGF-A, Gro-α, and IL-17, after everolimus treatment, but no reduction was observed in the plasma levels of IL-6 and IL-8, two cytokines often associated with SCCHN disease progression. Conclusions: Everolimus as monotherapy was well tolerated but did not have sufficient activity in this setting. This phase II study did not meet the predefined primary endpoint in the first stage of accrual.
Recurrent/metastatic salivary gland malignancies (RMSGM): Final report of 60 cases treated with cisplatin plus vinorelbine (DDP+VNB).
Authors: Pedani Fulvia , Airoldi Mario , Garzaro Massimiliano , Raimondo Luca , Carnio Simona , Fora Gianluca , Giordano Carlo , Pecorari Giancarlo
Published: March 2020

5548

Background: RMSGM are not amenable to the usual treatment with surgery and post-operative radiotherapy. The role of chemotherapy (CT) for RMSGM is palliative only. VNB showed moderate activity in our experience (Bull Cancer 85:892;1998) and in a randomized phase II trial we had demonstrated that the DDP+VNB combination had a better outcome than VNB alone (Cancer 91:541; 2001). In this abstract we report the final results of this combination in 60 cases. Methods: From April 2001 to February 2009 , 60 cases with RMSGM were enrolled. All patients received the following regimen: DDP 80 mg/sm d.1 + VNB 25 mg/sm d. 1,8 every 3 weeks. The study foresees a maximum of 6 cycles. Results: Patients characteristics were as follows: 35 males (58%) and 25 females (42%).; median age: 56 yrs (range 20-68); median ECOG PS: 1 (0-2); histology: adenocarcinoma 15 (25%), adenoid cystic ca. 34 (57%), others 11 (18%); site of disease: local 30 (50%) , mts +/- local 30 (50%). Forty-two pts received DDP+VNB as first line CT (70%) while 18 pts (30%) had the combination as second-line CT (30%). After a median of 5 cycles of first line DDP+VNB responses were: 3 CR (7%), 10 PR (24%), 14 NC (33%) and 15 PD (36%). After a median of 4 cycles of second line CT responses were: 0 CR; 1 PR (5%), 6 NC (33%) 11 PD (62%). Median survival: 10 months (3-29) for first line CT ; 4 months (1-12) for second line CT. G3-4 toxicity: neutropenia (20%), anemia (12%), nausea/vomiting (12%) , peripheral toxicity (3%). Conclusions: DDP+VNB is an effective first line CT in RMSGM ; second line CT has a low palliative activity. Toxicity seems acceptable. This regimen could be suitable for an integration with new biologic target agents.
Obesity at diagnosis and breast cancer (BC) recurrence risk based on the 21-gene assay recurrence score (RS).
Authors: Ridolfi Kimberly , Zhang Chong , Onitilo Adedayo A. , Ledesma Wendy M. , Andreason Molly , Engel Jessica Marie , Kim KyungMann , Wisinski Kari Braun , Tevaarwerk Amye , Charlson John A.
Published: March 2020

555

Background: Obesity at diagnosis has been associated with poorer overall survival in BC patients. The Oncotype Dx 21-gene assay RS has been shown to predict the risk of distant recurrence in estrogen receptor (ER) positive BC. This study aimed to evaluate if an association exists between body mass index (BMI) and RS. Methods: Retrospective chart review of patients (pts) with BC diagnosed 2005-2010 and a 21-gene assay was performed. Risk factors including BMI, hormone use, and menopausal status were collected as well as tumor characteristics such as ER/PR/HER2 status, stage, and grade. Univariate analysis of the association between BMI level (<30 vs ≥30), and RS (≤18 vs >18), stage (I vs II), and grade (1 vs 2 vs 3) was conducted using Chi square test. Correlation of BMI with RS (0-100) was also assessed via Spearman’s correlation. All tests were at a two sided significance level of 0.05. Results: Of 495 pts with a RS value, 482 had a BMI within 6 months of diagnosis. Median BMI was 27.7 kg/m2 (range 17-63). BMI for pts presenting with stage 2 disease is significantly higher (30±6.9) than those with stage 1 (29±7.8), p=0.04 (Wilcoxon rank sum test). No association was found between BMI level and stage, grade or RS. See Table. Mean RS was 18.8 vs 18.2 (BMI <30 vs ≥30), p=0.79 (Wilcoxon rank sum test). Conclusions: This is the largest study of the association between BMI and the RS. Obesity (BMI≥30) has been associated with increased recurrence and death from BC. However, we found no association between BMI and RS. This suggests that poorer outcomes among obese ER+ breast cancer patients may not be due to intrinsic tumor biology (as reflected in the RS), but to other non-tumor factors, whether higher circulating estrogen levels, reduced efficacy of aromatase inhibitors, other comorbidities, difficulty with chemotherapy or other unidentified factors. Further study is warranted. [Table: see text]
Patient-reported symptoms following IMRT alone for oropharynx cancer: A survivorship study.
Authors: Gunn Gary Brandon , Fuller Clifton David , Garden Adam S. , Frank Steven J. , Morrison William H. , Beadle Beth Michelle , Phan Jack , Mendoza Tito R. , Hanna Ehab Y. , Ang K. Kian , Cleeland Charles S. , Rosenthal David Ira
Published: March 2020

