bluuebunny/crossref_metadata_2025 huggingface dataset:
Cognitive impairment in breast cancer patients before surgery?: Results of a subgroup of the French CANTO cohort.
Authors: Lange Marie , Léger Isabelle , Rigal Olivier , Licaj Idlir , Rajpar Shanna , Lefel Johan , Levy Christelle , Capel Aurélie , Luis Ines Maria Vaz Duarte , Meyer Jonathan , Lerebours Florence , Petrucci Jean , Vanlemmens Laurence , Brion Marine , Martin Anne-Laure , Mesleard Christel , Arveux Patrick , Andre Fabrice , Dauchy Sarah , Joly Florence
Published: May 2019

561

Background: Cognitive impairment has been reported among breast cancer (BC) patients (pts) after adjuvant chemotherapy. However, very few studies focused on cognitive function at diagnosis. Here we aimed to describe cognitive impairment among recently diagnosed BC before any treatment. Methods: A predefined sub-study of the French national prospective cohort of cancer and toxicities performed extensive objective and subjective cognitive assessment before any BC treatment (surgery or neo-adjuvant treatment). This study included a group of pts with newly diagnosed invasive Stage I-III BC and a group of healthy control (HC) women matched on age and education level. Episodic and working memory, executive functions, processing speed, attention, cognitive complaints (FACT-COG), anxiety and depression (HADS) and fatigue dimensions (FA12) were assessed with neuropsychological tests and the referred self-report questionnaires. Objective and cognitive impairment were defined according to International Cognition and Cancer Task Force recommendations. Results: 264 women (median age 54±11 years) recently diagnosed (average of 37 days after initial diagnosis) with invasive BC (stage I-II, 69%) and 132 matched HC participated in this study. Impaired working memory (20% vs 4%), information processing speed (36% vs 17%), attention (16% vs 1%) and executive function (21% vs 8%) were higher among pts than in HC (p < 0.001). In addition, 24% (n = 64) of pts reported cognitive complaints versus 12% of HC (n = 16, p < 0.01). Emotional and cognitive fatigue were higher in pts than HC (mean 24 vs 15 and 18 vs 11, p < 0.01). Similarly, higher levels of anxiety and depression were observed in patients when compared with HC (respectively in 41% and 3% of patients vs 10 and 1% for HC, p < 0.001). Objective cognitive impairment was not associated with cognitive complains. Both objective and subjective cognitive impairment were not associated with anxiety or depression. However cognitive complain was associated with fatigue (p < 0.001). Conclusions: In this large study, compared to HC, patients recently diagnosed with a localized BC reported more cognitive complains and objective cognitive impairment before surgery, without link with emotional status, but with fatigue. Further understanding of the biology and correlates of cognitive dysfunction at BC diagnosis is needed (CANTO-NCT01993498).
Does the innovative 4R Care Delivery Model improve timing and sequencing of guideline recommended breast cancer care in safety net and non-safety net centers?
Authors: Weldon Christine B. , Trosman Julia Rachel , Makower Della F. , Rapkin Bruce D. , Bozier Moreen , Knightly Eileen , Schaeffer Cathleen M. , Hoskins Kent , Gallagher Christopher , Lo Shelly S. , Grace-Louthen Cathy , Throckmorton Alyssa , Vanderwalde Lindi , Krueger Editha A. , Van Horn Jennifer , Schapira Lidia , Santa-Maria Cesar Augusto , Ravelo Arliene , Benson Al Bowen , Gradishar William John
Published: May 2019

562

Background: Under the NCI ASCO Teams Project, we proposed a 4R Model which enables patient (pt) and care team to manage timing and sequencing of interdependent care with a novel multimodality 4R Care Project Plan (Trosman JOP ’16). 4R (Right Info/Care/Patient/Time) was previously piloted at 3 Chicago centers (Weldon ASCO ‘18). Methods: A new study tested impact of 4R on timing and sequencing of guideline recommended care at 4 safety net and 3 non safety net US centers. 4R Plans were provided to stage 0-III breast cancer pts Jan-Nov’18, 4R cohort. Clinical and pt reported data analyses compared 4R cohort (N=105) to a historical control cohort of pts who received care pre-4R, Jan - Dec ’17 (N=190). Results: We significantly improved 3 referral metrics and 4 referral completion metrics - receipt of care by pts who were referred (Table). After referrals, safety net pts had a significant increase in 4R vs control cohort in receiving genetic consult (72%, 21/29 vs. 42%, 18/43, p=.02) and dental visit (100%, 6/6 vs. 20%, 1/5, p=.02). They had lower increases in flu shot referrals (41%, 24/58, vs 36%, 37/104, NS) and dental referrals (10%, 6/58, vs 5%, 5/104, NS) than non safety net pts who had significant increases. Other metrics improved at a similar rate for safety net and non safety net pts. Conclusions: 4R markedly improved referral and receipt of interdependent guideline recommended breast cancer care. For most metrics safety net pts benefited from 4R at a similar or higher rate than non safety net pts, indicating that 4R may reduce care disparities. Low increases in referrals for safety net pts and in trial referral/enrollment for all pts must be addressed. An expansion of 4R across the US continues this work. [Table: see text]
TARGIT E(lderly): Prospective phase II trial of intraoperative radiotherapy (IORT) in elderly patients with small breast cancer.
Authors: Wenz Frederik ,   TARGIT E Trialists
Published: May 2019

