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The 15th edition of the Workshop on Recent Issues in Bioanalysis (15th WRIB) was held on 27 September to 1 October 2021. Even with a last-minute move from in-person to virtual, an overwhelmingly high number of nearly 900 professionals representing pharma and biotech companies, contract research organizations (CROs), and multiple regulatory agencies still eagerly convened to actively discuss the most current topics of interest in bioanalysis. The 15th WRIB included three Main Workshops and seven Specialized Workshops that together spanned 1 week in order to allow exhaustive and thorough coverage of all major issues in bioanalysis, biomarkers, immunogenicity, gene therapy, cell therapy and vaccines. Moreover, in-depth workshops on biomarker assay development and validation (BAV) (focused on clarifying the confusion created by the increased use of the term “context of use” [COU]); mass spectrometry of proteins (therapeutic, biomarker and transgene); state-of-the-art cytometry innovation and validation; and critical reagent and positive control generation were the special features of the 15th edition. This 2021 White Paper encompasses recommendations emerging from the extensive discussions held during the workshop, and is aimed to provide the bioanalytical community with key information and practical solutions on topics and issues addressed, in an effort to enable advances in scientific excellence, improved quality and better regulatory compliance. Due to its length, the 2021 edition of this comprehensive White Paper has been divided into three parts for editorial reasons. This publication (Part 2) covers the recommendations on ISR for Biomarkers, Liquid Biopsies, Spectral Cytometry, Inhalation/Oral & Multispecific Biotherapeutics, Accuracy/LLOQ for Flow Cytometry. Part 1A (Endogenous Compounds, Small Molecules, Complex Methods, Regulated Mass Spec of Large Molecules, Small Molecule, PoC), Part 1B (Regulatory Agencies' Inputs on Bioanalysis, Biomarkers, Immunogenicity, Gene & Cell Therapy and Vaccine) and Part 3 (TAb/NAb, Viral Vector CDx, Shedding Assays; CRISPR/Cas9 & CAR-T Immunogenicity; PCR & Vaccine Assay Performance; ADA Assay Comparability & Cut Point Appropriateness) are published in volume 14 of Bioanalysis, issues 9 and 11 (2022), respectively.

Opioid prescribing has more than doubled in the UK between 1998 and 2016. Potential adverse health implications include dependency, falls and increased health expenditure.To describe the predictors of long-term opioid prescribing (LTOP) (≥3 opioid prescriptions in a 90-day period).A retrospective cross-sectional study in 41 general practices in South London.Multi-level multivariable logistic regression to investigate the determinants of LTOP.Out of 320 639 registered patients ≥18 years, 2679 (0.8%) were identified as having LTOP. Patients were most likely to have LTOP if they had ≥5 long-term conditions (LTCs) (adjusted odds ratio [AOR] 36.5, 95% confidence interval [CI] 30.4-43.8) or 2-4 LTCs (AOR 13.8, CI 11.9-16.1) in comparison to no LTCs, were ≥75 years compared to 18-24 years (AOR 12.31, CI 7.1-21.5), were smokers compared to nonsmokers (AOR 2.2, CI 2.0-2.5), were female rather than male (AOR 1.9, CI 1.7-2.0) and in the most deprived deprivation quintile (AOR 1.6, CI 1.4-1.8) compared to the least deprived. In a separate model examining individual LTCs, the strongest associations for LTOP were noted for sickle cell disease (SCD) (AOR 18.4, CI 12.8-26.4), osteoarthritis (AOR 3.0, CI 2.8-3.3), rheumatoid arthritis (AOR 2.8, CI 2.2-3.4), depression (AOR 2.6, CI 2.3-2.8) and multiple sclerosis (OR 2.5, CI 1.4-4.4).LTOP was significantly higher in those aged ≥75 years, with multimorbidity or specific LTCs: SCD, osteoarthritis, rheumatoid arthritis, depression and multiple sclerosis. These characteristics may enable the design of targeted interventions to reduce LTOP.

Supplementary Figures S1, S2, S3 and Tables S1, S2

Purpose: Cyclin-dependent kinase (CDK) 4/6 drives cell proliferation in estrogen receptor–positive (ER+) breast cancer. This single-arm phase II neoadjuvant trial (NeoPalAna) assessed the antiproliferative activity of the CDK4/6 inhibitor palbociclib in primary breast cancer as a prelude to adjuvant studies.Experimental Design: Eligible patients with clinical stage II/III ER+/HER2− breast cancer received anastrozole 1 mg daily for 4 weeks (cycle 0; with goserelin if premenopausal), followed by adding palbociclib (125 mg daily on days 1–21) on cycle 1 day 1 (C1D1) for four 28-day cycles unless C1D15 Ki67 > 10%, in which case patients went off study due to inadequate response. Anastrozole was continued until surgery, which occurred 3 to 5 weeks after palbociclib exposure. Later patients received additional 10 to 12 days of palbociclib (Cycle 5) immediately before surgery. Serial biopsies at baseline, C1D1, C1D15, and surgery were analyzed for Ki67, gene expression, and mutation profiles. The primary endpoint was complete cell cycle arrest (CCCA: central Ki67 ≤ 2.7%).Results: Fifty patients enrolled. The CCCA rate was significantly higher after adding palbociclib to anastrozole (C1D15 87% vs. C1D1 26%, P < 0.001). Palbociclib enhanced cell-cycle control over anastrozole monotherapy regardless of luminal subtype (A vs. B) and PIK3CA status with activity observed across a broad range of clinicopathologic and mutation profiles. Ki67 recovery at surgery following palbociclib washout was suppressed by cycle 5 palbociclib. Resistance was associated with nonluminal subtypes and persistent E2F-target gene expression.Conclusions: Palbociclib is an active antiproliferative agent for early-stage breast cancer resistant to anastrozole; however, prolonged administration may be necessary to maintain its effect. Clin Cancer Res; 23(15); 4055–65. ©2017 AACR.