5561

Background: Patients (pts) with favorable oropharynx cancer (OPC) are often treated with single modality RT with excellent disease control. We present the pattern of pt-reported symptoms in OPC survivors treated with IMRT alone. This will represent a benchmark for later comparison to pts treated with other modalities (e.g., proton therapy, transoral surgery). Methods: Pts eligible for this cross-sectional questionnaire-based study had OPC treated with IMRT (no systemic therapy), in remission >18 mos, completed the MD Anderson Symptom Inventory – Head and Neck Module (MDASI-HN). Clinical data were tabulated and analyzed using non-parametric statistics. Results: 89 pts participated. OPC sub-site was tonsil in 58, base of tongue (BOT) in 30, and soft palate in 1 pt. 65% were TX/1, 28% T2, and 7% T3/4, while 53% were NX/1 with 47% N2. Mean RT dose was 66 Gy (SD±2.5). Median age was 54 years (SD±11). Mean follow-up at MDASI-HN was 74 months (SD±15). Mean MDASI-HN symptom rating (0 to 10 scale) was 1.3 (95% CI 0.97-1.6), with no significant difference by OPC sub-site. No single MDASI-HN items showed significant difference in the percentage of pts with moderate to severe (M/S) reports by OPC site, thou dry mouth approached significance (p=0.054), 53% in BOT vs. 32% for tonsil. Overall, 14% of pts were entirely symptom free (i.e. “0” across all 22 symptom items), 33% reported only mild symptoms, 23% only moderate symptoms, and 31% reported any symptom as severe . The top 7 symptoms were dry mouth, swallowing, sleep, taste, fatigue, distress, and teeth and these were reported at M/S levels by 39%, 24%, 19%, 17%, 16%, 14%, and 10% of pts, respectively. For those with any M/S symptom, the median number of symptoms reported at M/S levels was 3. 1/89 pts had a feeding tube at the time of MDASI-HN completion. Conclusions: The late symptom burden for long-term OPC survivors following IMRT alone was low, with nearly half of pts with only minimal symptoms across all items. Considering other endpoints (e.g. disease control, acute toxicity, second malignancies, and functional measures), future treatment strategies should seek to match or exceed these results. Future RT symptom prevention/reduction strategies should focus on the top symptoms identified here.
Predicting the Oncotype DX score: An inexpensive guesstimation.
Authors: Pesce Catherine , Stempel Michelle , Eaton Anne , Patil Sujata , Brogi Edi , Potz Brittany , Hudis Clifford , El-Tamer Mahmoud
Published: March 2020

557

Background: Oncotype DX Recurrence Score [RS] is used to predict the benefits of chemotherapy added to adjuvant hormone therapy in ER positive early stage breast cancer. It is also prognostic. However, its expense may be a concern in some health care systems and communities. In addition, it is labor intensive, requiring shipment of tissue samples to a single laboratory with an average 10-14 day turnaround time (in the US). A reliable and inexpensive estimator of the Oncotype DX risk score using readily available pathologic variables from tumor specimens could be useful. Methods: We reviewed our prospective database of patients with Oncotype DX results obtained over 2.5 years (1155 specimens with Oncotype DX scores, September 2008 – March 2011) and identified 766 invasive ductal carcinomas with known ER status, PR status, histologic grade, and nuclear grade. Through linear regression analysis, we predicted recurrence score for each tumor using these four parameters. After categorizing according to the same risk classification as in Oncotype DX (low risk: RS<18, intermediate risk: RS 18-30, or high risk: RS>30) we compared our predicted recurrence score to actual Oncotype DX recurrence score. Results: Overall 69.7% of specimens were assigned the same risk category as with the Oncotype DX level. In the predicted low risk group, 1.7% of patients were actually high risk. None of the predicted high risk patients had a low score. Conclusions: We found a strong correlation between scores estimated using our model and actual reported Recurrence Scores. If validated, our model could provide a clinically useful estimation of risk at lower cost. [Table: see text]
Genetic alterations in HRAS gene in relation to outcome and response to cetuximab in head and neck squamous cell carcinoma.
Authors: Rampias Theodoros , Giagini Athina , Matsuzaki Hiroumi , Bartzi Valentina , Siolos Spyros , Vaja Elena , Haralambakis Nick , Katsaounis Panagiotis , Scorilas Andreas , Psyrri Amanda
Published: March 2020

5574

Background: Aberrant signaling through RAS/MAPK pathway is implicated in resistance to EGFR-targeted agents in cancer. Genetic alterations in Hras gene such as mutations and specific polymorphisms are associated with aggressive phenotype in several smoking-related malignancies. We sought to determine the impact of Hras genetic alterations on response to cetuximab and prognosis in HNSCC. Methods: Clinical outcome according to Hras status was investigated in a retrospective cohort of 140 HNSCC specimens. Primary endpoints were overall survival (OS) and disease-free survival (DFS) and secondary endpoint was treatment response. For statistical analysis, T-test was used for continuous data and x2 –test for categorical data. Cetuximab-resistant cell lines harboring mutant Hras (BB49, T24) were infected with lentivirus expressing shRNA targeting the Hras or a scrambled- shRNA. MTT assay was used to determine the effect of cetuximab on growth of lentivirus infected cells. Biochemical analysis involved immunoblotting for pERK1/2. Results: Mutationanalysis of tumor samples showed that 5.7% participants harbored Hras mutations and 16.42% harbored Hras polymorphisms (rs12628, rs41258054) that are associated with tumorigenesis. Patients bearing tumors with mutated Hras had inferior mean OS ( 22.13vs 35.20, p=0.02) and a non-significant trend for inferior mean DFS. Patients with tumors containing Hras genetic alterations (mutation or polymorphism) had significantly inferior mean OS (p=0.02) compared to those harboring wt Hras and trended towards inferior DFS (p=0.07). Patients had received various treatments such as surgery plus/minus RT and various chemotherapy regimens. A subgroup analysis of 38 patients treated with cetuximab-based regimens showed that wt Hras was associated with higher likelihood of attaining CR or PR to treatment of borderline significance (p=0.06) due to small sample size. Silencing of Hras in Hras-mutant cell lines restored sensitivity to cetuximab and caused a direct downregulation of pERK1/2 levels. Conclusions: Hras genetic alterations are associated with aggressive clinical course and may affect response to cetuximab in HNSCC.
The role of postoperative radiotherapy (PORT) in the management of parotid gland malignancy (PGM).
Authors: Harrison Louis Benjamin , Hu Kenneth , Shourbaji Rania Ayman , Culliney Bruce , Li Zujun , Urken Mark , Persky Mark , Mourad Waleed Fouad
Published: March 2020