563

Background: TARGIT E is a prospective, multicentric single-arm phase II trial (NCT01299987; Neumaier et al. BMC Cancer 2012) that is based on the experimental arm of the protocol of the international randomized TARGIT A study. The trial was designed to investigate the efficiency of a risk-adapted approach consisting of a single dose of intraoperative radiotherapy (IORT) followed by whole breast radiotherapy (WBRT) only when risk factors are present in elderly patients. Methods: Patients with low-risk breast cancer (≥70 years, cT1, cN0, cM0, invasive carcinoma of no special type) were enrolled between February 2011 and September 2014. During breast conserving surgery, a single dose of 20 Gy of low-energy IORT was given (Intrabeam, Carl Zeiss Meditec, Germany). Additional postoperative WBRT (46 – 50 Gy) was applied in case risk factors (larger size, other histology, free margin < 1 cm, lymphatic vessel invasion (L1), positive nodes, multifocality/multicentricity, extensive intraductal component (EIC)) were present. Systemic therapy was applied according to international standards and guidelines. The primary outcome was the local relapse rate. Discontinuation of the trial was judged to be necessary if the local relapse rates exceed 3/4/6% at 2.5/5/7.5 years. Results: A total of 541 patients were screened. Of those 474 patients were enrolled, whereas 347 (73.1%) received IORT only, 99 (10.8%) IORT plus WBRT, 22 (4.6 %) WBRT only and 7 (1.5%) surgery only with no subsequent adjuvant therapies. After a median follow-up of 3.25 years, four ipsilateral in-breast recurrences were observed (after 11, 33, 42 and 43 months) resulting in an actuarial local relapse-free survival of 99.8% after 2.5 years and 98.5% after 5 years. Conclusions: The results of the prospective TARGIT E trial consolidate earlier reports from the randomized TARGIT A trial, supporting the use of accelerated partial breast radiotherapy (APBI) in selected patients. The observed local relapse rates at 2.5 and 5 years are far below the predefined stopping rules. Clinical trial information: NCT01299987.
Prediction of occult axillary metastases in treatment-naïve patients with breast cancer: A transSENTINA analysis.
Authors: Kolberg-Liedtke Cornelia , Kolberg Hans-Christian , Bauerfeind Ingo , Fehm Tanja N. , Fleige Barbara , Lebeau Annette , Schwentner Lukas , Staebler Annette , Loibl Sibylle , Untch Michael , Kühn Thorsten
Published: May 2019

566

Background: Prediction of occult axillary metastases through clinical / biological parameters may allow reduction of axillary staging. This is particularly important, as systemic therapies have become more efficient. We have conducted a systematic analysis among patients undergoing axillary sentinel lymph-node biopsy (SLNB) before initiation of primary systemic therapy as part of a clinical trial (SENTINA) with the goal to identify predictors of sentinel lymph node status in a well-defined patient cohort. Methods: Patients with a clinically negative axillary status who underwent SLNB as part of the prospective SENTINA trial were included. Univariate and multivariate analyses were carried out to identify clinical / pathological parameters associated with SLN status, using logistic regression models. Model performance was assessed by ROC analyses. Calculations were performed using R version 3.5.2. Results: Arms A and B of the SENTINA study contained 1022 patients. Among 805 cN0 patients, all parameters considered relevant for this analysis were available. 527 and 278 patients presented with negative and positive lymph nodes upon SLN biopsy, respectively. Univariate regression models identified largest tumor diameter (odds ratio (OR) 1.016, p-value 0.0041), tumor type (ductal vs. lobular, OR 2.004, p 0.00234), tumor grading (low vs. high, OR 0.537, p < 0.001), hormone receptor (HR) status (negative vs. positive, OR 2.668, p < 0.001), HER2 status (negative vs. positive, OR 1.462, p 0.0158) as being associated with SLN status with an a < 0.1. Multivariate analysis resulted in tumor diameter, HR status, HER2 status and tumor type being independently associated. These parameters were combined using stepwise (backward and forward) selection into a prediction model. This model predicted SLN status with an AUC of only 0.65. Conclusions: Using data obtained as part of the SENTINA trial we were able to build a prediction model that was able to predict SLN metastases in treatment naïve cN0 patients with limited accuracy. Additional (biological) parameters, such as response to systemic therapies (i.e. axillary conversion through PST) may be more appropriate to predict presence of occult sentinel lymph node metastases among patients with breast cancer.
Clinical pharmacogenomic testing impacts therapy decisions and supportive medication choices in breast cancer.
Authors: Harnden Kathleen Kiernan , Deeken John F. , Stankowicz Matthew , Stafford Arielle , Cocilovo Costanza , Khromykh Alina , Iyer Ramaswamy K , Barnett Scott , Lawrence Grace , Moeckel Franziska , Vogt Brittany , Philips Sheila , Solares Andrea , Edmiston Kirsten H.
Published: May 2019

569

Background: Pharmacogenomics, the study of the interaction between the patient’s genome and therapeutic drug response, evaluates the associations between efficacy and toxicity through analysis of drug metabolizing enzymes. As personalized medicine advances to the forefront of cancer care, pharmacogenomics can evaluate the individual’s ability to metabolize key medications in breast cancer treatment including anti-emetics, opioids, and tamoxifen. Women who do not achieve optimal levels of the active metabolites of tamoxifen are at higher risk of recurrence. Patients on chemotherapy who do not respond to anti-emetics can suffer from nausea and vomiting resulting in dehydration and hospitalization. This project evaluates the feasibility and therapeutic impact of real time pharmacogenomics in a selection of patients at the Inova Schar Cancer Institute (ISCI). Methods: An interdisciplinary team was created through the ISCI and the Inova Translational Medicine Institute to implement cheek swab based pharmacogenomic testing in 50 new patients undergoing mastectomy or neoadjuvant chemotherapy for breast cancer. Study patients were assessed for genotypic variability of key CYP enzymes and resulting impact on anti-emetic choices, perioperative pain control, and tamoxifen use. Results: Data was collected in a RedCap database. The 50 women enrolled were ages 28-83. Cheek swabs were performed in clinic and median turn around time was 7 days. 24 distinct genotypes were found in the 50 patients. 20% had abnormal CYP2D6 phenotypes indicating abnormalities in tamoxifen metabolism. 28% of patients had results leading to changes in dose or medication choice of perioperative pain control. 6% of patients had a CYP2D6 ultra-rapid metabolizer phenotype and were given granisetron in lieu of ondansetron. These patients had no documented nausea or vomiting requiring dose adjustments to the treatment plan or medical intervention. 40% of patients had results recommending avoidance of tamoxifen, 75% of which have ER+ breast cancer. 25% of patients had recommended changes to the dose of tamoxifen. Conclusions: Pharmacogenomic testing is feasible and available real-time for immediate use in the clinic. CYP mutations impact treatment decisions in a significant proportion of patients. Individualized treatment plans tailored to pharmacogenomic recommendations can be created in the multi-disciplinary setting and may decrease side effects of treatment and improve efficacy of curative therapy.
On-treatment changes in tumor-infiltrating lymphocytes (TIL) during neoadjuvant HER2 therapy (NAT) and clinical outcome.
Authors: Luen Stephen James , Griguolo Gaia , Nuciforo Paolo , Campbell Christine , Fasani Roberta , Cortes Javier , Untch Michael , Lin Suling Joyce , Savas Peter , Fox Stephen B. , Di Cosimo Serena , Llombart Cussac Antonio , de Azambuja Evandro , Piccart-Gebhart Martine J. , Pusztai Lajos , Sotiriou Christos , Salgado Roberto , Prat Aleix , Loi Sherene
Published: May 2019