Purpose: Mammaglobin-A (MAM-A) is overexpressed in 40% to 80% of primary breast cancers. We initiated a phase I clinical trial of a MAM-A DNA vaccine to evaluate its safety and biologic efficacy.Experimental Design: Patients with breast cancer with stable metastatic disease were eligible for enrollment. Safety was monitored with clinical and laboratory assessments. The CD8 T-cell response was measured by ELISPOT, flow cytometry, and cytotoxicity assays. Progression-free survival (PFS) was described using the Kaplan–Meier product limit estimator.Results: Fourteen subjects have been treated with the MAM-A DNA vaccine and no significant adverse events have been observed. Eight of 14 subjects were HLA-A2+, and the CD8 T-cell response to vaccination was studied in detail. Flow cytometry demonstrated a significant increase in the frequency of MAM-A–specific CD8 T cells after vaccination (0.9% ± 0.5% vs. 3.8% ± 1.2%; P < 0.001), and ELISPOT analysis demonstrated an increase in the number of MAM-A–specific IFNγ-secreting T cells (41 ± 32 vs. 215 ± 67 spm; P < 0.001). Although this study was not powered to evaluate progression-free survival (PFS), preliminary evidence suggests that subjects treated with the MAM-A DNA vaccine had improved PFS compared with subjects who met all eligibility criteria, were enrolled in the trial, but were not vaccinated because of HLA phenotype.Conclusion: The MAM-A DNA vaccine is safe, capable of eliciting MAM-A–specific CD8 T-cell responses, and preliminary evidence suggests improved PFS. Additional studies are required to define the potential of the MAM-A DNA vaccine for breast cancer prevention and/or therapy. Clin Cancer Res; 20(23); 5964–75. ©2014 AACR.

Supplementary Table S1 describes the AE profile, Supplementary S2 shows the results of clinical and radiologic responses.

Supplementary Figure 1: Expression of MAM-A and HLA-A2 in breast cancer cell lines. Supplementary Figure 2: MAM-A DNA vaccination increases breast cancer-induced TNF-α production by MAM-A-specific CD8 T cells. Supplementary Figure 3: MAM-A DNA vaccination increases NKG2D expression in MAM-A-specific CD8 T cells. Supplementary Figure 4: MAM-A DNA vaccination increases DAP10 adapter protein expression in MAM-A-specific CD8 T cells. Supplementary Figure 5: MAM-A DNA vaccination increases perforin expression in MAM-A-specific CD8 T cells. Supplementary Figure 6: Therapy received by the patients (screen failed and vaccinated).

Supplementary Figure Legends S1-S5

This supplementary figure shows the appearance of the rash and the histology of the skin biopsy. This needs to be a colored figure.

Supplementary Table S3 provides the result of the 83-gene panel next generation sequencing

Purpose: Based on promising preclinical data, we conducted a single-arm phase II trial to assess the clinical benefit rate (CBR) of neratinib, defined as complete/partial response (CR/PR) or stable disease (SD) ≥24 weeks, in HER2mut nonamplified metastatic breast cancer (MBC). Secondary endpoints included progression-free survival (PFS), toxicity, and circulating tumor DNA (ctDNA) HER2mut detection.Experimental Design: Tumor tissue positive for HER2mut was required for eligibility. Neratinib was administered 240 mg daily with prophylactic loperamide. ctDNA sequencing was performed retrospectively for 54 patients (14 positive and 40 negative for tumor HER2mut).Results: Nine of 381 tumors (2.4%) sequenced centrally harbored HER2mut (lobular 7.8% vs. ductal 1.6%; P = 0.026). Thirteen additional HER2mut cases were identified locally. Twenty-one of these 22 HER2mut cases were estrogen receptor positive. Sixteen patients [median age 58 (31–74) years and three (2–10) prior metastatic regimens] received neratinib. The CBR was 31% [90% confidence interval (CI), 13%–55%], including one CR, one PR, and three SD ≥24 weeks. Median PFS was 16 (90% CI, 8–31) weeks. Diarrhea (grade 2, 44%; grade 3, 25%) was the most common adverse event. Baseline ctDNA sequencing identified the same HER2mut in 11 of 14 tumor-positive cases (sensitivity, 79%; 90% CI, 53%–94%) and correctly assigned 32 of 32 informative negative cases (specificity, 100%; 90% CI, 91%–100%). In addition, ctDNA HER2mut variant allele frequency decreased in nine of 11 paired samples at week 4, followed by an increase upon progression.Conclusions: Neratinib is active in HER2mut, nonamplified MBC. ctDNA sequencing offers a noninvasive strategy to identify patients with HER2mut cancers for clinical trial participation. Clin Cancer Res; 23(19); 5687–95. ©2017 AACR.

Supplementary Fig. S2. Mutations in selected genes observed in this trial in contrast to that in COSMIC data

Purpose: Hyperactivation of AKT is common and associated with endocrine resistance in estrogen receptor–positive (ER+) breast cancer. The allosteric pan-AKT inhibitor MK-2206 induced apoptosis in PIK3CA-mutant ER+ breast cancer under estrogen-deprived condition in preclinical studies. This neoadjuvant phase II trial was therefore conducted to test the hypothesis that adding MK-2206 to anastrozole induces pathologic complete response (pCR) in PIK3CA mutant ER+ breast cancer.Experimental Design: Potential eligible patients with clinical stage II/III ER+/HER2− breast cancer were preregistered and received anastrozole (goserelin if premenopausal) for 28 days in cycle 0 pending tumor PIK3CA sequencing. Patients positive for PIK3CA mutation in the tumor were eligible to start MK-2206 (150 mg orally weekly, with prophylactic prednisone) on cycle 1 day 2 (C1D2) and to receive a maximum of four 28-day cycles of combination therapy before surgery. Serial biopsies were collected at preregistration, C1D1 and C1D17.Results: Fifty-one patients preregistered and 16 of 22 with PIK3CA-mutant tumors received study drug. Three patients went off study due to C1D17 Ki67 >10% (n = 2) and toxicity (n = 1). Thirteen patients completed neoadjuvant therapy followed by surgery. No pCRs were observed. Rash was common. MK-2206 did not further suppress cell proliferation and did not induce apoptosis on C1D17 biopsies. Although AKT phosphorylation was reduced, PRAS40 phosphorylation at C1D17 after MK-2206 persisted. One patient acquired an ESR1 mutation at surgery.Conclusions: MK-2206 is unlikely to add to the efficacy of anastrozole alone in PIK3CA-mutant ER+ breast cancer and should not be studied further in the target patient population. Clin Cancer Res; 23(22); 6823–32. ©2017 AACR.