5581

Background: To report the role of PORT in the management of PGM and to analyze the prognostic factors for optimal locoregional (LRC) and distant control (DC) Methods: This is a single institution retrospective study. From March 2001-2011, a total of 118 patients with PGM were treated with surgery and PORT (100%) of which 75% were treated with IMRT, 20 and 10% received concurrent carboplatin and CDDP respectively. Indications for PORT were: recurrent or gross residual disease, +ve or close margins, nerve invasion and +ve lymph nodes (LN). PORT fields comprehended parotid bed and ipsilateral neck. Median PORT doses delivered were 70, 63, 54 Gy (at 1.8-2 Gy/fraction) for gross, microscopic disease, and ipsilateral neck respectively. All PORT was delivered via 4-6 MV photons with daily 3-5 mm bolus. The median age was 52 (18-89). Females and Caucasian made up 56% and 64% of the population, respectively. Histologic findings were adenoid cystic carcinoma 20%, mucoepidermoid carcinoma 19%, adenocarcinoma 18%, pleomorphic carcinoma 16%, salivary duct carcinoma 9%, acinic cell carcinoma 8%, ex-pleomorphic carcinoma 7%, and sarcoma 3%. Pathological stages I, II, III, IV were 10, 30, 20 and 40% respectively Results: With a median follow up of 56 months (12-124), the LRC and DC for the whole cohort were 96% (5/118) and 93% (8/118) respectively. The median duration of PORT was 45 days (40-60). The median time to LR failure (LRF) and distant metastases were 16 (12 - 30) and 28 months (24-48) respectively. Late RT toxicity was; grade I xerostomia 30%, altered taste 15%, trismus 6%, dysphagia and neck stiffness 2%. Kaplan-Meier curve shows the 5-year cause-specific survival to be 100%. Chi square and regression analysis tests show significant relationship (P=0.001) between salivary duct ca (70%) and distant metastases (DM), also males are at higher risk (17%) to develop LRF and DM, compared to females (6%). Poor prognostic features for DM and LRF were salivary duct ca, stage IV, PNI, and multiple LN involvement. Conclusions: Our data show that surgery followed by PORT to the tumor bed and ipsilateral neck provide excellent long standing oncologic and functional outcomes. Further studies are warranted to optimize the management of patients at higher risk of DM despite LRC and RT ± chemotherapy administered.
Association of the phosphorylation of the estrogen receptor at serine 118 and 167 with prognosis in postmenopausal breast cancer patients.
Authors: Beelen Karin J. , Opdam Mark , Koornstra Rutger H.T. , Vincent Andrew D. , Vermorken Jan Baptist , van Diest Paul J. , Sanders Joyce , Wesseling Jelle , Linn Sabine C.
Published: March 2020

562

Background: The sensitivity of the estrogen receptor (ERα) to anti-estrogen therapy can be affected by phosphorylation events. In premenopausal breast cancer patients, phosphorylation of the ERα at serine 118 (ERαS118-p) is predictive for benefit from adjuvant tamoxifen. Since ERαS118-p represents the common hallmark of different signaling cascades that differ in E2 dependency, the resulting effect on estrogen sensitivity may differ between pre- and postmenopausal patients. Phosphorylation of serine 167 (ERαS167-p) has been associated with favorable disease outcome, but whether ERαS167-p can predict tamoxifen sensitivity is currently unknown. We tested the predictive value of both ERαS118-p and ERαS167-p for benefit from adjuvant tamoxifen in postmenopausal breast cancer patients. Methods: We collected primary tumor blocks from 563 ERα positive (stage I-III) postmenopausal patients who had been randomized between tamoxifen (1 to 3 years) vs. no adjuvant therapy (IKA trial). The median follow-up of patients without a recurrence event was 9.4 years. Immunohistochemistry was performed on a TMA using monoclonal antibodies for ERαS118-p and ERαS167-p. The percentage of positive nuclei was scored and a score of ≥ 10 % was considered as positive. Multivariate Cox models were used to assess hazard ratios (HRs) for recurrence free interval and the interaction between these phosphorylations and tamoxifen treatment. Results: We did not find a significant interaction between either ERαS118-p (p=0.99) or ERαS167-p (p=0.44) and tamoxifen, suggesting that the relative benefit from adjuvant tamoxifen in postmenopausal patients is not dependent on the presence of one of these phosphorylations. Both tamoxifen treated patients as well as control patients had a better prognosis when their tumor was positive for ERαS118-p (adjusted HR 0.60 p=0.02) or ERαS167-p (adjusted HR 0.62, p=0.02) compared to patients whose tumor did not express these ERα phosphorylations. Conclusions: In postmenopausal patients ERαS118-p and ERαS167-p are both associated with better prognosis, but do not predict differential benefit from tamoxifen.
Synchronous bilateral breast cancer (SBBC): Concordance of receptor status between right and left breast.
Authors: Desai Palak , Braun Eduardo , Dehghan-Paz Irene , Gattuso Paolo , Canar Jeff , Cobleigh Melody A.
Published: March 2020