574

Background: Higher quantity of pretreatment TIL (PT) is associated with improved pCR and EFS in HER2+ early breast cancer (BC). The value of on-treatment TIL is unknown. Methods: The NeoALTTO trial randomized 455 women with HER2+ BC to 12 weeks NAT with trastuzumab, lapatinib or combination with paclitaxel, followed by FEC after surgery. In the PAMELA trial 151 women received 18 weeks NAT with lapatinib and trastuzumab (±hormonal therapy). TIL were quantified on PT and on-treatment (W2) biopsies using the published method on H&E slides, and tested for associations with pCR (logistic regression), EFS and OS (Cox models) in univariate (UV) and multivariate (MV) analyses. The likelihood ratio test assessed added prognostic value to clinicopathological (CP) variables. pCR associations were validated in PAMELA. We investigated enrichment of immune cell subsets using previously published RNAseq data from NeoALTTO. Results: In NeoALTTO, PT and W2 TIL were evaluable in 277/455 (61%). We defined two groups: immune-poor (L+F) and immune-enriched (II+P), see Table. Immune-enriched (41%; 134) vs poor (59%; 164) patients had significantly higher pCR rates (40% vs 21%; UV OR 2.24; 95%CI 1.31-3.85; P = .003; MV P = .009), and added significant value to CP + PT TIL for prediction of pCR (P = .003). This was further confirmed in PAMELA (N = 94/151) (26% vs 6%; UV P = .021; MV P = .028). In NeoALTTO, the immune-enriched vs poor patients had significantly improved EFS (5 yr est 85% vs 60%; UV HR 0.31; 95%CI 0.18-0.54; P < .001; MV P < .001) and OS (5 yr est 91% vs 77%; UV HR 0.40; 95%CI 0.20-0.82; P = .012; MV P = 0.026), and provided significant added prognostic value beyond CP + pCR + PT TIL (EFS P < .001) In NeoALTTO PT samples, II vs F patients had enrichment of DCs, NKs and CD8+ including tissue resident memory cells (P = .009) suggesting requirement of key immune subsets. Further validation by IHC is ongoing. Conclusions: On-treatment TIL identifies patients more likely to achieve pCR and have improved EFS in early-stage HER2+ BC, beyond CP + PT TIL. This information could aid future trial design. Clinical trial information: NCT00553358, NCT01973660. [Table: see text]
Phase II randomized study of neoadjuvant metformin plus letrozole versus placebo plus letrozole for ER-positive postmenopausal breast cancer [METEOR Study].
Authors: Kim Jisun , Han Wonshik , Kim Eun-Kyu , Jung Yongsik , Kim Hyun-Ah , Chae Soo Min , Lee Eun Sook , Ahn Sei-Hyun , Kim Tae Hyun , Jeong Joon , Choi Su Yun , Nam Seok Jin , Paik Nam-Sun , Kim Lee Su , Gong Gyungyub , Yu Jong Han , Jung So-Youn , Kim Hee Jeong , Ahn Sung Gwe , Kim Min Kyoon
Published: May 2019

576

Background: Neoadjuvant endocrine therapy with an aromatase inhibitor has shown efficacy comparable to that of neoadjuvant chemotherapy in postmenopausal breast cancer. Pre-/Clinical data have shown that metformin, a widely used anti-diabetic drug also one of mTOR inhibitor have shown anti-tumor activity. We report the result of prospective, multicenter, phase II randomized, placebo controlled trial aiming to evaluate the direct anti-tumor effect of metformin in non-diabetic postmenopausal women with hormone-receptor (HR) positive breast cancer. Methods: 203 postmenopausal women diagnosed with hormone receptor positive, T1-3/N0-2 invasive breast cancer were randomized to 24 weeks of neoadjuvant letrozole (2.5 mg/day) and either metformin (2000 mg/day) or placebo. Women with history of diabetes were excluded. Primary endpoint was clinical response rate (complete, partial response by caliper). Secondary endpoint was pathologic complete response rate, breast conservation rate, percent mammographic density change. PEPI score and toxicity profile were compared between two groups. Results: 153 intention-to treat population were analyzed (72 metformin, 75 placebo group). Overall clinical response rate was 61.4% (94/153) by caliper and did not reach statistical significance between metformin versus placebo groups (66.7% versus 56.4%, p = 0.193). Breast conservation rate was 68.0% (100/147) (66.7% versus 69.3%). Overall, 87.3% (103/118) displayed Ki67 < 10% at surgical specimen and 16.7% (21/126) had zero PEPI score. Neither Ki67% nor PEPI score was different between two groups. However, among the 20 patients with core-needle biopsy after 4 weeks of medication, greater number of patients displayed Ki67 < 10% in metformin group than in placebo group (87.5% versus 33.3%, p = 0.017). Patients with 4week Ki67 < 10% had higher clinical response rate (100% versus 57.1%, p = 0.038). Grade 3 side effects were reported in three patients (vomiting, high blood pressure, weight loss) and no hypoglycemia event was observed. Conclusions: 61.7% overall clinical response was achieved with 24-weeks of neoadjuvant letrozole, with numerically > 10% higher response rate in letrozole+metformin group (66.7% versus 56.4%). 4-weeks Ki67 < 10% level was predictive of clinical response. With < 2% grade 3 side effects, preoperative letrozole (with/without metformin) followed by 4-week Ki67 evaluation may indeed serve as primary choice to postmenopausal hormone receptor positive breast cancers. Clinical trial information: NCT01589367.
Race and response to neoadjuvant chemotherapy according to MammaPrint risk.
Authors: Nunes Raquel , De Snoo Femke , Stork-Sloots Lisette , Treece Hong-Khanh (Tina) Dinh , Dreezen Christa , Audeh M. William
Published: May 2019

