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Background: CFI-400945 is a selective oral inhibitor of Polo-like Kinase 4 (PLK4), a controller of centriole duplication and mitotic progression identified by functional screening of genomically unstable breast cancer (BC). IND.237 (NCT01954316) is an open label, multicentre, phase 2 study in HER2 negative metastatic breast cancer (MBC) with 3 cohorts, 1 enriched for PTEN loss of function. Enrollment started in 2018 at 64mg based on a previously established recommended phase 2 dose (RP2D). The initial patients had higher than expected grade 3/4 neutropenia which led to a voluntary hold and dose de-escalation; the new RP2D was declared at 32mg as previously reported Here we report the results of the phase 2 study of CFI-400945 in advanced BC patients. Materials and Methods: 49 patients were enrolled across 3 cohorts: 1: triple negative; 2: ER+/HER2- PTEN low (by IHC); 3: ER+/HER2-, PTEN intact. The primary outcome is objective response rate (ORR); secondary outcomes included disease control rate (DCR) >16w, and safety. A Simon 2-stage design was used (9 – 25 pts planned for each cohort). CFI-400945 would be considered active if ≥3 responses were observed in any given cohort. Eligibility included ECOG 0-1, adequate organ function and receipt of at ≥1 prior line of cytotoxic chemotherapy in any setting including anthracycline taxane (unless contraindicated). Treatment was 32mg 7d on 7d off in cycle 1 (cycle length=28d), then continuously starting cycle 2. Safety assessments were performed each cycle and response (RECIST 1.1) every 2 cycles. Results: 60 patients have been screened, 49 enrolled: 10 were in initial dose ranging and were excluded from phase 2 response assessment. 10 patients were enrolled in cohort 1, 4 in cohort 2, and 25 in cohort 3. Table 1 presents patient characteristics and response results. 1 patient in cohort 3 has not had disease re-assessed at time of abstract submission. The most common adverse events have been cytopenias, nausea, fatigue, headache, constipation and vomiting. Less than 5% of patients experienced a non-hematologic AE > grade 3; 33% experienced ≥ grade 3 neutropenia. Conclusions: CFI-400945 32mg is well tolerated in this MBC population with moderate incidence of uncomplicated neutropenia. The TNBC cohort so this arm has been closed to further accrual for lack of responses. The PTEN loss group has been slow to accrue and remains open. Responses in the ER+/HER2- arm are encouraging – results from patients remaining on study are awaited and correlative studies to identify features associated with responses are underway. Acknowledgements: Sponsored by the Canadian Cancer Trials Group. Supported by Stand Up To Cancer Canada (scientific partner AACR) Canadian Cancer Society (CCS) Breast Cancer Dream Team Research Funding, Ontario Institute for Cancer Research (funding provided by the Government of Ontario) and grants from CCS to CCTG. Table 1. Table 1. Patient characteristics and response rates in each cohort treated with CFI-400945. Citation Format: David W. Cescon, John Hilton, Philippe Bedard, Phillip Blanchette, Rossanna C. Pezo, Ayesha Bashir, Vikaash Kumar, Terry L. Ng, Arif Awan, Anthony Lott, Jacques Antoun Raphael, Linda Hagerman, Mark Bray, Lindsay Muyot, Jesus Fuentes Antras, Lesley Seymour, Dongsheng Tu, Pierre-Olivier Gaudreau, Moira Rushton. A phase II study of CFI-400945 in patients with advanced/metastatic cancer: Canadian Cancer Trials Group (CCTG) IND.237 [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-07-14.