572

Background: This analysis was prompted by a patient who presented with SBBC who had and ER+, HER2- cancer in one breast and an ER-, HER2+ cancer in the other. Since both breasts have the same genetic background and environmental exposures, concordance should be virtually identical unless other factors are at play. Methods: SBBC was defined as bilateral cancer diagnosed concurrently or within 6 months of each other. Cases were identified retrospectively from patients seen at Rush University Medical Center. This analysis was limited to invasive SBCC (ISBBC). Estrogen receptor (ER) and Her2/neu (HER2) status were assessed according current ASCO/CAP guidelines. Correlation between ER and HER2 status was determined using κ statistic. Results: From January 1998 to December 2012, 33 cases of ISBBC were diagnosed. In 65% of cases synchronous disease was diagnosed concurrently. The average age at diagnosis was 56. The majority were multiparous and 79% post menopausal. About half of the patients (55%) had at least one first degree relative with a history of breast or ovarian cancer and 9% of the cohort had a deleterious mutation in BRCA1 or BRCA2. Infiltrating ductal was most common (74%) followed by infiltrating lobular (21%). 53% of breasts specimens also contained ductal carcinoma in situ. 68% of tumors were ER positive and 8% were HER2 positive. Concordance in ER status was seen in 73% of cases (kappa coefficient 0.14) and in HER2 status was 64% (Kappa coefficient 0.35). Conclusions: Despite identical hereditary and environmental exposure, some patients develop ISBBC cancers with discordant receptor status. While this is the exception, it suggests that other factors influence important tumor characteristics. [Table: see text]
In situ quantitative measurement of mRNA to predict response to trastuzumab in a cohort of metastatic breast cancer patients.
Authors: Vassilakopoulou Maria , Bordeaux Jennifer , Neumeister Veronique , Cheng Huan , Schalper Kurt , Skarlos Dimosthenis V. , Pectasides Dimitrios G. , Pavlidis Nicholas , Koutras Angelos , Linardou Helena , Razis Evangelia , Bobos Mattheos , Kotoula Vassiliki , Rimm David , Fountzilas George , Psyrri Amanda
Published: March 2020

573

Background: Trastuzumab therapy is currently selected based on assessment of HER2 by either immunohistochemistry (IHC) for protein over-expression or fluorescence in situ hybridization (FISH) to detect gene amplification. We sought to determine the predictive value of in situ quantitative measurement of mRNA on a cohort of trastuzumab-treated metastatic breast cancer patients. Methods: A tissue microarray composed of ninety metastatic breast cancers treated with various chemotherapy regimens combined with trastuzumab was constructed. HER2 intracellular domain (ICD), HER2 extracellular domain (ECD) and HER2 mRNA were assessed using the AQUA method for quantitative immunofluorescence. For HER2 protein evaluation CB11was used to measure ICD and SP3 to measure ECD of the HER2 receptor. In addition, HER2 mRNA status was assessed using the RNAscope assay ERRB2 probe according to manufacturer’s protocol modified for detection with Cy-5 Tyramide. Cytokeratin was used in order to create the tumor mask and signal was quantified within the mask. Primary endpoints included time to progression (TTP) from trastuzumab initiation and overall survival (OS) times. Statistical analysis was performed using Kaplan-Meier analysis and the Cox proportional hazard model. Results: HER mRNA was tightly correlated with ICD HER2, as measured by CB11 (r2=0.35), but not with ECD HER2 as measured by SP3 (r2=0.14). Both ICD HER2 and HER2 mRNA were predictive of response to trastuzumab, but ECD was not. Multivariate analysis including age, histological grade and hormone receptor status shows the ICD to be predictive of TTP (p=0.0377). HER2 mRNA levels were significant for prediction of TTP (p=0.0344) in multivariate analysis including age and histological grade. Conclusions: The expression of ICD, as detected by CB11 and HER2 mRNA levels were significantly associated with TTP in this trastuzumab-treated metastatic cohort. The ECD, as detected by SP3 is neither predictive of response, nor tightly correlated with HER2 mRNA. In situ assessment of HER2 mRNA has the potential to identify breast cancer patients who derive benefit from trastuzumab treatment.
Relationship between body mass index (BMI) at diagnosis of ER+ node negative breast cancer (BC) and Oncotype DX recurrence score.
Authors: Lohrisch Caroline A. , Davidson Ashley , Chia Stephen K. L. , Gelmon Karen A. , Shenkier Tamara Nina , Ellard Susan , Woods Ryan , Wong Linda , Pope Janice
Published: March 2020

