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PURPOSE To examine longitudinal relationships between levels of C-reactive protein (CRP) and cognition in older breast cancer survivors and noncancer controls. METHODS English-speaking women age ≥ 60 years, newly diagnosed with primary breast cancer (stage 0-III), and frequency-matched controls were enrolled from September 2010 to March 2020; women with dementia, neurologic disorders, and other cancers were excluded. Assessments occurred presystemic therapy/enrollment and at annual visits up to 60 months. Cognition was measured using the Functional Assessment of Cancer Therapy-Cognitive Function and neuropsychological testing. Mixed linear effect models tested for survivor-control differences in natural log (ln)-transformed CRP at each visit. Random effect–lagged fluctuation models tested directional effects of ln-CRP on subsequent cognition. All models controlled for age, race, study site, cognitive reserve, obesity, and comorbidities; secondary analyses evaluated if depression or anxiety affected results. RESULTS There were 400 survivors and 329 controls with CRP specimens and follow-up data (average age of 67.7 years; range, 60-90 years). The majority of survivors had stage I (60.9%), estrogen receptor–positive (87.6%) tumors. Survivors had significantly higher adjusted mean ln-CRP than controls at baseline and 12-, 24-, and 60-month visits (all P < .05). Higher adjusted ln-CRP predicted lower participant-reported cognition on subsequent visits among survivors, but not controls ( P interaction = .008); effects were unchanged by depression or anxiety. Overall, survivors had adjusted Functional Assessment of Cancer Therapy-Cognitive Function scores that were 9.5 and 14.2 points lower than controls at CRP levels of 3.0 and 10.0 mg/L. Survivors had poorer neuropsychological test performance ( v controls), with significant interactions with CRP only for the Trails B test. CONCLUSION Longitudinal relationships between CRP and cognition in older breast cancer survivors suggest that chronic inflammation may play a role in development of cognitive problems. CRP testing could be clinically useful in survivorship care.

Purpose To assess whether crofelemer would prevent chemotherapy-induced diarrhea (CID) diarrhea in patients with HER2-positive, any-stage breast cancer receiving trastuzumab (H), pertuzumab (P), and a taxane (T; docetaxel or paclitaxel), with/without carboplatin (C; always combined with docetaxel rather than paclitaxel). Methods Patients scheduled to receive ≥ 3 consecutive TCHP/THP cycles were randomized to crofelemer 125 mg orally twice daily during chemotherapy cycles 1 and 2 or no scheduled prophylactic medication (control). All received standard breakthrough antidiarrheal medication (BTAD) as needed. The primary endpoint was incidence of any-grade CID for ≥ 2 consecutive days. Secondary endpoints were incidence of all-grade and grade 3/4 CID by cycle/stratum; time to onset and duration of CID; stool consistency; use of BTAD; and quality of life (Functional Assessment of Chronic Illness Therapy for Patients With Diarrhea [FACIT-D] score). Results Fifty-one patients were randomized to crofelemer (n = 26) or control (n = 25). There was no statistically significant difference between arms for the primary endpoint; however, incidence of grade ≥ 2 CID was reduced with crofelemer vs control (19.2% vs 24.0% in cycle 1; 8.0% vs 39.1%, in cycle 2). Patients receiving crofelemer were 1.8 times more likely to see their diarrhea resolved and had less frequent watery diarrhea. Conclusion Despite the choice of primary endpoint being insensitive, crofelemer reduced the incidence and severity of CID in patients with HER2-positive breast cancer receiving P-based therapy. These data are supportive of further testing of crofelemer in CID. Trial registration Clinicaltrials.gov, NCT02910219, prospectively registered September 21, 2016.