578

Background: African-American (AA) women with breast cancer have a less favorable prognosis, likely due to differences in tumor biology. This is not only driven by the higher rate of triple negative/basal tumors in patients with AA ancestry, as worse outcome has also been seen in patients with luminal tumors. The Neoadjuvant BReast Cancer Symphony Trial (NBRST, NCT01479101) was a prospective trial that has shown an association of MammaPrint/BluePrint (MP/BP) with a rate of pathologic Complete Response (pCR) of 2% in Luminal A with 95% Distant Metastasis Free Interval at 3 years. Here, we determine the MP/BP risk distribution, response to therapy, and outcome in African American (AA) and Caucasian (Cau) patients. Methods: NBRST enrolled 1,072 breast cancer patients (pts) in the US (June 2011 and December 2014), median follow-up 34.9 months. The current unplanned analysis compared clinicopathological characteristics, molecular risk assignment and outcome with neoadjuvant chemotherapy (NACT) in AA and Cau pts. Molecular subtyping groups were assessed by MP/BP as follows: Luminal A (MammaPrint Low Risk), Luminal B (MammaPrint High Risk), HER2 and Basal types. Results: Out of 1,072 pts, 157 (15%) were AA, and 780 (73%) were Cau. AA patients were younger at diagnosis (52 vs 54 yrs; p = 0.016), had a higher likelihood of having higher grade (gr 3, 65% vs 53%; p = 0.005), ER-negative (45% vs 33%; p = 0.005) and lymph node positive tumors (71% vs 51; p < 0.001). MP/BP classified more AA patients as Basal type, 45% compared to 33% of Cau patients (p = 0.004). Fewer AA patients were classified as Luminal A (15%) compared to Cau pts (33%; p = 0.004). In multivariate analysis race was a significant factor for higher pCR rates to NACT in AA compared to Cau pts, together with PR, HER2, T-stage and Grade (HR = 1.679, 95% CI = (1.057, 2.67), p = 0.028). The pCR rate to NACT in patients with Basal tumors was 38% and similar in AA and Cau patients. In patients with hormone receptor positive and HER2 negative tumors, patients classified by MP/BP as Luminal A had lower pCR (2%) compared to non-luminal A (13%) (p = 0.0015). MP low risk patients had higher 3 yr DMFS (97%) than MP high risk patients (86%; p = 0.010). DMFS for AA MP Low Risk patients was 100%. Conclusions: In this study, MP was able to identify patients with hormone receptor positive tumors with low sensitivity to chemotherapy and good outcome, irrespective of race, suggesting that this test can be helpful to characterize the tumor’s biology and select patients who will not benefit from chemotherapy independently of their ancestry. Clinical trial information: NCT01479101.
Health-related quality of life in the Swedish PREDIX HER2 trial, evaluating docetaxel, trastuzumab, pertuzumab versus trastuzumab emtansine as neoadjuvant treatment of HER2-positive breast cancer.
Authors: Brandberg Yvonne , Andersson Anne , Bjohle Judith , Bosch Ana , Carlsson Lena , Dreifaldt Ann Charlotte , Einbeigi Zakaria , Fredholm Hanna , Isaksson-Friman Erika , Foukakis Theodoros , Elinder Ellinor , Hellstrom Mats , Johansson Hemming , Lekberg Tobias , Lindman Henrik , Bergh Jonas C. S. , Hatschek Thomas
Published: May 2019

583

Background: Neoadjuvant therapy combining docetaxel, trastuzumab and pertuzumab (DTP) was compared to trastuzumab emtansine (T-DM1) in the randomized phase 2 PREDIX HER2 trial. Patients, ≥18 years with HER2 positive breast cancer, ≥20mm or with verified lymph node metastases, were randomized to six courses of DTP (Standard arm) or T-DM1 (Experimental arm). Primary endpoint was pathological objective response to primary medical therapy at post-treatment surgery. Health related quality of life (HRQoL) was a secondary outcome, and is of specific interest as there was no difference between the randomization groups regarding the main endpoint (results presented in a separate abstract sent to ASCO 2019, Bergh et al.). Methods: Of 202 randomized patients, 190 are available for evaluation at this point. HRQoL was measured, using EORTC QLQ-C30 + EORTC QLQ-BR23, at baseline before randomization and after six courses. Results: No differences between the randomization arms were found at baseline. Results after six courses, based on 163 patients (86%) and adjusted to baseline values, revealed statistical significant differences (p≤0.01), favoring the experimental T-DM1 arm on 7 out of 15 of the EORTC QLQ-C30 variables (Physical functioning, Role functioning, Social functioning, Global quality of Life, Fatigue, Dyspnea, and Diarrhea). For the breast cancer specific questionnaire (EORTC-BR23), the experimental arm scored statistically significantly better on 5 out of 7 subscales (Body image, Sexual functioning, Sexual enjoyment, Systemic therapy side effects and Upset by hair loss). All of the statistical significant differences were of moderate or large clinical significance (≥10 scale scores). No differences between the randomization arms were found for the remaining HRQoL variables. Conclusions: The experimental arm reported better HRQoL than the control arm after six courses. Trastuzumab emtansine may be a useful treatment alternative due to better HRQoL and lower toxicity. Clinical trial information: NCT02568839.
Development and external validation of a deep learning model for predicting response to HER2-targeted neoadjuvant therapy from pretreatment breast MRI.
Authors: Vulchi Manasa , El Adoui Mohammed , Braman Nathaniel , Turk Paulette , Etesami Maryam , Drisis Stylianos , Plecha Donna , Benjelloun Mohammed , Madabhushi Anant , Abraham Jame
Published: May 2019