582

Background: Inferior stage-adjusted survival for BC among obese (O) women has been reported. This may reflect differences in treatment planned for O women, in treatment received (due to toxicity), or in tumor biology arising in different cellular environments, such as high serum insulin levels, which are associated with a higher risk of recurrence. Methods: We examined whether overweight (BMI 25-30) or obese (BMI >30) women had a higher Oncotype Dx Recurrence Score (RS) after ER+, node negative (NN) or N0i+ BC than normal weight women. Included were all participants at the BC Cancer Agency in a RS clinical utility study in consecutive ER+ NN, N0i+ BC (n=156) at the BC Cancer Agency and in the TAILORx trial (n=56). Sixteen were excluded (n=5 withdrew consent; 1 triple negative; 3 test failed; 2 her2+; 1 neoadjuvant treatment, n=4 height and weight missing). Results: A similar proportion of O patients had low, intermediate, and high RS tumors. Cancers with a high RS were more likely to be grade 3 (55% of grade 3 tumours had high RS, 33% intermediate RS, 12% low RS) and fewer were strongly ER positive (69% of high RS versus 97% of intermediate and low RS). Conclusions: While this data does not support differences in tumor risk arising in O versus non obese environments in ER+, NN BC, examination of a larger data set may be more informative. [Table: see text]
Correlation, comparison, and combined analysis of Ki-67 and histological grade for early luminal breast cancer.
Authors: Naito Yoichi , Fujii Satoshi , Itoh Kuniaki , Nezu Masahiko , Matsubara Nobuaki , Sasaki Masaoki , Wada Noriaki , Yoneyama Kimiyasu , Mukai Hirofumi
Published: March 2020

585

Background: Both Ki-67 and histological grade are established prognostic factors in patients with early breast cancer. Recent international expert consensus employs Ki-67 to classify luminal breast cancer, and histological grade is described as an alternative. We investigated the prognostic value of Ki-67, histological grade, and their combination. Methods: Patients with early breast cancer treated with surgery between January 2000 and December 2008 were retrospectively reviewed. Inclusion criteria were as follows: estrogen receptor positive, HER2 negative, available for Ki-67 and histological grade. Clinicopathological data were retrieved from medical records. Ki-67 labeling index was investigated using MIB-1 antibody and subdivided into three categories: low 0-9%; intermediate 10-19%; high >20%. Histological grade was scored between 1 and 3. Disease-free survival (DFS) was defined as time from surgery to the first documented disease recurrence or death. Ki-67 categories and histological grade were analyzed respectively and then concomitantly for prognostic impact on DFS. Results: A total of 606 patients were included. Median age was 58 and 28.1% were over 65 years. 65.4% were postmenopausal women. Progesterone receptor was positive in 84.0% of patients. 29.6% received neoadjuvant or adjuvant chemotherapy. Number of lymph node metastasis was 0 in 70.0%, 1-3 in 21.3%, and >4 in 8.7% of patients. Ki-67 categories and histological grade showed weak but significantly correlation (Spearman’s rho = 0.385, p<0.001). High Ki-67 and histological grade 3 were correlated with worse prognosis to the same extent (HR 2.518, p = 0.002 and HR 2.541, p = 0.048, respectively). For combined analysis, patients represented concomitant with high Ki-67 and histological grade 3 showed worse prognosis compared with those with Ki-67 low and histological grade 1 (HR 3.137, p = 0.021). Conclusions: Ki-67 and histological grade were significantly but weakly correlated. Combined use of these two factors could better predict recurrence of early luminal breast cancer.
Docetaxel and cyclophosphamide as neoadjuvant chemotherapy in ER+ HER2- breast cancer.
Authors: Yagata Hiroshi , Yamauchi Hideko , Yoshida Atsushi , Hayashi Naoki , Kajiura Yuka , In Reika , Kitano Atsuko , Tsugawa Koichiro , Nakamura Seigo
Published: March 2020

590

Background: Recently, docetaxel plus cyclophosphamide (TC) has been established as a standard regimen for adjuvant chemotherapy in operable breast cancer. However, the efficacy of TC as neoadjuvant chemotherapy remains unclear, especially in hormone-responsive breast cancer. We prospectively evaluated the response to TC neoadjuvant chemotherapy in patients with ER+ HER2- operable breast cancer. Methods: Eligible patients had ER+ and HER2- invasive breast cancer that measured more than 2 cm in diameter or was node-positive clinically between March 2009 and February 2011. Four cycles of TC (75 and 600 mg/m2) were administered intravenously every 3 weeks as neoadjuvant chemotherapy, followed by breast and axillary surgery. We investigated the clinical response on MRI and the pathological complete response (pCR) of primary invasive breast tumors. Results: We enrolled 43 patients in 45 lesions. Allred score of ER was 7 to 8 in 40 lesions, 6 in 3 lesions and 4 in 2 lesions. PgR was 7 to 8 in 31 lesions, 5 to 6 in 6 lesions, 3 to 4 in 5 lesions, and 0 in 3 lesions. Nuclear grade was 1 in 31 lesions, 2 in 7 lesions, and 3 in 7 lesions. MIB-1 index was median 22% (range, 6 to 71%) in 40 measurable lesions. Clinical response (CR and PR) was observed in 33 lesions (73%) and SD in 12 lesions without any lesions of clinical PD. pCR was achieved in only 1 lesions (ER 8, PgR 3, Nuclear grade 3, MIB-1 index 32.6%). Conclusions: Neoadjuvant TC produced a good clinical response in ER+ HER2- operable breast cancer, while the pCR rate was very low, regardless of the characteristics of cancer cells. Therefore, pCR is not an appropriate prognostic factor in women with ER+ HER2- operable breast cancer who receive neoadjuvant TC. Whether clinical response is related to survival should be addressed in future studies. The efficacy of neoadjuvant TC in ER+ HER2- operable breast cancer is very limited, and more effective regimens are needed to achieve higher pCR rates.
A short-term neoadjuvant pilot study comparing exemestane and letrozole in postmenopausal women with estrogen receptor-positive HER2-negative breast cancer.
Authors: Miura Daishu , Iwatani Tsuguo , Kawabata Hidetaka
Published: March 2020