CCTG IND.239: A phase 2 study of combined CFI-400945 and durvalumab in patients with advanced triple negative breast cancer (aTNBC) John Hilton, David W. Cescon, Andrew Robinson, Sukhbinder Dhesy-Thind, Sara Kristina Taylor, Arif Awan, Terry Ng, Moira Rushton, Marie-France Savard, Lindsay Muyot, Marie Claude Reeves, Linda Hagerman, Hongbo Lui, Mark Bray, Dongsheng Tu, Lesley Seymour, Pierre-Olivier Gaudreau Background: CFI-400945 is a selective oral inhibitor of Polo-like Kinase 4 (PLK4), which controls centriole duplication and mitotic progression, and was identified as a drug target based on functional screening of genomically unstable breast cancers. CFI-400945 monotherapy has anti-proliferative activity and enhances antitumor activity when combined with anti-PD-1 immune checkpoint blockade in transplantable murine cancer models. Material and methods: In this multi-centre phase II trial of CFI-400945 and durvalumab combination therapy, the primary objective was overall response rate (ORR) per RECIST 1.1. Patients with aTNBC with adequate organ function, PS 0-1, previously treated with >1 line of chemotherapy including anthracycline and/or taxane, were eligible. CFI-400945 32mg monotherapy was administered on a 7-day on, 7-day off schedule for cycle 1 (which reduced the likelihood of significant hematologic toxicity). From cycle 2 onwards, CFI-400945 32mg daily was administered in combination with durvalumab 1500mg IV every 28 days; responses were assessed every 8 weeks. Following trial activation, 3 patients received a CFI-400945 dose of 40mg (same schedule) for a total of 9 cycles before 32mg was declared as the new recommended phase 2 dose (based on other ongoing trials using CFI-400945). A Simon 2-stage design was used; ≥3/15 responses in stage 1 were required to expand to stage 2. Exploratory PD-L1 expression was measured on immune and tumor cells using the SP263 assay. Results: 15 patients received a total of 45 cycles (1-12 cycles per patient). Median age was 56 (31-76); 53% PS1; 20% 3 prior chemotherapy lines and; 27% 4 sites of metastatic disease. Immune vs tumor cell PD-L1 expression was 1% in 50% and 23% of patients, respectively (immune and tumor cell expression was mutually exclusive). Immune vs tumor cell PD-L1 expression was 10% in 17% and 15% of patients, respectively. Grade 3 hematological adverse events (AEs) were lymphopenia (40%), neutropenia (20%), anemia and thrombocytopenia (7% for both). One serious AE at least possibly related to treatment was seen: grade 3 febrile neutropenia. Frequent AEs (˃5%) considered at least possibly related to CFI-400945 were: nausea and anorexia (both 20%), fatigue and dysgeusia (both 13%), headache, dizziness, maculo-papular rash, back pain and gastroesophageal reflux disease (all 7%), Frequent AEs (˃5%) considered at least possibly related to durvalumab were: anorexia (13%), arthritis, fatigue, back pain, pain in extremity and hot flashes (all 7%). No responses were observed in 14 evaluable patients during stage 1, therefore the pre-specified threshold for anti-tumor activity to proceed to stage 2 was not met. Disease control rate (complete response, partial response or stable disease ˃16 weeks in duration) was 7% (1/14). Conclusions: CFI-400945 and durvalumab was well tolerated, with no unexpected toxicities of the combination. However, in this heavily pretreated and PD-L1 unselected TNBC population, no responses were observed and the pre-specified threshold for anti-tumor activity for stage 2 was not met. The trial was closed to accrual on April 26, 2022. Final analysis and correlative analyses are ongoing. Acknowledgements: Coordinated by the CCTG. Funding supported by Astra Zeneca. CFI-400945 provided by Treadwell Therapeutics and durvalumab provided by Astra Zeneca. Citation Format: John Hilton, David W. Cescon, Andrew Robinson, Sukhbinder Dhesy-Thind, Sara Taylor, Arif Awan, Terry L. Ng, Moira Rushton, Marie-France Savard, Lindsay Muyot, Marie Claude Reeves, Linda Hagerman, Hongbo Lui, Mark Bray, Dongsheng Tu, Lesley Seymour, Pierre-Olivier Gaudreau. CCTG IND.239: A phase 2 study of combined CFI-400945 and durvalumab in patients with advanced triple negative breast cancer (aTNBC) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-07-18.