593

Background: HER2-targeted neoadjuvant chemotherapy (NAC) possesses heterogeneous outcomes and currently lacks clinically-accepted markers of response. A means of predicting which patients will benefit prior to the treatment could reduce toxicity and the delay to effective intervention. Computational analysis of MRI via a deep neural network has shown promise in identifying NAC responders among mixed receptor subtype and treatment regimen cohorts, but faces challenges due to reproducibility across institutions and has not yet been explored in the context of HER2-targeted therapy. Here we present a deep learning approach for predicting response to HER2-targeted NAC from pre-treatment MRI. Methods: 100 HER2+ breast cancer patients who received NAC with docetaxel, carboplatin, trastuzumab, and pertuzumab at Cleveland Clinic (CCF) and had pre-treatment contrast-enhanced MRI’s were included in this analysis. 49 patients achieved pathological complete response (pCR, ypT0/is), while 51 patients retained presence of residual disease following NAC (non-pCR). 85 patients were used to train a convolutional neural network to predict pCR based on pre- and post-contrast MRI images, and the model design was optimized based on performance within a 15 patient internal validation cohort. An external, held-out testing dataset consisting of 28 patients (16 pCR, 12 non-pCR) imaged and treated at University Hospitals (UH) Cleveland Medical Center was used to validate the performance of the model. Performance was assessed by area under the receiver operating characteristic curve (AUC), accuracy, sensitivity, and specificity. A multivariable model incorporating age, hormone receptor status, stage, and tumor size was developed and similarly evaluated. Results: The neural network was able to predict the response to HER2-targeted NAC in the internal validation cohort (AUC = 0.93) as well as in an independent cohort from a separate institution (AUC = 0.85). This model offered superior performance compared to a multivariate clinical model, which achieved AUC = 0.67 and AUC = 0.52, in internal validation and external held-out testing cohorts, respectively. Conclusions: Deep learning analysis of contrast-enhanced MRI could be used to better target anti-HER2 therapy by pre-treatment prediction of response.[Table: see text]
Induction chemotherapy followed by concurrent chemoradiotherapy versus concurrent chemoradiotherapy alone in locoregionally advanced nasopharyngeal carcinoma: Long-term results of a phase 3 multicenter randomized controlled trial.
Authors: Chen Ming-Yuan , Yang Qi , Hong Minghuang , Hong Ming-Huang
Published: May 2019

6004

Background: Initial 3-year results from our clinical trial in locoregionally advanced nasopharyngeal carcinoma (NPC) patients showed that induction chemotherapy (IC) with cisplatin and fluorouracil (PF) resulted in improved disease-free survival (DFS) with a marginally significant effect on distant metastasis-free survival (DMFS), but the effect of IC on locoregional relapse-free survival (LRRFS) and overall survival (OS) did not differ significantly. Here, we present 5-year follow-up results. Methods: Our trial was a randomized, open-label phase 3 trial comparing IC followed by concurrent chemoradiotherapy (CCRT) versus CCRT alone in patients with stage III-IVB (except T3N0-1) NPC. The IC followed by CCRT group received cisplatin (80 mg/m² d1) and fluorouracil (800 mg/m² d1-5) every three weeks for two cycles before CCRT. Both groups were treated with 80 mg/m² cisplatin every three weeks concurrently with radiotherapy. The primary endpoints were DFS and DMFS. We did efficacy analyses in the 476 randomized patients (intention-to-treat population). Results: After a median follow-up of 82.6 months, the 5-year DFS rate was 73.4% (95% confidence interval (CI) 67.7-79.1) in the IC followed by CCRT group and 63.1% (95% CI 56.8-69.4) in the CCRT alone group (P = 0.005). The 5-year DMFS rate was also significantly higher in the IC followed by CCRT group (82.8%, 95% CI 77.9-87.7) than in the CCRT alone group (73.1%, 95% CI 67.2-79.0, P = 0.013). Our updated analysis revealed an OS benefit of IC: the 5-year OS rate was 80.8% in the IC followed by CCRT group versus 76.8% in the CCRT alone group (P = 0.045). There were no significant differences in the rate of grade 3–4 late adverse events during follow-up between the two groups. Conclusions: IC followed by CCRT provides long-term DFS, DMFS, and OS benefits compared with CCRT alone in locoregionally advanced NPC and, therefore, can be recommended for these patients. Clinical trial information: NCT00705627.
Palbociclib plus cetuximab versus placebo plus cetuximab in platinum-resistant, cetuximab-naive, HPV-unrelated head and neck cancer: A double-blind randomized phase II trial (PALATINUS).
Authors: Adkins Douglas , Lin Jin-Ching , Sacco Assuntina Gesualda , Ley Jessica C. , Oppelt Peter , Shen Qi , Kern Kenneth Alan , Thurm Holger C. , Wang Shaw-Ling , Martini Jean-Francois , Hoffman Justin , Melichar Bohuslav , Tahara Makoto
Published: May 2019