Supplementary Table S3. All observed coding mutations with detailed annotations

Purpose: PI3K/AKT pathway activation is an important endocrine resistance mechanism in estrogen receptor–positive (ER+) breast cancer. After promising preclinical modeling of MK-2206, an allosteric pan-AKT inhibitor, with either estrogen deprivation or fulvestrant, we conducted a phase I trial in patients with metastatic ER+HER2− breast cancer to determine the recommended phase II treatment dose (RPTD) of MK-2206 when combined with either anastrozole, fulvestrant, or anastrozole/fulvestrant.Experimental Design: ER+ breast cancer cell lines were exposed in vitro to MK-2206 plus estrogen deprivation with or without fulvestrant and monitored for apoptosis. A standard 3+3 design was employed to first determine the maximum tolerated dose (MTD) of MK-2206 plus anastrozole based on cycle 1 toxicity. Each cycle was 28 days. The RPTD was determined on the basis of toxicities observed at MTD level during the first 3 cycles. Subsequent patients received MK-2206, at the RPTD determined above, plus fulvestrant or anastrozole/fulvestrant to define RPTD for these additional regimens.Results: MK-2206 induced apoptosis in parental ER+ but not in long-term estrogen-deprived cell lines, for which fulvestrant was required for apoptosis induction. Thirty-one patients enrolled. The RPTD was defined as MK-2206 150 mg orally weekly with prednisone prophylaxis for each combination. Grade 3 rash was dose limiting. 42% (95% CI, 23%–63%) patients derived clinical benefit without progression within 6 months. Response was not associated with tumor PIK3CA mutation.Conclusions: MK-2206 plus endocrine treatments were tolerable. MK-2206 in combination with anastrozole is being further evaluated in a phase II neoadjuvant trial for newly diagnosed ER+HER2− breast cancer. Clin Cancer Res; 22(11); 2650–8. ©2016 AACR.See related commentary by Jansen et al., p. 2599

Purpose: This trial was conducted to determine the maximum tolerated dose (MTD) and preliminary efficacy of buparlisib, an oral pan-class I PI3K inhibitor, plus fulvestrant in postmenopausal women with metastatic estrogen receptor positive (ER+) breast cancer.Experimental Design: Phase IA employed a 3+3 design to determine the MTD of buparlisib daily plus fulvestrant. Subsequent cohorts (phase IB and cohort C) evaluated intermittent (5/7-day) and continuous dosing of buparlisib (100 mg daily). No more than 3 prior systemic treatments in the metastatic setting were allowed in these subsequent cohorts.Results: Thirty-one patients were enrolled. MTD was defined as buparlisib 100 mg daily plus fulvestrant. Common adverse events (AE) included fatigue (38.7%), transaminases elevation (35.5%), rash (29%), and diarrhea (19.4%). C-peptide was significantly increased during treatment, consistent with on-target effect of buparlisib. Compared with intermittent dosing, daily buparlisib was associated with more frequent early onset AEs and higher buparlisib plasma concentrations. Among the 29 evaluable patients, the clinical benefit rate was 58.6% (95% CI, 40.7%–74.5%). Response was not associated with PIK3CA mutation or treatment cohort; however, loss of PTEN, progesterone receptor (PgR) expression, or mutation in TP53 was most common in resistant cases, and mutations in AKT1 and ESR1 did not exclude treatment response.Conclusions: Buparlisib plus fulvestrant is clinically active with manageable AEs in patients with metastatic ER+ breast cancer. Weekend breaks in buparlisib dosing reduced toxicity. Patients with PgR negative and TP53 mutation did poorly, suggesting buparlisib plus fulvestrant may not be adequately effective against tumors with these poor prognostic molecular features. Clin Cancer Res; 22(7); 1583–91. ©2015 AACR.

Table S3

Supplementary Table S1. Adverse events that led to dose interruption or reduction Supplementary Table S2. Treatment-related Psychiatric Adverse Events (AEs) Supplementary Table S4. PgR Status of the Primary versus Metastatic (Recurrent) Disease of the 29 Evaluable Patients

Supplementary Fig. S1 is the consort diagram; Supplementary Fig. S2 describes the clinicopathologic and molecular features of the 6 palbociclib resistant tumors; Supplementary Fig S3 shows the proliferation score and correlation with Ki67 at each time point; Supplementary Fig S4 shows the heatmap of the proliferation score genes and ER regulated genes

The caption provides the title and description for the Supplementary Tables S3 adn S4.

Fig S1 Study Flowchart Fig S2 PIK3CA somatic mutation pattern Fig S3 Lack of apoptotic effect by anastrozole monotherapy (C1D1) and in combination with MK-2206 (C1D17 and surgery) Fig S4 CDH1 somatic mutation pattern Fig S5 ESR1 somatic mutation pattern

Aim To examine the risk of non-steroidal anti-inflammatory drug-induced heart failure in patients with chronic kidney disease. Methods Embase, Medline, CENTRAL, Web of Science, and Google Scholar were searched for papers published in English between 1st January 1999 and 31st May 2020. Papers were included if some participants had chronic kidney disease, were exposed to non-steroidal anti-inflammatory drugs, and where heart failure was measured as an outcome. Papers were assessed for risk of bias using the Cochrane Risk of Bias 2 tool for randomised controlled trials, and ROBINS-I for observational studies. Results A total of 2480 independent papers were retrieved. Following abstract screening, 165 full texts were reviewed to identify seven eligible papers: two randomised controlled trials, four cohort studies, and one case-control study. For chronic kidney disease (stage 3–5), relative risk for heart failure ranged from 0.3 to 1.9 with 95% confidence interval 0.04 to 15.1. Results were not pooled due to study heterogeneity. We attributed bias to heterogenous populations studied, probable confounding due to partially adjusted risk estimates, and heterogenous measurement of the heart failure outcome. Conclusion Overall, there are only a few studies to refute or support an increased risk of heart failure associated with taking non-steroidal anti-inflammatory drugs in patients with chronic kidney disease, and therefore no robust evidence was available.