Purpose:Estrogen receptor 1 (ESR1) mutations and fusions typically arise in patients with hormone receptor-positive breast cancer after aromatase inhibitor therapy, whereby ESR1 is constitutively activated in a ligand-independent manner. These variants can impact treatment response. Herein, we characterize ESR1 variants among molecularly profiled breast cancers.Methods:DNA next-generation sequencing (592-gene panel) data from 9860 breast cancer samples were retrospectively reviewed. Gene fusions were detected using the ArcherDx fusion assay or whole transcriptome sequencing (N = 344 and N = 4305, respectively). Statistical analyses included Chi-square and Fisher’s exact tests.Results:An ESR1 ligand binding domain (LBD) mutation was detected in 8.6% of tumors evaluated and a pathogenic ESR1 fusion was detected in 1.6%. The majority of ESR1 LBD mutations/fusions were from estrogen receptor (ER)-positive samples (20.1% and 4.9%, respectively). The most common ESR1 LBD mutations included D538G (3.3%), Y537S (2.3%), and E380Q (1.1%) mutations. Among biopsy sites, ESR1 LBD mutations were most observed in liver metastases. Pathogenic ESR1 fusions were identified in 76 samples (1.6%) with 40 unique fusion partners. ESR1 variant (mutation/fusion) samples more frequently expressed androgen receptor (78.0% vs 58.6, pESR1 wild-type (PD-1 20.0% vs 53.4, pConclusion:We have described one of the largest series of ESR1 fusions reported. ESR1 LBD mutations were commonly identified in ER-positive disease. Limited data exists regarding the clinical impact of ESR1 fusions, which could be an area for future therapeutic exploration.

Purpose: Tumor features associated with aggressive cancers may affect cognition prior to systemic therapy. We evaluated associations of pre-treatment cognition and tumor aggressivity in older breast cancer patients. Methods: Women diagnosed with non-metastatic breast cancer (n=705) ages 60-98 were enrolled from August 2010-March 2020. Cognition was measured post-surgery, pre-systemic therapy using self-reported (FACT-Cog Perceived Cognitive Impairment [PCI]) and objective tests of attention, processing speed, and executive function (APE domain) and learning and memory [LM domain]. Linear regression tested associations of pre-treatment tumor features and cognition, adjusting for age, race, and study site. HER2 positivity and higher stage (II/III vs. 0/I) were a priori predictors of cognition; in secondary analyses we explored associations of other tumor features and cognitive impairment (i.e., PCI score Results: HER2 positivity and the hormone receptor negative/HER2+ molecular subtype were associated with lower adjusted mean self-reported cognition scores and higher impairment rates (p values Conclusions: Pre-adjuvant therapy cognition was associated with HER2 positivity and higher stage of disease and other features of aggressive tumors. Additional research is needed to confirm these results and assess potential mechanisms and clinical management strategies.

Association results between minor alleles of 467 variants incorportated in cross tissue gene expression prediction model for the gene of CRHR1.

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Association results after the adjustment for nearby GWAS index SNPs for genes with predicted gene expression levels associated with ovarian cancer risk at P < 2.21E-6.

Online Supplementary Documents

Background: Genome-wide association studies (GWAS) identified variants at 19p13.1 and ZNF365 (10q21.2) as risk factors for breast cancer among BRCA1 and BRCA2 mutation carriers, respectively. We explored associations with ovarian cancer and with breast cancer by tumor histopathology for these variants in mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA).Methods: Genotyping data for 12,599 BRCA1 and 7,132 BRCA2 mutation carriers from 40 studies were combined.Results: We confirmed associations between rs8170 at 19p13.1 and breast cancer risk for BRCA1 mutation carriers [HR, 1.17; 95% confidence interval (CI), 1.07–1.27; P = 7.42 × 10−4] and between rs16917302 at ZNF365 (HR, 0.84; 95% CI, 0.73–0.97; P = 0.017) but not rs311499 at 20q13.3 (HR, 1.11; 95% CI, 0.94–1.31; P = 0.22) and breast cancer risk for BRCA2 mutation carriers. Analyses based on tumor histopathology showed that 19p13 variants were predominantly associated with estrogen receptor (ER)-negative breast cancer for both BRCA1 and BRCA2 mutation carriers, whereas rs16917302 at ZNF365 was mainly associated with ER-positive breast cancer for both BRCA1 and BRCA2 mutation carriers. We also found for the first time that rs67397200 at 19p13.1 was associated with an increased risk of ovarian cancer for BRCA1 (HR, 1.16; 95% CI, 1.05–1.29; P = 3.8 × 10−4) and BRCA2 mutation carriers (HR, 1.30; 95% CI, 1.10–1.52; P = 1.8 × 10−3).Conclusions: 19p13.1 and ZNF365 are susceptibility loci for ovarian cancer and ER subtypes of breast cancer among BRCA1 and BRCA2 mutation carriers.Impact: These findings can lead to an improved understanding of tumor development and may prove useful for breast and ovarian cancer risk prediction for BRCA1 and BRCA2 mutation carriers. Cancer Epidemiol Biomarkers Prev; 21(4); 645–57. ©2012 AACR.