591

Background: Current approaches of neoadjuvant endocrine therapy (NAET) are focusing on biomarker analysis of the diagnostic specimens. One of the important things in neoadjuvant treatment is to determine the in-vivo responsiveness to the agent. Little is known regarding biomarker changes in specific agents and the association with biomarker changes and treatment duration. A pilot study was conducted to investigate the differences of biomarker changes in short-term NAET (letrozole vs. exemestane) and also the difference in treatment durations of each AI. Methods: Totally 120 samples from 60 postmenopausal women with ER positive HER2 negative stage 1-3 breast cancers in NAET comparing letrozole (LET) and exemestane (EXE) were analyzed with pre- and post-treatment mRNA expression of ERα, ERβ, PR, HER2, Ki67, PIK3CA, and MAPK using QuantiGene Assay. Thirty-one patients took letrozole 2.5mg daily and 29 did exemestane 25mg daily until the surgery (median duration 22 days). Statistical tests were two-sided. Results: Clinical characteristics were well balanced between the two treatment arms. Median % changes of Ki67 were -58%, ERα -44%, ERβ +93%, and PR -69% in LET and Ki67 -59%, ERα -30%, ERβ +135%, PR -72% in EXE. There were no significant differences of these marker changes between two agents. Dividing into 4 groups in treatment duration, 10-14 days (q1), 15-21 days (q2), 22-28 days (q3), and over 29 days (q4), LET had 2 peaks in Ki67 decreases (-69% (q1), -28% (q2), -78% (q3), -59% (q4)), whereas EXE had a peak in q2 (-62%, -77%, -49%, -26%). Ki67 increasing cases including primary resistance and tachyphylaxis were 5 (16%) in LET (3 in q2 and 2 in q4) and 3 (10%) in EXE (one of each in q2-4). All 8 cases had increases of ERβ, PIK3CA, and MAPK. Conclusions: Although both LET and EXE for short duration had significantly decreased Ki67 mRNA level irrespective of treatment duration, no significant differences was found between two agents. Tumor resistance with AIs may be associated with the other pathways.
Real-world aromatase inhibitor use and failure in women with metastatic ER+/HER2- breast cancer.
Authors: Landsman-Blumberg Pamela , Namjoshi Madhav , Thomson Erin , Johnson William
Published: March 2020

593

Background: Aromatase Inhibitors (AIs) have replaced tamoxifen as first-line therapy for postmenopausal women with metastatic, ER+ breast cancer (BC). However, little information is available on the real-world use of AIs. The objectives of this retrospective claims study were to compare demographic, clinical and treatment characteristics of postmenopausal women with metastatic ER+/HER2- BC treated with AIs and experiencing 0, 1, 2 or ≥ 3 AI failures (AIF). Methods: Women ≥ 55 years old, newly diagnosed with metastatic BC (index) were identified in the 2006-2010 Thomson Reuters MarketScan databases and followed until chemotherapy or 03/31/2011. ER+/HER2- disease was defined as any endocrine therapy (ET: tamoxifen, fulvestrant) or AI (anastrozole, letrozole, or exemestane) use and no trastuzumab or lapatinib use in the 6-month pre-or variable post-index periods. Those with any post-index AI use were retained for study. AIF post-index was defined as a switch to an alternative AI, ET or chemotherapy, or AI discontinuation with no further BC treatment. Patients were stratified by number of post-index AIF: 0, 1, 2 or ≥ 3. Results: Among 4,274 patients identified, 61% had ≥ 1 AIF (1: 80%, 2: 15%, ≥3: 5%). There was no difference in pre-index AI use across AIF cohorts: 0, 1, 2, and ≥3 (54%, 52%, 48%, 56%; p=0.073). AIFs increased with Medicare-eligibility (51%, 56%, 60%, 61%) and bone metastases at index (48%, 53%, 62%, 63%). Among those with ≥1 AIF, median follow-up (FU) increased with each failure but there was no notable pattern to reason for FU end. Median FU of the 0 AIF cohort (408 days) fell between those of the 1 and 2 AIF cohorts, 335 and 517 days. Anastrozole was the most common first line treatment for all cohorts except ≥ 3 AIFs where letrozole was most common. Pre-index and first line fulvestrant use both increased with the number of post-index AIFs: 0.3%, 1.9%, 2.0%, 5.0% and 0.7%, 2.5%, 4.0%, 14.9% respectively. There was no association between number of AIFs and chemotherapy use (36%, 29%, 38%). Conclusions: Over 60% of women with ER+/HER2- metastatic BC treated with AIs failed at least 1 and 20% of those failed ≥ 2. Surprisingly, increased rates of prior fulvestrant treatment appear associated with increasing numbers of AIF.
Limited efficacy and significant toxicities of lapatinib (Lap) plus chemotherapy as neoadjuvant therapy (NAC) for HER2-positive inflammatory breast cancer (IBC) patients (Pts).
Authors: Alvarez Ricardo H. , Cristofanilli Massimo , Ensor Joe , Lucci Anthony , Yang Wei Tse , Le-Petross Huong T. , Reuben James M. , Babiera Gildy , Huo Lei , Gong Yun , Woodward Wendy A. , Parker Charla A. , Willey Jie S. , Buchholz Thomas A. , Ueno Naoto T. , Valero Vicente
Published: March 2020