PURPOSE Anti–epidermal growth factor receptor (EGFR) antibodies are effective treatments for metastatic colorectal cancer. Improved understanding of acquired resistance mechanisms may facilitate circulating tumor DNA (ctDNA) monitoring, anti-EGFR rechallenge, and combinatorial strategies to delay resistance. METHODS Patients with treatment-refractory metastatic colorectal cancer (n = 169) enrolled on the CO.26 trial had pre–anti-EGFR tissue whole-exome sequencing (WES) compared with baseline and week 8 ctDNA assessments with the GuardantOMNI assay. Acquired alterations were compared between patients with prior anti-EGFR therapy (n = 66) and those without. Anti-EGFR therapy occurred a median of 111 days before ctDNA assessment. RESULTS ctDNA identified 12 genes with increased mutation frequency after anti-EGFR therapy, including EGFR ( P = .0007), KRAS ( P = .0017), LRP1B ( P = .0046), ZNF217 ( P = .0086), MAP2K1 ( P = .018), PIK3CG ( P = .018), BRAF ( P = .048), and NRAS ( P = .048). Acquired mutations appeared as multiple concurrent subclonal alterations, with most showing decay over time. Significant increases in copy-gain frequency were noted in 29 genes after anti-EGFR exposure, with notable alterations including EGFR ( P < .0001), SMO ( P < .0001), BRAF ( P < .0001), MET ( P = .0002), FLT3 ( P = .0002), NOTCH4 ( P = .0006), ERBB2 ( P = .004), and FGFR1 ( P = .006). Copy gains appeared stable without decay 8 weeks later. There were 13 gene fusions noted among 11 patients, all but one of which was associated with prior anti-EGFR therapy. Polyclonal resistance was common with acquisition of ≥ 10 resistance related alterations noted in 21% of patients with previous anti-EGFR therapy compared with 5% in those without ( P = .010). Although tumor mutation burden (TMB) did not differ pretreatment ( P = .63), anti-EGFR exposure increased TMB ( P = .028), whereas lack of anti-EGFR exposure resulted in declining TMB ( P = .014). CONCLUSION Paired tissue and ctDNA sequencing identified multiple novel mutations, copy gains, and fusions associated with anti-EGFR therapy that frequently co-occur as subclonal alterations in the same patient.

Patients in randomized controlled trials (RCTs) must be successfully randomized to reduce or eliminate bias. Because pre-treatment symptoms have prognostic significance in cancer patients, qualitative and quantitative tools were developed to assess similarity of baseline pre-treatment symptoms across different treatment arms of RCTs as one measure of randomization success. Clinician-reported symptom data from two colorectal cancer RCTs, CO.20 and CO.17, were used to demonstrate the utility of a qualitative visualization tool and quantitative machine learning K-means tool, which grouped patients into clusters using baseline symptoms. Qualitatively, reflection bar graphs (RBGs) visualized potential imbalances in baseline symptoms (i) across treatment arms and (ii) by corresponding patient clusters identified within each treatment arm. RBGs found that the treatment arms for both RCTs had similar symptom profiles, while the lack of significant differences in the proportions of patients in each cluster across treatment arms further confirmed successful randomization. This paper details the creation of visualization, machine-learning, and statistical tools to compare baseline symptoms across RCT treatment arms, demonstrating that the CO.20 and CO.17 trials were successfully randomized by baseline symptoms and are comparable. These tools can therefore be implemented easily to ensure an extra layer of quality assurance of the randomization process for study assessment.

Patient-reported outcomes (PROs), such as symptoms, functioning, and other health-related quality-of-life concepts are gaining a more prominent role in the benefit–risk assessment of cancer therapies. However, varying ways of analysing, presenting, and interpreting PRO data could lead to erroneous and inconsistent decisions on the part of stakeholders, adversely affecting patient care and outcomes. The Setting International Standards in Analyzing Patient-Reported Outcomes and Quality of Life Endpoints in Cancer Clinical Trials-Innovative Medicines Initiative (SISAQOL-IMI) Consortium builds on the existing SISAQOL work to establish recommendations on design, analysis, presentation, and interpretation for PRO data in cancer clinical trials, with an expanded set of topics, including more in-depth recommendations for randomised controlled trials and single-arm studies, and for defining clinically meaningful change. This Policy Review presents international stakeholder views on the need for SISAQOL-IMI, the agreed on and prioritised set of PRO objectives, and a roadmap to ensure that international consensus recommendations are achieved.