6013

Background: Cetuximab monotherapy results in a median overall survival (OS) of approximately 6 months (mo) in platinum-resistant recurrent/metastatic head and neck squamous cell carcinoma (HNSCC). HNSCC unrelated to human papillomavirus (HPV) is driven by hyperactivation of the CDK4/6 and cyclin D1 (CD1) regulatory complex, resulting in cell cycle progression and tumor growth, suggesting that CDK4/6 inhibition can be a rational therapeutic strategy in this setting. Palbociclib (PAL) is a selective CDK4/6 inhibitor that may reverse cetuximab resistance by countering the actions of deregulated CD1. PAL plus an epidermal growth factor receptor inhibitor synergistically reduced cell viability of HPV-unrelated HNSCC cell lines. In a single-arm, multicenter trial of platinum-resistant, cetuximab-naive, HPV-unrelated HNSCC, PAL in combination with cetuximab resulted in a median OS of 9.5 mo. Methods: In a double-blind randomized phase II trial, patients (pts) with platinum-resistant, cetuximab-naïve, HPV-unrelated HNSCC were treated with cetuximab plus either PAL (arm A) or placebo (arm B). Pts were stratified by performance status (PS) and prior immunotherapy (IT). 120 pts were required for 1:1 randomization to have ≥ 80% power to detect a hazard ratio (HR) of 0.6 (corresponding to a median OS of 10 mo in arm A and 6 mo in arm B) using a 1-sided log-rank test P=0.10). Key secondary endpoints included progression-free survival (PFS), adverse events (AEs), and p16 status. Results: Pts (n=125) were randomized (arm A, 65; arm B, 60). PS and prior IT were balanced between the arms. Median (95% CI) follow-up for OS was 15.9 (15.0–19.4) mo. Median OS was 9.7 (7.3–13.9) mo in arm A and 7.8 (6.7–10.6) mo in Arm B (stratified by PS: HR=0.82 [95% CI, 0.54–1.25], P=0.18). Median PFS was 3.9 mo in arm A and 4.6 mo in arm B (stratified by PS: HR=1.00 [0.7–1.5], P=0.5). Hematologic AEs were more common in arm A. Only 11 pts (9%) received IT after being treated on the trial. Conclusions: Among pts with platinum-resistant, HPV-unrelated HNSCC, PAL plus cetuximab resulted in a trend of prolongation of median OS compared with cetuximab. Clinical trial information: NCT02499120.
Results of a phase 2a, multicenter, open-label, study of RM-1929 photoimmunotherapy (PIT) in patients with locoregional, recurrent head and neck squamous cell carcinoma (rHNSCC).
Authors: Cognetti David M. , Johnson Jennifer Maria , Curry Joseph M. , Mott Frank , Kochuparambil Samith Thomas , McDonald Darren , Fidler Mary J. , Stenson Kerstin , Vasan Nilesh R. , Razaq Mohammad , Campana John P. , Biel Merrill A. , Gillenwater Ann M.
Published: May 2019

6014

Background: Patients with rHNSCC who have failed standard of care have poor prognoses and limited therapeutic options. In this study, final results are reported of a phase 2a trial of photoimmunotherapy (PIT) with a targeted drug RM-1929, consisting of the EGFR-directed antibody cetuximab conjugated to a photoactivatable dye (IRDye 700DX). Binding of the antibody-dye conjugate to cancer cells followed by photoactivation with nonthermal red light induces selective and rapid necrosis of the cancer cells, with minimal damage to surrounding tissue. Methods: A phase 2a, multicenter, open-label, study of RM-1929 PIT in patients with locoregional, rHNSCC who could not be satisfactorily treated with surgery, radiation, or platinum chemotherapy was conducted to evaluate the safety and efficacy of the drug, RM-1929. For each treatment, nonthermal red light (690 nm) was applied to the tumors 24 hours post IV infusion of the drug. Surface illumination was administered for superficial tumors and interstitial illumination via intratumoral placement of fiber optic diffusers for deep tumors. Therapeutic response was assessed using CT RECIST 1.1 by an independent blinded radiologist. Results: Thirty rHNSCC patients were enrolled. There were no dose-limiting toxicities and one Grade 1 photosensitivity reaction. Most reported AEs were mild to moderate in severity with 96.7% (29/30) of patients with Grade 1 and 83.3% (25/30) with Grade 2, respectively. There were 13 (43.3%) patients who had at least one SAE. 86% (19/22) of SAEs were deemed unlikely related to treatment, including all 3 fatal SAEs. Three SAEs were reported to be possibly/probably related to treatment (site/oral pain, tumor hemorrhage, and airway obstruction). ORR was 50% (15/30) with 16.7% (5/30) CR and 86.7% (26/30) DCR. Median PFS and OS results will be forthcoming. Conclusions: These data indicate that RM-1929 PIT treatment was generally well tolerated with majority of AEs as mild to moderate in severity. Preliminary data showed favorable response rates in a heavily pre-treated population. A global phase 3 clinical trial is currently underway. Clinical trial information: NCT02422979.
Primary analysis of phase 2 results of cemiplimab, a human monoclonal anti-PD-1, in patients (pts) with locally advanced cutaneous squamous cell carcinoma (laCSCC).
Authors: Migden Michael Robert , Khushalani Nikhil I. , Chang Anne Lynn S. , Rischin Danny , Schmults Chrysalyne D. , Hernandez-Aya Leonel Fernando , Meier Friedegund Elke , Schadendorf Dirk , Guminski Alexander David , Hauschild Axel , Wong Deborah J.L. , Daniels Gregory A. , Berking Carola , Jankovic Vladimir , Stankevich Elizabeth , Booth Jocelyn , Li Siyu , Lowy Israel , Fury Matthew G. , Lewis Karl D.
Published: May 2019