594

Background: IBC is a rare disease but the most aggressive form of locally advanced breast cancer with a higher frequency of HER2 neu amplification (HER2+) compared to non-IBC. The EGFR pathways are also important therapeutic targets in IBC. (Zhang D, 2009). Lap is an oral reversible dual kinase inhibitor of epidermal growth factor receptor of EGFR and HER2. Our objective was to determine the efficacy of Lap in combination with paclitaxel as NAC in pts with previously untreated HER2+ IBC. The primary end-point was to determine the rate of pathological complete response (pCR) defined as no residual invasive disease in the breast and the axillary lymph nodes or Residual Cancer Burden (RCB) of 0. (Symmans FW, 2008). The second endpoint was to assess general safety and cardiac toxicity of this combination therapy. Methods: From October 2008 to May 2011, 15 chemo-naïve pts were treated with Lap 1,250 mg/day as a single agent for 2 weeks, followed by 12 weeks of paclitaxel (80 mg/m2 weekly) plus Lap (1,000 mg/day), and finally with 4 cycles of FEC-75 mg/m2 regimen plus Lap (1,000 mg/day) before surgery. Among 12 first pts enrolled, 6 pts had grade 3 diarrhea (CTCAC v3.0) and the protocol was amended to reduce the Lap dose to 750 mg/day. After modified radical mastectomy (MRM), patients received radiation therapy and one year of adjuvant trastuzumab. Results: Median age was 53.8 (range, 39 -70), performance status was 0 (13 pts), 1 (2 pts), 4 pts had metastatic disease at diagnosis. 10 of 15 pts had MRM. One pt achieved pCR. Five pts did not complete the NAC due to grade 2 cardiomyopathy (1), liver dysfunction (2), diarrhea (1), and insurance denial after pt started treatment (1). The trial was stopped early due to severe toxicity (>15%) and lack of efficacy. Conclusions: Lap in combination with chemotherapy as NAC has a limited anti-tumor activity in pts with HER2+ IBC with a pCR rate of 6.6%. Lap and paclitaxel was associated with severe diarrhea toxicity and required multiple dose reductions of Lap. With the recent promising results in HER2+ NAC studies, the role of Lap should continue to be explored in combination with other anti-HER2 agents in IBC patients.
Neoadjuvant chemotherapy versus neoadjuvant hormonal therapy in postmenopausal women with ER-positive, HER2/neu negative locally advanced breast cancer.
Authors: Ambros Tadeu Frantz , Reis Isildinha M. , Bagga Dilprit , Villasboas Jose Caetano , Blieden Clifford , Sujoy Victoria , Wright Jean L. , Saigal Kunal , Fernandez Carmen Gomez , Hurley Judith
Published: March 2020

595

Background: Postmenopausal women with large ER+/HER-2 negative tumors frequently receive neoadjuvant chemotherapy (NC), but pathological complete response (pCR) rates are low. Neoadjuvant hormonal therapy (NH) may offer benefit in this setting. Methods: Retrospective review of medical records from University of Miami/Jackson Memorial Hospital from 1998-2011. Primary outcomes: pCR (absence of invasive tumor in breast and lymph nodes at surgery), recurrence free survival (RFS) and tumor size reduction evaluated through comparison of palpable breast mass size at presentation with pathological tumor size in surgical specimen, and categorized as good response (GR) ≥ 30% reduction or no response (NR) < 30%. The Kaplan-Meier method and the log-rank test were used in the analysis of RFS. Results: Data from 151 post-menopausal women with ER+/HER-2 negative BC who received NC (57%) or NH (43%) was analyzed. Median follow-up among alive patients with no evidence of disease was 5.4 years in NC and 2.9 years in NH. Mean age was higher in the NH group (63.3 vs 56.1, p<0.0001). There were no racial or ethnic differences between the groups. Clinical stage was comparable in NC and NH (IIA 5.8% vs 9.2%, IIB 25.6% vs 20%, IIIA 37.2% vs 29.2%, IIIB/IIIC 31.4% vs 41.5%, p=0.775). Tumor histology was predominantly ductal in both groups (NC 85.7% and NH 78.5%, p=0.247). pCR was similar in NC and NH (4.7% vs 0%, p=0.078) along with RFS (median 8.5 yrs vs 6.0 yrs, p=0.946). In the NC group, GR was significantly more frequent (77.9% vs 60%, p=0.017). Among patients in the NH group, having GR was predictive of longer RFS (5-year rate 83.7% vs 50.5%, p=0.014). Breast only pCR occurred at equivalent rates between NC and NH (9.3% vs 3.1%, p=0.189) as did the absence of lymph node metastasis (29.1% vs 26.2%, p=0.606). In the NH cohort 38.5% received no adjuvant chemotherapy. Conclusions: NH provides an effective alternative to NC and, if there is a GR, may preclude the need for chemotherapy in over one third of postmenopausal women with large ER positive/HER-2 negative breast cancer.
Adjuvant lapatinib in women with early-stage HER2-positive breast cancer (HER2+ BC): Analysis of the hormone receptor-negative subgroup of the intent-to-treat (ITT) population of the TEACH trial.
Authors: Smith Ian Edward , Finkelstein Dianne M , O'Shaughnessy Joyce , Moy Beverly , Ejlertsen Bent , Kaufmann Manfred , Buzdar Aman , Fumoleau Pierre , Gradishar William John , Martin Miguel , Boyle Frances , Piccart-Gebhart Martine J. , Pritchard Kathleen I. , Lindquist Deborah , Rappold Erica , Williams Lisa Simone , Liedke Pedro E.R. , Chavarri-Guerra Yanin , Goss Paul Edward
Published: March 2020