The development of novel cancer therapies, including immuno-oncology agents, has increased interest in reconstructed individual patient data (IPD) based restricted mean survival time (RMST) analyses. Additionally, reconstructed IPD-based RMST is recommended in cost-effectiveness analyses when original trial IPD are not available. Nevertheless, recently concerns regarding potential bias of reconstructed-IPD RMST have been presented, because reconstructed-IPD RMSTs have not been validated and previous validation endpoints may not capture the entire Kaplan-Meier (KM) curve, especially the "tail." Our study aims to validate the recommended method of IPD reconstruction by comparing reconstructed IPD- and original trial IPD-based RMST.Canadian Cancer Trials Group trials from 1990 to 2017 were included. Overall survival and progression-free survival IPD were reconstructed based on published KM curves using the Guyot method. Analysts were blinded to original trial IPD. RMST was calculated at 1 year and over the entire KM curve. Reconstructed-IPD and original trial-IPD (gold-standard) RMSTs were compared for accuracy and predictive error via mean deviation, mean absolute error (MAE), mean percentage bias, and Bland-Altman plots and across KM curve quality (vector traced or bitmapped).We identified 39 trials. The mean deviation, MAE, and mean percentage bias of RMST between the reconstructed IPD and original trial IPD were small. In particular, the mean deviation was -0.01 months and -0.04 months, MAE was 0.19 months and 0.24 months, and mean percentage bias was 0.82% and 0.84% in overall survival KM curves in control and experimental arms, respectively. Accuracy was generally not associated with KM curve quality.RMST derived from reconstructed IPD displayed excellent accuracy and predictive error compared with the gold standard. Reconstructed IPD could be used to calculate RMST in lieu of original trial IPD, to facilitate decision making for clinicians, researchers, and policy makers.

Correlative studies and additional data as requested by reviewers

Supplementary Table 1 Sequencing Primers used for FcGR 2a ( H/R,rs1801274) and FcGR3a (F/V;rs396991) polymorphisms genotyping

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Survival analysis showing the primary endpoint of disease-free survival for patients receiving tamoxifen (red lines) vs. placebo (black lines) in the MA.12 translational study cohort.

Supplemental Tables and Figure Caption

Supplemental Figure 1

PDF file, 68KB, Supplemental Table 1: Intrinsic subtype definitions by immunohistochemistry. Supplemental Table 2: C-Index for Risk-of-Relapse (ROR) Scores.

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Purpose:Accurate IHC biomarkers incorporating nestin positivity or inositol polyphosphate-4-phosphate (INPP4B) loss have recently been optimized to identify the basal-like intrinsic breast cancer subtype regardless of estrogen, progesterone, or Her2 status. We examined the predictive capacity of these basal biomarkers in the CCTG MA.5 chemotherapy and MA.12 endocrine therapy trials.Experimental Design:Formalin-fixed paraffin embedded blocks of primary tumors from patients randomized in the two trials were used to build tissue microarrays. IHC staining for nestin and INPP4B followed published methods and REMARK criteria. A prespecified statistical plan tested the hypothesis that patients with basal breast cancer (nestin+ or INPP4B−) would not benefit from anthracycline substitution in MA.5 or from tamoxifen in MA.12.Results:Nestin positivity or INPP4B loss was observed in 110/453 (24%) interpretable samples from MA.5 and 47/366 (13%) from MA.12, and was associated with high grade, younger age, estrogen receptor negativity, triple-negative, core basal, and PAM50 basal-like subtypes. In the MA.5 trial, patients assigned as basal experienced lower benefit from anthracycline versus nonanthracycline adjuvant chemotherapy [HR, 1.49; 95% confidence interval (CI), 0.72–3.10] when compared with non-basal (nestin− and INPP4B+) cases where there was a higher benefit from anthracyclines (HR, 0.75; 95% CI, 0.54–1.04; Pinteraction = 0.01). In the MA.12 trial, patients assigned as basal did not demonstrate a benefit from adjuvant tamoxifen versus placebo (HR, 0.48; 95% CI, 0.12–1.86; P = 0.29), whereas nonbasal cases displayed significant benefit (HR, 0.66; 95% CI, 0.45–0.98; P = 0.04), although the interaction test was not significant.Conclusions:The nestin/INPP4B IHC panel identifies women with basal breast cancers who benefit from nonanthracycline chemotherapy but not endocrine adjuvant treatments.

PDF file, 125KB, Supplemental Figure 1: REMARK Diagram for MA.12 Trial and Biospecimens Supplemental Figure 2: Forest plot for Disease free Survival across various Classifiers.