The impact of COVID‐19 has underlined the need for reliable information to guide clinical practice and policy. This urgency has to be balanced against disruption to journal handling capacity and the continued need to ensure scientific rigour. We examined the reporting quality of highly disseminated COVID‐19 research papers using a bibliometric analysis examining reporting quality and risk of bias (RoB) amongst 250 top scoring Altmetric Attention Score (AAS) COVID‐19 research papers between January and April 2020. Method‐specific RoB tools were used to assess quality. After exclusions, 84 studies from 44 journals were included. Forty‐three (51%) were case series/studies, and only one was an randomized controlled trial. Most authors were from institutions based in China (n = 44, 52%). The median AAS and impact factor was 2015 (interquartile range [IQR] 1,105–4,051.5) and 12.8 (IQR 5–44.2) respectively. Nine studies (11%) utilized a formal reporting framework, 62 (74%) included a funding statement, and 41 (49%) were at high RoB. This review of the most widely disseminated COVID‐19 studies highlights a preponderance of low‐quality case series with few research papers adhering to good standards of reporting. It emphasizes the need for cautious interpretation of research and the increasingly vital responsibility that journals have in ensuring high‐quality publications.

The 15th edition of the Workshop on Recent Issues in Bioanalysis (15th WRIB) was held on 27 September to 1 October 2021. Even with a last-minute move from in-person to virtual, an overwhelmingly high number of nearly 900 professionals representing pharma and biotech companies, contract research organizations (CROs), and multiple regulatory agencies still eagerly convened to actively discuss the most current topics of interest in bioanalysis. The 15th WRIB included three Main Workshops and seven Specialized Workshops that together spanned 1 week in order to allow exhaustive and thorough coverage of all major issues in bioanalysis, biomarkers, immunogenicity, gene therapy, cell therapy and vaccines. Moreover, in-depth workshops on biomarker assay development and validation (BAV) (focused on clarifying the confusion created by the increased use of the term "context of use" [COU]); mass spectrometry of proteins (therapeutic, biomarker and transgene); state-of-the-art cytometry innovation and validation; and critical reagent and positive control generation were the special features of the 15th edition. This 2021 White Paper encompasses recommendations emerging from the extensive discussions held during the workshop, and is aimed to provide the bioanalytical community with key information and practical solutions on topics and issues addressed, in an effort to enable advances in scientific excellence, improved quality and better regulatory compliance. Due to its length, the 2021 edition of this comprehensive White Paper has been divided into three parts for editorial reasons. This publication (Part 2) covers the recommendations on ISR for Biomarkers, Liquid Biopsies, Spectral Cytometry, Inhalation/OralMultispecific Biotherapeutics, Accuracy/LLOQ for Flow Cytometry. Part 1A (Endogenous Compounds, Small Molecules, Complex Methods, Regulated Mass Spec of Large Molecules, Small Molecule, PoC), Part 1B (Regulatory Agencies' Inputs on Bioanalysis, Biomarkers, Immunogenicity, GeneCell Therapy and Vaccine) and Part 3 (TAb/NAb, Viral Vector CDx, Shedding Assays; CRISPR/Cas9CAR-T Immunogenicity; PCRVaccine Assay Performance; ADA Assay ComparabilityCut Point Appropriateness) are published in volume 14 of Bioanalysis, issues 9 and 11 (2022), respectively.

Background: Anthracycline- and taxane-based neoadjuvant chemotherapy (NAT) in triple negative breast cancer (TNBC) patients yields a pathological complete response (pCR) rate of approximately 45%. Anthracyclines can lead to long-term toxicities including congestive heart failure and leukemia. TNBC patients achieving pCR have excellent long-term outcomes irrespective of NAT regimen. This study was designed to evaluate the efficacy of a non-anthracycline NAT regimen with carboplatin and docetaxel in TNBC. Correlative studies include detecting and tracking plasma circulating tumor DNA (ctDNA) to determine if it will predict clinical outcomes, and whole exome sequencing (WES) on tissue samples to decipher the genomic architecture of those who achieve pCR versus those who do not. Methods: This is a joint analysis of two identical multicenter trials. Eligible patients with AJCC 7 clinical stages II and III TNBC received docetaxel 75mg/m2 and carboplatin AUC 6 every 3 weeks X 6 cycles. Following NAT, all patients underwent definitive surgery. The primary endpoint is pCR (no invasive tumor in the breast and axilla). Secondary objectives include evaluating ctDNA as a prognostic biomarker that may be used in identifying TNBC patients at a high risk of disease relapse, and evaluating differences in the genomic architecture between pCR and non-pCR patients. Patients have a research biopsy at baseline, cycle 1 day 3 (optional), and at definitive surgery for those with residual disease. Plasma for ctDNA is collected at baseline, cycle 1 day 3, at definitive surgery, and every 6 months for 5 years. Results: Between 2014 and 2019, 103 patients have been registered. Median age is 53 years (range 25-74), 27.2%: African-American, 77.7%: clinical stage II. Ninety-nine have completed NAT and have had surgery. In the intent to treat population, the preliminary pCR rate is 46.5% (95% CI 36.9% - 56.2%). Nine (8.7%) have developed recurrent disease, and 7 (6.8%) have died. Preliminary ctDNA results from 6 patients (4 non-pCR, 2 pCR) show that ctDNA is detectable in 67%. We identified 627 somatic variants by exome analysis. Of these, 10 variants overlapped with the Swift panel (Accel-Amplicon™ 56G Oncology Panel v2) used for ctDNA sequencing and variant detection. TP53 variants were identified in all 6 patients’ tumor tissue samples. At least one TP53 variant was identified in 4 patients’ baseline pre-chemotherapy ctDNA. Both pCR patients had either no detectable ctDNA TP53 mutations, or clearance of ctDNA following chemotherapy. Three non-PCR patients had persistent TP53 mutations in ctDNA during the treatment course. WES and ctDNA analysis on all patients is currently ongoing. Conclusions: We report a very encouraging pCR rate of 46.5% in TNBC patients with carboplatin and docetaxel NAT. This rate is similar to observed rates with anthracycline- and taxane-based NAT and may represent an option for treatment for TNBC patients. Correlative genomic and ctDNA studies are ongoing. Clinical trial information: NCT02124902 & NCT02547987. Citation Format: FOLUSO O ADEMUYIWA, Mothaffar F Rimawi, Tracy Summa, Jingqin Luo, Tao Wang, Rama Suresh, Lindsay Peterson, Michael Naughton, Ashley Frith, Leonel Hernandez-Aya, Katherine Weilbaecher, Cynthia Ma, Aadel A Chaudhuri, Yang-Yang Feng, Zachary L Skidmore, Obi L Griffith, Malachi Griffith, Matthew Ellis. Neoadjuvant treatment of triple negative breast cancer patients with docetaxel and carboplatin to assess anti-tumor activity [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-16-03.