596

Background: TEACH is a randomized, double-blind, placebo (P)-controlled trial evaluating lapatinib (L) in reducing relapse risk in trastuzumab -naive patients (pts) previously treated with chemotherapy for HER2+ BC. The primary results (presented at SABCS 2011) showed a hazard ratio (HR) for disease-free survival (DFS) in L arm compared with P of 0.83 (95% confidence interval [CI] 0.70-1.00; stratified log-rank 2-sided P=.053). The predefined hormone receptor negative subgroup was analyzed, which in contrast to the hormone receptor positive subgroup of the ITT population (N=3147) had a significantly improved DFS. Methods: 3161 HER2+ BC pts (Stage I-IIIc) were randomized 1:1 to L daily or P for 1 year (yr). Primary endpoint was DFS in the ITT population. Central nervous system (CNS) recurrence rate was a secondary endpoint. A subgroup analysis by Cox Proportional Hazards Regression Models was performed for the hormone receptor negative pts from the ITT population. Results: 1288 pts (41%) comprised the hormone receptor negative subgroup of the ITT (L:639, and P:649). Median time from diagnosis to randomization was 2.4 (0.3-15) yrs, median follow-up was 4 yrs. Median age for this subgroup was 53 (24-87) yrs. With 85 events in L arm and 128 in P arm, the HR for DFS for hormone receptor negative pts was 0.68 (95%CI 0.52-0.89) favoring L. Most hormone receptor negative subgroups showed benefit for L: pts up to 1 yr from diagnosis (HR 0.64; 95%CI 0.41-0.99), node negative (HR 0.57; 95%CI 0.35-0.92), premenopausal (HR 0.59, 95%CI 0.37-0.94), and those who received prior anthracycline chemotherapy without taxanes (HR 0.63; 95%CI 0.43-0.92). Node positive patients had a trend to benefit from L (HR 0.74; 95%CI 0.53-1.03). CNS as one site of initial recurrence occurred in 1% in L (n=7) and P (n=8) arms. Conclusions: Lapatinib improved DFS in patients early or late in follow-up from diagnosis of HER2+, hormone receptor negative BC. Similar subset analyses are important in other large adjuvant anti-HER2 therapy trials. Results might provide a better understanding of the subtypes of HER2+ disease and help to further individualized therapy.
Adverse events with pertuzumab and trastuzumab: Evolution during treatment with and without docetaxel in CLEOPATRA.
Authors: Baselga José , Cortes Javier , Im Seock-Ah , Pivot Xavier B. , Clark Emma , Knott Adam , Ross Graham , Swain Sandra M.
Published: March 2020

597^

Background: In CLEOPATRA, the HER2-dimerization inhibitor pertuzumab (P) was combined with trastuzumab (T) and docetaxel (D) in HER2-positive 1st-line MBC. P+T+D significantly improved efficacy compared with placebo (Pla)+T+D while having little effect on safety. Pts were recommended to receive ≥6 cycles of D but could discontinue D prior to Cycle 6 due to poor tolerability or progressive disease (PD) or continue D beyond Cycle 6 at investigators’ discretion. Once D was discontinued, pts received Pla+T or P+T until PD. To understand the full safety profile of the regimen, adverse events (AEs) occurring before and after D discontinuation were analyzed. Methods: Treatment was given q3w (Pla/P: 840 mg loading, then 420 mg; T: 8 mg/kg loading, then 6 mg/kg; D: 75 mg/m2, escalating to 100 mg/m2 if tolerated; de-escalation by 25% allowed). AEs were graded according to NCI-CTCAE v3.0, monitored continuously during the treatment period, and their relationship to study drugs was assessed by investigators. Results: From 808 pts enrolled, 804 were analyzed in the safety population (pts who received ≥1 dose of study treatment). AEs that led to discontinuation of all study treatment were experienced by 5.3% (Pla+T+D) and 6.1% (P+T+D) of pts, whereas discontinuation of D alone due to AEs occurred in 23.2% (Pla+T+D) and 23.6% (P+T+D) of pts. Conclusions: Treatment in both arms was well tolerated. After discontinuation of D, there was a clear reduction in grade ≥3 AEs; however, the incidence of grade ≥3 diarrhea remained slightly elevated with P+T+D. The AE profile of P+T is consistent with that seen in previous Phase II studies (Gianni Lancet Oncol 2012; Baselga JCO 2010). These data suggest that the combination of P+T may also be well tolerated in other breast cancer settings, such as in adjuvant therapy, which is currently under phase III study (APHINITY; NCT01358877). [Table: see text]