Purpose: Gene expression profiling classifies breast cancer into intrinsic subtypes based on the biology of the underlying disease pathways. We have used material from a prospective randomized trial of tamoxifen versus placebo in premenopausal women with primary breast cancer (NCIC CTG MA.12) to evaluate the prognostic and predictive significance of intrinsic subtypes identified by both the PAM50 gene set and by immunohistochemistry.Experimental Design: Total RNA from 398 of 672 (59%) patients was available for intrinsic subtyping with a quantitative reverse transcriptase PCR (qRT-PCR) 50-gene predictor (PAM50) for luminal A, luminal B, HER-2–enriched, and basal-like subtypes. A tissue microarray was also constructed from 492 of 672 (73%) of the study population to assess a panel of six immunohistochemical IHC antibodies to define the same intrinsic subtypes.Results: Classification into intrinsic subtypes by the PAM50 assay was prognostic for both disease-free survival (DFS; P = 0.0003) and overall survival (OS; P = 0.0002), whereas classification by the IHC panel was not. Luminal subtype by PAM50 was predictive of tamoxifen benefit [DFS: HR, 0.52; 95% confidence interval (CI), 0.32–0.86 vs. HR, 0.80; 95% CI, 0.50–1.29 for nonluminal subtypes], although the interaction test was not significant (P = 0.24), whereas neither subtyping by central immunohistochemistry nor by local estrogen receptor (ER) or progesterone receptor (PR) status were predictive. Risk of relapse (ROR) modeling with the PAM50 assay produced a continuous risk score in both node-negative and node-positive disease.Conclusions: In the MA.12 study, intrinsic subtype classification by qRT-PCR with the PAM50 assay was superior to IHC profiling for both prognosis and prediction of benefit from adjuvant tamoxifen. Clin Cancer Res; 18(16); 4465–72. ©2012 AACR.

Purpose:Expanded RAS/BRAF mutations have not been assessed as predictive for single-agent cetuximab in metastatic colorectal cancer (mCRC), and low mutant allele frequency (MAF) mutations are of unclear significance. We aimed to establish cetuximab efficacy in optimally selected patients using highly sensitive beads, emulsion, amplification, and magnetics (BEAMing) analysis, capable of detecting alterations below standard clinical assays.Patients and Methods:CO.17 trial compared cetuximab versus best supportive care (BSC) in RAS/BRAF-unselected mCRC. We performed RAS/BRAF analysis on microdissected tissue of 242 patients in CO.17 trial using BEAMing for KRAS/NRAS (codons 12/13/59/61/117/146) and BRAF V600E. Patients without BEAMing but with previous Sanger sequencing–detected mutations were included.Results:KRAS, NRAS, and BRAF mutations were present in 53%, 4%, and 3% of tumors, respectively. Cetuximab improved overall survival [OS; HR, 0.51; 95% confidence interval (CI), 0.32–0.81; P = 0.004] and progression-free survival (PFS; HR, 0.25; 95% CI, 0.15–0.41; P < 0.0001) compared with BSC in RAS/BRAF wild-type patients. Cetuximab did not improve OS/PFS for KRAS-, NRAS-, or BRAF-mutated tumors, and tests of interaction confirmed expanded KRAS (P = 0.0002) and NRAS (P = 0.006) as predictive, while BRAF mutations were not (P = 0.089). BEAMing identified 14% more tumors as RAS mutant than Sanger sequencing, and cetuximab lacked activity in these patients. Mutations at MAF < 5% were noted in 6 of 242 patients (2%). One patient with a KRAS A59T mutation (MAF = 2%) responded to cetuximab. More NRAS than KRAS mutations were low MAF (OR, 20.50; 95% CI, 3.88—96.85; P = 0.0038).Conclusions:We establish single-agent cetuximab efficacy in optimally selected patients and show that subclonal RAS/BRAF alterations are uncommon and remain of indeterminate significance.