Background:This study evaluated factors predictive of locoregional recurrence (LRR) in women with triple-negative breast cancer (TNBC) treated with neoadjuvant chemotherapy who do not experience pathologic complete response (pCR).Methods:This is a single-institution retrospective review of women with TNBC treated with neoadjuvant chemotherapy, surgery, and radiation therapy in 2000 through 2013. LRR was estimated between patients with and without pCR using the Kaplan-Meier method. Patient-, tumor-, and treatment-specific factors in patients without pCR were analyzed using the Cox proportional hazards method to evaluate factors predictive of LRR. Log-rank statistics were then used to compare LRR among these risk factors.Results:A total of 153 patients with a median follow-up of 48.6 months were included. The 4-year overall survival and LRR were 70% and 15%, respectively, and the 4-year LRR in patients with pCR was 0% versus 22.0% in those without (PP=.002) and extranodal extension (ENE; hazard ratio, 3.32; 95% CI, 1.35–8.15;P=.009) were significant predictors of LRR in multivariable analysis. In these patients, the 4-year LRR with LVSI was 39.8% versus 15.0% without (PP=.002). In patients without pCR, the presence of both LVSI and ENE were associated with an even further increased risk of LRR compared with patients with either LVSI or ENE alone and those with neither LVSI nor ENE in the residual tumor (PConclusions:In patients without pCR, the presence of LVSI and ENE increases the risk of LRR in TNBC. The risk of LRR is compounded when both LVSI and ENE are present in the same patient. Future clinical trials are warranted to lower the risk of LRR in these high-risk patients.

BACKGROUND Triple negative breast cancer (TNBC) has worse prognosis than other subtypes of breast cancer, and many patients develop brain metastasis (BM). We developed a simple predictive model to stratify the risk of BM in TNBC patients receiving neo-adjuvant chemotherapy (NAC), surgery, and radiation therapy (RT). METHODS Patients with TNBC who received NAC, surgery, and RT were included. Cox proportional hazards method was used to evaluate factors associated with BM. Significant factors predictive for BM on multivariate analysis (MVA) were used to develop a risk score. Patients were divided into three risk groups: low, intermediate, and high. A receiver operating characteristic (ROC) curve was drawn to evaluate the value of the risk group in predicting BM. This predictive model was externally validated. RESULTS A total of 160 patients were included. The median follow-up was 47.4 months. The median age at diagnosis was 49.9 years. The 2-year freedom from BM was 90.5%. Persistent lymph node positivity, HR 8.75 (1.76-43.52, P = 0.01), and lack of downstaging, HR 3.46 (1.03-11.62, P = 0.04), were significant predictors for BM. The 2-year rate of BM was 0%, 10.7%, and 30.3% (P

Background: Platinum-based chemotherapy is still considered investigational for the treatment of sporadic triple negative breast cancer (TNBC). Since patients with TNBC have a high rate of chemotherapy resistance, it is critical to identify platinum-sensitive individuals prior to initiating therapy. Higher absolute lymphocyte count (ALC) is associated with improved clinical response to anthracycline-based chemotherapy, the current standard of care in TNBC. We report the initial results of a phase II single arm study evaluating the efficacy of neoadjuvant carboplatin and docetaxel in TNBC. We also report results of an exploratory analysis assessing whether ALC can be used to predict pathologic complete response (pCR) after treatment with platinum-based chemotherapy. Patients and Methods: 78 patients with clinical stage II or III TNBC have been enrolled in this ongoing study evaluating the efficacy of neoadjuvant carboplatin and docetaxel (NCT201404107). Patients received docetaxel 75 mg/m2 and carboplatin AUC 6 every three weeks for a total of 6 cycles. Blood samples were collected prior to each cycle, and a posttreatment sample was collected > 3 weeks after completing cycle 6. pCR was defined as no residual invasive disease in the breast, with or without ductal carcinoma in situ, and no tumor deposits in sampled lymph nodes. Baseline characteristics of patients were summarized with descriptive statistics. Univariate and multivariate logistic regression analyses were used to identify factors associated with pCR. Results: Out of the 78 enrolled patients, 60 have completed all 6 treatment cycles and surgery. The preliminary pCR rate is 46.7%. Age, race, clinical stage, and tumor grade determined at time of diagnosis were not significantly different between pCR patients and non-pCR patients. In univariate analyses, patients with higher ALCs at the posttreatment time point were more likely to have pCR than those who had lower ALCs (OR 5.5, 95% CI 1.5-20.7, p=0.011). Additionally, patients who had higher minimum ALCs were also more likely to have pCR (OR 9.1, 95% CI 1.5-54.9, p=0.016). Baseline ALC values were not associated with pCR. The associations of posttreatment and minimum ALCs to pCR remained statistically significant even after controlling for age and clinical stage at time of diagnosis (posttreatment ALC OR 7.6, 95% CI 1.7-34.8, p=0.009; minimum ALC OR 9.0, 95% CI 1.5-55.2, p=0.018). Conclusion: The pCR rate of our cohort is similar to that of other trials evaluating neoadjuvant platinum-based chemotherapy in TNBC. Baseline ALC did not predict which patients would achieve pCR. However, the associations of posttreatment and minimum ALCs with pCR indicate patients who are able to maintain a robust population of circulating lymphocytes throughout treatment with platinum-based chemotherapy are more likely to respond favorably. The link between patient immunity and platinum-based chemotherapy suggests addition of immunotherapy agents to neoadjuvant chemotherapy may improve patient outcomes. Citation Format: Chen I, Guo F, Summa T, Luo J, Ellis MJ, Ma CX, Weilbaecher KN, Naughton MJ, Suresh R, Peterson LL, Cherian MA, Bose R, Frith AE, Hernandez-Aya LF, Gillanders WE, Ademuyiwa FO. Is absolute lymphocyte count associated with platinum-sensitivity? A phase II single arm study evaluating the efficacy of neoadjuvant carboplatin and docetaxel in triple negative breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-15-05.