6015

Background: Cemiplimab (REGN2810) produced substantial antitumor activity with durable responses in Phase 1 CSCC expansion cohorts and Phase 2 metastatic (m) CSCC cohort. We now present the primary analysis of the Phase 2 laCSCC cohort (NCT02760498; data cutoff date: Oct 10, 2018). Methods: Pts with laCSCC received cemiplimab 3 mg/kg IV every 2 weeks (Q2W). Tumor measurements were performed Q8W. The primary objective was to evaluate objective response rate (ORR; complete response [CR] + partial response [PR]) according to independent central review (per RECIST 1.1 for scans; modified WHO criteria for photos). Results: 78 pts were enrolled (59 M/ 19 F; median age: 74 years; ECOG PS: 0 in 38 pts, 1 in 40 pts; primary CSCC site: head/neck in 79.5%; prior systemic therapy: 15.4%; prior radiotherapy: 55.1%). Median duration of follow-up was 9.3 months (range: 0.8–27.9). ORR by central review was 43.6% (95% CI: 32.4–55.3; 10 CRs and 24 PRs); investigator-assessed (INV) ORR was 52.6% (95% CI: 40.9–64.0; 13 CRs and 28 PRs). Median duration of response (DOR) has not been reached. The longest DOR at data cut-off was 24.2 months and was still ongoing. Durable disease control rate (stable disease or response for ≥16 weeks) was 62.8% (95% CI: 51.1–73.5). Median observed time to response was 1.9 months (range: 1.8–8.8). Median progression-free and overall survival have not been reached. Tumor PD-L1 status is available for 48/78 pts, tumor mutational burden analysis (from targeted exome panel) is ongoing for ≥40/78 pts; response correlation analyses are planned. The most common treatment-emergent adverse events (AEs; all grades, Grade ≥3) were fatigue (42.3%, 1.3%), diarrhea and pruritus (both 26.9%, 0%), and nausea (21.8%, 0%). INV grade ≥3 immune-related AEs occurred in 10.3% of pts. One pt died due to an unknown cause that was assessed as treatment-related. Conclusions: Cemiplimab 3 mg/kg Q2W showed substantial antitumor activity, durable responses, and acceptable safety profile in pts with laCSCC. These data strongly support the recent FDA approval of cemiplimab-rwlc for pts with mCSCC or laCSCC who are not candidates for curative surgery or curative radiation. Clinical trial information: NCT02760498.
Recombinant humanized anti-PD-1 monoclonal antibody (JS001) in patients with refractory/metastatic nasopharyngeal carcinoma: Interim results of an open-label phase II clinical study.
Authors: Wang Fenghua , Wei Xiao-Li , Feng Ji Feng , Li Qi , Xu Nong , Hu Xi-Chun , Jiang Yi , Liao Wangjun , Zhang Qingyuan , Yuan Xianglin , Huang Haixin , Chen Ye , Dai Guanghai , Shi Jianhua , Shen Lin , Yang Shujun , Shu Yongqian , Liu Yunpeng , Xu Rui-hua ,   Shanghai Junshi Biosciences Co., Ltd.
Published: May 2019

6017

Background: Metastatic nasopharyngeal cancer (NPC) patients progressed afterstandardtherapy have limited treatment options. Toripalimab, also known as JS001, a humanized IgG4 antibody specific for human PD-1, has been approved for 2nd line treatment of metastatic melanoma in China. Here we report the results from a phase IIstudy in metastatic NPC patients treated with toripalimab.(Clinical trial ID: NCT02915432). Methods: This multi-center, open-label, phase II registration study is designed to evaluate the safety and efficacy of toripalimab in metastaticNPC patients who have failed systemic treatment. Toripalimabis given at 3 mg/kg IV Q2W until disease progression or intolerable toxicity.Tumor PD-L1 expression, plasma EBV DNA level and other biomarkerswill be correlatedwith clinical response. Results: Enrollment of 190chemo-refractory metastatic NPCpatients was completed by Feb 2019 from 17 participating centers. The median age was 46 years, with 89.5% patients received at least 2 lines of prior systemic therapies. Treatment related adverse events (TRAE)occurred in 92% patients, which were mostly grade 1 or 2.Common TRAE includedanemia, hypothyroidism, AST increased, proteinuria, pyrexia, cough, constipation, ALT increased, hypoalbuminemia and pruritus.Grade 3 or higherTRAEoccurred in 25% patients.By the cut-off date of Jan 7 2019, among 135 evaluable patients, 3 complete responses, 31 partial responses and 40 stable diseaseswere observed for an objective response rate (ORR) of 25.2% and a disease control rate of 54.8%. PD-L1 expression results were obtained from 125 patients and 45.6% (57/125) were PD-L1+.PD-L1+ patientsachieved slightly higherORR than PD-L1- patients, 29.8% versus 22.1%. In addition, an average drop of 47-fold plasma EBV DNA copy number was observed in responding patients, which typically proceeded the radiographic identification of clinical benefit. Conclusions: Toripalimab has demonstrated a manageable safety profileand encouraging clinical activity in the largest check-point blockade study in NPC to date. A change in plasma EBV DNA copy number might serve as a predictive marker for favorable clinical response. Patients will be continuously monitored for additional safety and survival readouts. Clinical trial information: NCT02915432.
Alliance A091404: A phase II study of enzalutamide (NSC# 766085) for patients with androgen receptor-positive salivary cancers.
Authors: Ho Alan Loh , Foster Nathan R. , Zoroufy Alexander J. , Worden Francis P. , Price Katharine Andress Rowe , Adkins Douglas , Bowles Daniel W. , Kang Hyunseok , Burtness Barbara , Sherman Eric Jeffrey , Morton Roscoe F. , Katabi Nora , Munster Pamela N. , Schwartz Gary K.
Published: May 2019