Purpose:Monalizumab binds CD94/NKG2A, preventing HLA-E inhibition of tumor lymphocytes. A dose-ranging/cohort expansion trial of monalizumab for recurrent gynecologic malignancies was conducted to determine the recommended phase II dose (RP2D) and to explore clinical activity, pharmacokinetics, pharmacodynamics, safety, and immunogenicity.Patients and Methods:Participants (and part 2 expansion cohorts) included (i) platinum-sensitive ovarian, (ii) platinum-resistant ovarian, (iii) squamous cervical (CX), and (iv) epithelial endometrial (END) carcinomas. Part 1 assessed monalizumab at 1, 4, or 10 mg/kg every 2 weeks. In part 2, ≥4 patients/cohort underwent pre- and on-treatment tumor biopsies. Preset criteria determined cohort expansion.Results:A total of 58 participants were evaluable. The RP2D was 10 mg/kg i.v. every 2 weeks. Dose proportionality and 100% NKG2A saturation were observed. Related adverse events were mild: headache, abdominal pain, fatigue, nausea, and vomiting. Grade 3 related adverse events were nausea (1), vomiting (1), dehydration (1), fatigue (2), anorexia (1), dyspnea (1), and proctitis (1). Dose-limiting toxicities were not observed. Hematologic and biochemical changes were mild and not dose related. Best response was SD: part 1, 7 of 18 (39%) [3.4 months (1.4–5.5)], and part 2, 7 of 39 (18%) [1.7 months (CX) to 14.8 months (END)]. Neither a predictive biomarker for SD nor evidence of pharmacodynamic effects was identified. There was a trend to significance between a reduction in lymphocyte HLA-E total score and pharmacodynamics.Conclusions:Monalizumab 10 mg/kg i.v. every 2 week is well tolerated in patients with pretreated gynecologic cancers. Short-term disease stabilization was observed. Future studies should assess combinations with other agents, including immunotherapeutics.

Purpose: Two germline Fc-γ receptor (FCGR) polymorphisms, rs1801274 [FCGR2A;His(H)131Arg(R)] and rs396991 [FCGR3A;Phe(F)158Val(V)] produce altered proteins through amino acid substitutions; both are reported to be associated with cetuximab-related outcomes. We performed a validation of these polymorphisms in NCIC CTG CO.17, a randomized trial of cetuximab monotherapy in refractory, metastatic colorectal cancer expressing EGFR.Experimental Design: DNA extracted from formalin-fixed paraffin-embedded tissue was genotyped. In addition to log-rank tests, Cox proportional hazard models assessed their relationships with overall (OS) and progression-free survival (PFS), adjusting for clinically important prognostic factors, along with a polymorphism–treatment arm interaction term.Results: Somatic KRAS status was wild-type for exon 2 in 153 (52%) of 293 patients, from whom tumor DNA was available. For FCGR2A H/H, a genotype–treatment interaction for KRAS wild-type patients was observed for OS (P = 0.03). In KRAS wild-type patients carrying FCGR2A H/H, cetuximab (vs. no cetuximab) improved survival substantially, with adjusted HRs (aHR) of 0.36 (OS) and 0.19 (PFS) and absolute benefits of 5.5 months (OS; P = 0.003) and 3.7 months (PFS; P = 0.02). In contrast, patients carrying FCGR2A R alleles (H/R or R/R) had aHRs of only 0.78 (OS; 2.8-month benefit) and 0.53 (PFS; 1.6-month benefit). No relationships were found for rs396991 (FCGR3A).Conclusions: In the CO.17 trial, cetuximab worked best for patients with KRAS wild-type colorectal cancers carrying FCGR2A H/H genotypes. Significantly lower benefits were observed in patients carrying germline FCGR2A R alleles. Clin Cancer Res; 22(10); 2435–44. ©2016 AACR.

Supplementary Table S1: Patient characteristics in the CCTG MA.5 original trial versus the CCTG MA.5 translational study cohort classifiable by immunohistochemistry; Supplementary Table S2: Patient characteristics in the CCTG MA.12 original trial versus the CCTG MA.12 translational study cohort classifiable by immunohistochemistry; Supplementary Table S3: The distribution of the possible Nestin/INPP4B IHC staining categories in the translational study cohorts of MA.5 and MA.12; Supplementary Table S4: The distribution of the different combinations of nestin/INPP4B IHC staining according to "PAM50 basal-like vs. non basal-like" in MA.5 and MA.12; Supplementary Table S5: Performance characteristics of the IHC basal panel against the intrinsic PAM50 breast cancer subtype assay as a gold standard