Integral ecology is an increasingly important term in Catholic social teaching. This paper brings this term in relation to business drawing upon the integral relationship between human and natural ecology. Pope Francis and his two predecessors believe that the current ecological conversation can increase our sensitivity to our impact on the natural environment as well as help us to rediscover the moral and spiritual consciousness of human nature and development that has been weakened and disordered in the wider culture. An integral ecology can enlarge our notion of the good, especially the good in business. Without the cultural and environmental insights from an integral ecology that has the capacity to provide deep moral and spiritual roots, business will always be prone to see itself within its own autonomous and utilitarian sphere failing to connect to the natural and human realities in which it is embedded.

This chapter defines “good wealth” in terms of its interdependent and organic relationship among wealth’s creation, distribution and charitable dimensions. The relationship among these three functions of wealth fits well with what Catholic social teaching refers to as “moral ecology.” In terms of wealth creation, business enterprises are the economic engine of society. We also need to speak of wealth distribution, and in particular a just distribution. The third dimension of wealth is its charitable function, in many respects the most excellent of the three functions of wealth. This chapter addresses the tensions and challenges among these three dimensions and points to innovative practices where the three dimensions of good wealth can be integrated.

Genome-wide genotyping data are increasingly available for pharmacogenetic association studies, but application of these data for development of prediction models is limited. Prediction methods, such as elastic net regularization, have recently been applied to genetic studies but only limitedly to pharmacogenetic outcomes. An elastic net was applied to a pharmacogenetic study of progression-free survival (PFS) of 468 patients with advanced breast cancer in a clinical trial of paclitaxel, nab-paclitaxel, and ixabepilone. A final model included 13 single nucleotide polymorphisms (SNPs) in addition to clinical covariates (prior taxane status, hormone receptor status, disease-free interval, and presence of visceral metastases) with an area under the curve (AUC) integrated over time of 0.81, an increase compared to an AUC of 0.64 for a model with clinical covariates alone. This model may be of value in predicting PFS with microtubule targeting agents and may inform reverse translational studies to understand differential response to these drugs.

This article shows that the competing discourses on uncorroborated allegations of child sexual abuse (UACSA) each rests on unreliable epistemic assumptions, meaning that in any given case it is uncertain whether the individual making the accusation is a genuine victim or the perpetrator of a false allegation against an innocent individual. It argues that this presents a fatal challenge to the existing fields of knowledge and practise on either side of the discursive divide in terms of how alleged victims in UACSA cases are conceptualized and measured and how they are acted upon. It concludes with a call for an open-minded approach, which prioritizes the pursuit of truth in investigations to try to ensure that criminal justice system interventions in such an inherently problematic area are just and that they do not cause or compound the forms of harm and injustice currently at play.

Background: CALGB 40502/NCCTG N063H (Alliance) compared weekly NP or Ix to P; most patients received bevacizumab. Ix was inferior to P, and NP was not superior with a trend toward inferiority. Toxicity was increased in the experimental arms compared to P (Rugo et al, JCO 2015). We report long-term follow-up (FU) of this trial with an unplanned subset analysis in hormone receptor positive (HR+) and triple negative (TNBC) breast cancer. Methods: Patients were randomized 1:1:1 to receive P (90 mg/m2), Ix (16 mg/m2) or NP (150 mg/m2) on a 3 week (wk) on, 1 wk off schedule, stratified by prior adjuvant taxane use and hormone receptor status. B was initially given to all patients, but became optional in 3/2011 and was added to stratification. The primary endpoint was progression-free survival (PFS); secondary endpoints included safety and overall survival (OS). With a target N=900 patients, the study was powered to detect a hazard ratio of 1.36 (median PFS 10 vs 13.6 months). Eligibility included no prior chemotherapy for MBC, >12 mo from adjuvant P and measurable disease. Results: 799 patients were randomized between 11/08 and11/11 (283 to P, 271 to NP, 245 to Ix); 98% received bevacizumab. 68% (546) had HR+ disease, 25% (201) had TNBC. Median FU is 5 years. Median PFS is unchanged at 10.8, 9.2 and 7.4 mo for P, NP and Ix with hazard ratios (95% CIs) of 1.13 (0.94-1.34) and 1.44 (1.2-1.72) for NP and Ix to P, respectively. Median OS was 27.1, 24.2 and 23.6 months for P, NP and Ix with hazard ratios of 1.10 (0.91-1.34) and 1.3 (1.07-1.57) for NP and Ix to P, respectively. The effects of NP vs P on PFS and OS were significantly modified by subtype (interaction p=0.0018 and 0.0073), whereas Ix vs P was unchanged (interaction p's > 0.9, Table). More patients discontinued treatment due to adverse events in the experimental arms (14 vs 27 vs 23% for P, NP and Ix). Table P (mo)NP (mo)NP to P; HR (95% CI)Ix (mo)Ix to P, HR (95% CI)TNBC, PFS6.47.40.79 (0.55-1.12)15.61.39 (0.99-1.96)3HR+, PFS12.29.61.29 (1.04-1.59)181.5 (1.21-1.86)3TNBC, OS15.3210.74 (0.51-1.07)215.11.28(0.9-1.82)4HR+, OS33.226.61.25 (0.99-1.58)225.41.35(1.07-1.714Interaction tests: 1. p=0.0018; 2. p=0.0073; 3. p=0.96; 4. p=0.92 mo: months; HR: hazard ratio·· Conclusion: In patients with chemotherapy-naive MBC, Ix was inferior to P for PFS, and P was better tolerated than either NP or Ix. In this retrospective subset analysis, Ix and NP were inferior to P in HR+ disease, with a suggestion of improved PFS and OS with NP in patients with TNBC. Further investigation is required to explain and validate the subtype specificity seen in this exploratory analysis. Support: U10CA180820, U10CA180821, U10CA180882, U10CA180888. ClinicalTrials.gov Identifier: NCT00785291 Citation Format: Rugo HS, Barry WT, Moreno-Aspitia A, Lyss A, Huebner L, Mayer EL, Naughton M, Layman RM, Carey LA, Somer RA, Toppmeyer D, Velasco M, Perez EA, Hudis CA, Winer E. Long-term follow-up of CALGB 40502/NCCTG N063H (Alliance): A randomized phase III trial of weekly paclitaxel (P) compared to weekly nanoparticle albumin bound nab-Paclitaxel (NP) or ixabepilone (Ix) +/- bevacizumab as first-line therapy for locally recurrent or metastatic breast cancer (MBC) [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr GS3-06.