6020

Background: A subset of salivary gland cancer (SGCs) express the androgen receptor (AR). This phase II trial evaluated the anti-androgen enzalumatide (Astellas) for patients with AR+ SGCs. Methods: Locally advanced/unresectable or metastatic AR+ SGCs were enrolled (AR status was centrally confirmed). Prior therapy with AR-targeted drugs was allowed. Enzalutamide 160 mg orally once daily was given (1 cycle= 28 days). The primary endpoint was confirmed response (RR) according to RECIST v1.1 within the first 8 cycles. Secondary endpoints were progression-free survival (PFS), overall survival (OS), and safety. A Simon-Optimal two-stage design was used to detect a 20% RR (vs. 5%) (alpha = 5%; beta = 90%). > 1 response(s) in the first 21 would trigger accrual to 41; > 4 responses would be considered promising. Results: 46 eligible patients (pts) were enrolled (40 M, 6 F; median age 65) in 22 months. In the first 21 pts, we initially had 2 confirmed PRs allowing for full study accrual, though one was later changed to stable disease. Among the 46 pts, 7 had PR as best response, though only 2 were confirmed within the first 8 cycles (4% (95% CI: 0.5-15%). Two other PRs did not count towards the primary endpoint due to 1) development beyond 8 cycles (cycles 12-18) and 2) a confirmatory scan completed <4 weeks apart. The other 3 pts with unconfirmed PR developed progression of disease (PD) after the first PR scan. 24 pts had stable disease; 15 pts PD as best response. Among 11 pts previously treated with AR-targeted therapy, best responses were 1 confirmed PR, 7 SD, 3 PD. With a median follow-up of 11.7 months (mo), OS at 12 mo was 66% (95% CI: 52-83%), PFS at 12 mo was 24% (95% CI: 14-42%), and median PFS was 5.5 mo (95% CI: 3.7-7.3). Conclusions: This is the first prospective trial evaluating an antiandrogen alone for AR+ SGCs. The failure to meet the protocol-defined measure of success was due in part to the lack of durability of initial responses. The clinical activity observed suggests the AR-dependence of AR+ SGCs, even among those previously treated with other hormonal therapies. Support: U10CA180821, U10CA180882; Astellas; https://acknowledgments.alliancefound.org. Clinical trial information: NCT02749903.
CDX3379-04: Phase II evaluation of CDX-3379 in combination with cetuximab in patients with advanced head and neck squamous cell carcinoma (HNSCC).
Authors: Bauman Julie E. , Saba Nabil F. , Wise-Draper Trisha Michel , Adkins Douglas , O'Brien Paul E. , Heath-Chiozzi Margo , Golden Philip , Drescher Jennifer , Alvarado Diego , Gedrich Richard , Cohen Roger B.
Published: May 2019

6025

Background: CDX-3379, an anti-ErbB3 monoclonal antibody with a half-life-extending YTE modification in its Fc region, binds a unique epitope that locks ErbB3 in an inactive form and inhibits ErbB3 signaling, the latter implicated in tumor growth/resistance to anticancer therapies. CDX-3379 enhances antitumor activity of targeted therapies in preclinical models. In a Phase 1 clinical study, CDX-3379 was well-tolerated alone and in combination with cetuximab. A durable complete response (CR) to CDX-3379 + cetuximab was observed (8.3 months) in a patient (pt) with cetuximab-refractory HNSCC (Falchook ASCO 2016). Methods: This open-label phase 2 study (NCT03254927) was designed to enroll up to 30 pts with advanced, HPV-, HNSCC, previously treated with cisplatin, anti-PD-1 antibodies, and cetuximab-resistant (progression within 6 months), according to a Simon’s 2-stage design (13 evaluable pts in Stage 1 with ≥1 objective response allows enrollment of 14 more pts in 2nd stage). Pts receive CDX-3379 (initial dose 12 mg/kg IV every 21 days) + cetuximab (loading dose 400 mg/m2; 250 mg/m2 IV weekly) until disease progression/toxicity. Endpoints include objective response rate (primary), progression-free and overall survival, safety, pharmacokinetics, immunogenicity, and exploratory biomarkers. Results: Stage 1 accrual is complete with 14 evaluable pts treated. All pts were heavily pretreated; prior therapies included surgery (10/14) and chemotherapy (13/14). All pts had prior radiation, cetuximab and PD-1 targeted therapy. One confirmed ongoing CR (8.1+ months) was observed. 7/14 pts experienced stable disease (SD), including 4 with tumor shrinkage (8-27.5% reduction). Three pts continue treatment. Treatment-related adverse events were generally grade 1-2 and included diarrhea (53%), hypokalemia (20%), prolonged QT interval (13%) and rash (13%). Conclusions: CDX-3379 in combination with cetuximab is well tolerated with the primary toxicity of diarrhea. Signs of antitumor activity were observed in these cetuximab-resistant HNSCC pts, including an ongoing, durable CR. Complete stage 1 results will be presented. Clinical trial information: NCT03254927.
Pembrolizumab (pembro) for recurrent head and neck squamous cell carcinoma (HNSCC): Post hoc analyses of phase 3 KEYNOTE-040 prior radiation treatment (RT) and disease state.
Authors: Harrington Kevin J. , Cohen Ezra E.W. , Soulieres Denis , Dinis José , Licitra Lisa F. , Ahn Myung-Ju , Soria Ainara , Machiels Jean-Pascal H. , Mach Nicolas , Mehra Ranee , Burtness Barbara , Lin Jianxin , Cheng Jonathan D. , Swaby Ramona F. , Le Tourneau Christophe
Published: May 2019

6026

Background: The open-label, randomized, phase 3 KEYNOTE-040 study (NCT02252042) showed that pembro vs standard of care (SOC) chemotherapy prolonged survival in patients (pts) with recurrent and/or metastatic HNSCC whose disease progressed during/after platinum-based therapy. Post hoc analyses were conducted to evaluate pembro vs SOC by prior RT and disease state (metastatic, locoregionally recurrent [referred to as recurrent herein], or recurrent and metastatic [R/M]). Methods: Pts (N = 495) were randomly assigned (1:1) to receive pembro (200 mg Q3W) or investigator choice of methotrexate (40 mg/m2 QW), docetaxel (75 mg/m2 Q3W), or cetuximab (400 mg/m2 loading dose, then 250 mg/m2 QW). Primary end point was OS; PFS and ORR were secondary end points. Results: 175, 97, and 195 pts had metastatic, recurrent, and R/M disease, respectively (28 pts had unknown disease state); 64 pts had no prior RT; 431 pts had prior RT. As in the ITT population, prolonged survival benefit and trend toward improved PFS and ORR was observed with pembro vs SOC in pts with prior RT (Table), and prolonged survival benefit was observed with pembro vs SOC in pts with metastatic and R/M, but not recurrent, disease. Conclusions: In this post hoc analysis, patients with prior RT benefited from treatment with pembro vs SOC. For patients without RT, sample sizes are too small to draw any definitive conclusions. Survival benefit of pembro vs SOC was observed in pts with metastatic and R/M disease. Clinical trial information: NCT02252042. [Table: see text]