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Purpose: Recent studies suggest that intrinsic breast cancer subtypes may differ in their responsiveness to specific chemotherapy regimens. We examined this hypothesis on NCIC.CTG MA.5, a clinical trial randomizing premenopausal women with node-positive breast cancer to adjuvant CMF (cyclophosphamide-methotrexate-fluorouracil) versus CEF (cyclophosphamide-epirubicin-fluorouracil) chemotherapy.Experimental Design: Intrinsic subtype was determined for 476 tumors using the quantitative reverse transcriptase PCR PAM50 gene expression test. Luminal A, luminal B, HER2-enriched (HER2-E), and basal-like subtypes were correlated with relapse-free survival (RFS) and overall survival (OS), estimated using Kaplan–Meier plots and log-rank testing. Multivariable Cox regression analyses determined significance of interaction between treatment and intrinsic subtypes.Results: Intrinsic subtypes were associated with RFS (P = 0.0005) and OS (P < 0.0001) on the combined cohort. The HER2-E showed the greatest benefit from CEF versus CMF, with absolute 5-year RFS and OS differences exceeding 20%, whereas there was a less than 2% difference for non–HER2-E tumors (interaction test P = 0.03 for RFS and 0.03 for OS). Within clinically defined Her2+ tumors, 79% (72 of 91) were classified as the HER2-E subtype by gene expression and this subset was strongly associated with better response to CEF versus CMF (62% vs. 22%, P = 0.0006). There was no significant difference in benefit between CEF and CMF in basal-like tumors [n = 94; HR, 1.1; 95% confidence interval (CI), 0.6–2.1 for RFS and HR, 1.3; 95% CI, 0.7–2.5 for OS].Conclusion: HER2-E strongly predicted anthracycline sensitivity. The chemotherapy-sensitive basal-like tumors showed no added benefit for CEF over CMF, suggesting that nonanthracycline regimens may be adequate in this subtype although further investigation is required. Clin Cancer Res; 18(8); 2402–12. ©2012 AACR.

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PURPOSE The time spent in pursuing treatments for advanced cancer can be substantial. We have previously proposed a pragmatic and patient-centered metric of these time costs—which we term time toxicity—as any day with physical health care system contact. This includes outpatient visits (eg, bloodwork, scans, etc), emergency department visits, and overnight stays in a health care facility. Herein, we sought to assess time toxicity in a completed randomized controlled trial (RCT). METHODS We conducted a secondary analysis of the Canadian Cancer Trials Group CO.17 RCT that evaluated weekly cetuximab infusions versus supportive care alone in 572 patients with advanced colorectal cancer. Initial results reported a 6-week improvement in median overall survival (OS) with cetuximab (6.1 v 4.6 months). Subsequent analyses reported that benefit was restricted to patients with K-ras wild-type tumors. We calculated patient-level time toxicity by analyzing trial forms. We considered days without health care contact as home days. We compared medians of time measures across arms and stratified results by K-ras status. RESULTS In the overall population, median time toxic days were higher in the cetuximab arm (28 v 10, P < .001) although median home days were not statistically different between arms (140 v 121, P = .09). In patients with K-ras–mutated tumors, cetuximab was associated with almost numerically equal home days (114 days v 112 days, P = .571) and higher time toxicity (23 days v 11 days, P < .001). In patients with K-ras wild-type tumors, cetuximab was associated with more home days (186 v 132, P < .001). CONCLUSION This proof-of-concept feasibility study demonstrates that measures of time toxicity can be extracted through secondary analyses of RCTs. In CO.17, despite an overall OS benefit with cetuximab, home days were statistically similar across arms. Such data can supplement traditional survival end points in RCTs. Further work should refine and validate the measure prospectively.

Identifying subpopulations that may be sensitive to the specific treatment is an important step toward precision medicine. On the other hand, longitudinal data with dropouts is common in medical research, and subgroup analysis for this data type is still limited. In this paper, we consider a single-index threshold linear marginal model, which can be used simultaneously to identify subgroups with differential treatment effects based on linear combination of the selected biomarkers, estimate the treatment effects in different subgroups based on regression coefficients, and test the significance of the difference in treatment effects based on treatment-subgroup interaction. The regression parameters are estimated by solving a penalized smoothed generalized estimating equation and the selection bias caused by missingness is corrected by a multiply robust weighting matrix, which allows multiple missingness models to be taken account into estimation. The proposed estimator remains consistent when any model for missingness is correctly specified. Under regularity conditions, the asymptotic normality of the estimator is established. Simulation studies confirm the desirable finite-sample performance of the proposed method. As an application, we analyze the data from a clinical trial on pancreatic cancer.