Background The cyclin-dependent kinase (CDK) 4/6 inhibitor Pal is approved for HR+ HER2- MBC. However, the optimal therapy following Pal progression is unknown. Therefore we conducted this retrospective study to review Pal efficacy and summarize the practice pattern and responses to subsequent treatments post Pal progression. Methods We performed a chart review of pts with HR+ HER2- MBC who began Pal treatment at Washington University Siteman Cancer Center between Feb 16, 2015 and July 13, 2016 and collected information on pts demographics, diagnosis, and treatment history. Duration of therapy was used to calculate the progression free survival (PFS) for each regimen. Treatment was considered first-line if administered without any prior systemic therapy or at least 1 year from completion of adjuvant hormonal therapy (HT). Treatments received after progression on 1st line therapy or upon relapse during or within 1 year from the completion of adjuvant HT were considered second-line regimens. Statistical analyses were performed on SAS software, version 9.4. The Kaplan-Meier method was used to generate time-to-event curves, from which median PFS was calculated. A stratified log-rank test was used for all comparisons, and the P value derived from the comparison was reported. Results We completed a chart review for 81 pts (78 female and 3 male; 63 Caucasian, 14 African American, and 4 other races) with HR+ HER2- MBC (68 were ER+PR+, 13 were ER+PR-) who received Pal plus letrozole (n=65) or fulvestrant (n=15) or anastrozole (n=1), with a median age of 62.0 years (range 28.1 - 85.6) at the start of Pal. The median follow up was 20.0 months (mos) (range 10.8 – 27.9). 25 pts were still on Pal treatment. The median PFS on Pal was 19.9 mos in the first-line setting (n=20), compared to 12.1 mos and 4.4 mos in the second-line (n=14) and subsequent lines (n=47), respectively (p=0.0287). Among the 54 pts who progressed on Pal, 38 moved on to the next treatment. 20 pts received chemotherapy and 16 pts received HT or a HT combination. 2 pts received fulvestrant plus Pal upon progression on letrozole plus Pal, and treatment was still ongoing at 4 mos and 7 mos of follow up, respectively. The most common treatments post Pal were single-agent capecitabine (Cape) (n=9) and the combination of exemestane (Exe) and everolimus (Eve) (n=8). The median PFS was 4.7 mos with Cape compared to 8.4 mos with Exe and Eve (p=0.60). The median PFS was 4.7 mos for the 20 pts who received chemo, whereas the median PFS was 4.9 mos with subsequent HT (n=16) (p=0.75). Conclusion Pal plus letrozole or fulvestrant is effective for the treatment of HR+ HER2- MBC, with activity observed beyond the 1st and 2nd line treatment settings. The PFS of Pal observed in this single center retrospective study is consistent with that of published data. Single-agent cape or the Exe and Eve combination were common treatment choices following progression on Pal. Although the study is limited by its small sample size, the median PFS of 8.4 mos with Exe and Eve indicates its potential efficacy in the setting of Pal progression. Additional pts and followup data will be presented. Citation Format: Xi J, Oza A, Thomas S, Naughton M, Ademuyiwa F, Weilbaecher KN, Suresh R, Bose R, Cherian MA, Hernandez-Aya L, Frith A, Peterson LL, Krishnamurthy J, Ma CX. Retrospective review of palbociclib (Pal) efficacy and benefit from subsequent treatments following Pal progression in patients (pts) with hormone receptor positive (HR+) and HER2 negative (HER2-) metastatic breast cancer (MBC) [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P5-21-30.

To evaluate whether tumor uptake of [89Zr]trastuzumab can distinguish HER2-positive from HER2-negative breast cancer. Women with HER2-positive (n = 34) and HER2-negative (n = 16) breast cancer underwent PET/CT 5 ± 2 days following [89Zr]trastuzumab administration. HER2 status was determined based on immunohistochemistry and/or fluorescence in situ hybridization of primary or metastatic/recurrent tumor. Tumor [89Zr]trastuzumab uptake was assessed qualitatively and semiquantitatively as maximum standardized uptake value (SUVmax), and correlated with HER2 status. Additionally, intrapatient heterogeneity of [89Zr]trastuzumab uptake was evaluated. On a per-patient basis, [89Zr]trastuzumab-PET/CT was positive in 30/34 (88.2%) HER2-positive and negative in 15/16 (93.7%) HER2-negative patients. Considering all lesions, the SUVmax was not significantly different in patients with HER2-positive versus HER2-negative disease (p = 0.06). The same was true of when only hepatic lesions were evaluated (p = 0.42). However, after excluding hepatic lesions, tumor SUVmax was significantly higher in HER2-positive compared to HER2-negative patients (p = 0.003). A cutoff SUVmax of 3.2, determined by ROC analysis, demonstrated positive-predictive value of 83.3% (95% CI 65.3%, 94.4%), sensitivity of 75.8% (57.7%, 88.9%), negative-predictive value of 50% (24.7%, 75.3%), and specificity of 61.5% (95% 31.6%, 86.1%) for differentiating HER2-positive from HER2-negative lesions. There was intrapatient heterogeneity of [89Zr]trastuzumab uptake in 20% of patients with multiple lesions. [89Zr]trastuzumab has the potential to characterize the HER2 status of the complete tumor burden in patients with breast cancer, thus obviating repeat or multiple tissue sampling to assess intrapatient heterogeneity of HER2 status.

Purpose: Hyperactivation of AKT is common and associated with endocrine resistance in estrogen receptor–positive (ER+) breast cancer. The allosteric pan-AKT inhibitor MK-2206 induced apoptosis in PIK3CA-mutant ER+ breast cancer under estrogen-deprived condition in preclinical studies. This neoadjuvant phase II trial was therefore conducted to test the hypothesis that adding MK-2206 to anastrozole induces pathologic complete response (pCR) in PIK3CA mutant ER+ breast cancer. Experimental Design: Potential eligible patients with clinical stage II/III ER+/HER2− breast cancer were preregistered and received anastrozole (goserelin if premenopausal) for 28 days in cycle 0 pending tumor PIK3CA sequencing. Patients positive for PIK3CA mutation in the tumor were eligible to start MK-2206 (150 mg orally weekly, with prophylactic prednisone) on cycle 1 day 2 (C1D2) and to receive a maximum of four 28-day cycles of combination therapy before surgery. Serial biopsies were collected at preregistration, C1D1 and C1D17. Results: Fifty-one patients preregistered and 16 of 22 with PIK3CA-mutant tumors received study drug. Three patients went off study due to C1D17 Ki67 >10% (n = 2) and toxicity (n = 1). Thirteen patients completed neoadjuvant therapy followed by surgery. No pCRs were observed. Rash was common. MK-2206 did not further suppress cell proliferation and did not induce apoptosis on C1D17 biopsies. Although AKT phosphorylation was reduced, PRAS40 phosphorylation at C1D17 after MK-2206 persisted. One patient acquired an ESR1 mutation at surgery. Conclusions: MK-2206 is unlikely to add to the efficacy of anastrozole alone in PIK3CA-mutant ER+ breast cancer and should not be studied further in the target patient population. Clin Cancer Res; 23(22); 6823–32. ©2017 AACR.

Purpose: Based on promising preclinical data, we conducted a single-arm phase II trial to assess the clinical benefit rate (CBR) of neratinib, defined as complete/partial response (CR/PR) or stable disease (SD) ≥24 weeks, in HER2mut nonamplified metastatic breast cancer (MBC). Secondary endpoints included progression-free survival (PFS), toxicity, and circulating tumor DNA (ctDNA) HER2mut detection. Experimental Design: Tumor tissue positive for HER2mut was required for eligibility. Neratinib was administered 240 mg daily with prophylactic loperamide. ctDNA sequencing was performed retrospectively for 54 patients (14 positive and 40 negative for tumor HER2mut). Results: Nine of 381 tumors (2.4%) sequenced centrally harbored HER2mut (lobular 7.8% vs. ductal 1.6%; P = 0.026). Thirteen additional HER2mut cases were identified locally. Twenty-one of these 22 HER2mut cases were estrogen receptor positive. Sixteen patients [median age 58 (31–74) years and three (2–10) prior metastatic regimens] received neratinib. The CBR was 31% [90% confidence interval (CI), 13%–55%], including one CR, one PR, and three SD ≥24 weeks. Median PFS was 16 (90% CI, 8–31) weeks. Diarrhea (grade 2, 44%; grade 3, 25%) was the most common adverse event. Baseline ctDNA sequencing identified the same HER2mut in 11 of 14 tumor-positive cases (sensitivity, 79%; 90% CI, 53%–94%) and correctly assigned 32 of 32 informative negative cases (specificity, 100%; 90% CI, 91%–100%). In addition, ctDNA HER2mut variant allele frequency decreased in nine of 11 paired samples at week 4, followed by an increase upon progression. Conclusions: Neratinib is active in HER2mut, nonamplified MBC. ctDNA sequencing offers a noninvasive strategy to identify patients with HER2mut cancers for clinical trial participation. Clin Cancer Res; 23(19); 5687–95. ©2017 AACR.

We address how the leaders of a Catholic business school can articulate and assess how well their schools implement the following six principles drawn from Catholic social teaching (CST): (1) produce goods and services that are authentically good; (2) foster solidarity with the poor by serving deprived and marginalized populations; (3) advance the dignity of human work as a calling; (4) exercise subsidiarity; (5) promote responsible stewardship over resources; and (6) acquire and allocate resources justly. We first discuss how the CST principles give substantive content and meaning to the Good Goods, Good Work, and Good Wealth framework in The Vocation of the Business Leader (Pontifical Council for Justice and Peace in Vocation of the business leader, Pontifical Council for Justice and Peace, Vatican City, 2012) and then discuss their congruencies and tensions with the UNGC and UNPRME principles. Next, we describe the Catholic Identity Matrix, an assessment tool that provides a quantitative and qualitative portrait of how well a Catholic business school integrates, within the scope of its mission and capacities, the three goods and related CST principles in its strategies, policies, activities, and processes. The concluding section discusses implications for ongoing UNGC and UNPRME assessment, reporting, and development efforts, and addresses the generalizability of our approach to business schools who draw their inspiration and moral principles from other faith-based or secular traditions.

People affected by mental illness often come from families with patterns of mental illness that span across generations. Hence, child and adolescent mental health services (CAMHS) likely provide treatment to many children with parents who also experience mental illness. The aim of this scoping review was to: (1) identify the prevalence of mental illness among parents of children in CAMHS; (2) identify and appraise the methodologies that have been implemented to assess the prevalence of parental mental illness in CAMHS; (3) identify additional circumstances associated with families where both parent and child experience mental illness; and (4) present recommendations that have been made for CAMHS practice based on these findings. English language, peer-reviewed studies (2010-2018) that had investigated the mental health of parents in CAMHS were included in the review. Literature searching yielded 18 studies which were found to have utilised diverse methodologies to assess parental mental health. Overall, reported prevalence of parental mental illness ranged from 16 to 79%; however, a single study that was deemed to be comprehensive reported prevalence rates of 36% for mothers and 33% for fathers. Across studies, parent and child mental illness was found to be associated with additional adversities impacting family functioning and wellbeing. For children who receive treatment for mental illness, having a parent who also experiences mental illness is a frequent family circumstance that has implications for their prospects for recovery. Accordingly, the mental health of parents should be an important consideration within the mental health care CAMHS provide to children.