PDF file - 55K, Study Drug Dosing (Safety Population)

Genes coregulated in predicted expression at 2q31.1, 9p22.3, 17q21.31 and 17q21.32.

Internal performance of ovarian and cross-tissue gene expression prediction models built using GTEx data.

Large-scale genome-wide association studies (GWAS) have identified approximately 35 loci associated with epithelial ovarian cancer (EOC) risk. The majority of GWAS-identified disease susceptibility variants are located in noncoding regions, and causal genes underlying these associations remain largely unknown. Here, we performed a transcriptome-wide association study to search for novel genetic loci and plausible causal genes at known GWAS loci. We used RNA sequencing data (68 normal ovarian tissue samples from 68 individuals and 6,124 cross-tissue samples from 369 individuals) and high-density genotyping data from European descendants of the Genotype-Tissue Expression (GTEx V6) project to build ovarian and cross-tissue models of genetically regulated expression using elastic net methods. We evaluated 17,121 genes for their cis-predicted gene expression in relation to EOC risk using summary statistics data from GWAS of 97,898 women, including 29,396 EOC cases. With a Bonferroni-corrected significance level of P < 2.2 × 10−6, we identified 35 genes, including FZD4 at 11q14.2 (Z = 5.08, P = 3.83 × 10−7, the cross-tissue model; 1 Mb away from any GWAS-identified EOC risk variant), a potential novel locus for EOC risk. All other 34 significantly associated genes were located within 1 Mb of known GWAS-identified loci, including 23 genes at 6 loci not previously linked to EOC risk. Upon conditioning on nearby known EOC GWAS-identified variants, the associations for 31 genes disappeared and three genes remained (P < 1.47 × 10−3). These data identify one novel locus (FZD4) and 34 genes at 13 known EOC risk loci associated with EOC risk, providing new insights into EOC carcinogenesis.Significance: Transcriptomic analysis of a large cohort confirms earlier GWAS loci and reveals FZD4 as a novel locus associated with EOC risk. Cancer Res; 78(18); 5419–30. ©2018 AACR.

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Supplementary Table 1 from Genetic Variation in IGF2 and HTRA1 and Breast Cancer Risk among BRCA1 and BRCA2 Carriers

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Association results between associated genes with P < P < 2.21E-6 and risk of different histotypes of epithelial ovarian cancer.

Known common variants identified from genome-wide assocation studies and their bioinformatically predicted target genes.

Variants with P < 5E-8 either in BCAC or OCAC between 42,836,399 and 44,910,520 on the chromosome 17.

Background: Previously, small studies have found that BRCA1 and BRCA2 breast tumors differ in their pathology. Analysis of larger datasets of mutation carriers should allow further tumor characterization.Methods: We used data from 4,325 BRCA1 and 2,568 BRCA2 mutation carriers to analyze the pathology of invasive breast, ovarian, and contralateral breast cancers.Results: There was strong evidence that the proportion of estrogen receptor (ER)-negative breast tumors decreased with age at diagnosis among BRCA1 (P-trend = 1.2 × 10−5), but increased with age at diagnosis among BRCA2, carriers (P-trend = 6.8 × 10−6). The proportion of triple-negative tumors decreased with age at diagnosis in BRCA1 carriers but increased with age at diagnosis of BRCA2 carriers. In both BRCA1 and BRCA2 carriers, ER-negative tumors were of higher histologic grade than ER-positive tumors (grade 3 vs. grade 1; P = 1.2 × 10−13 for BRCA1 and P = 0.001 for BRCA2). ER and progesterone receptor (PR) expression were independently associated with mutation carrier status [ER-positive odds ratio (OR) for BRCA2 = 9.4, 95% CI: 7.0–12.6 and PR-positive OR = 1.7, 95% CI: 1.3–2.3, under joint analysis]. Lobular tumors were more likely to be BRCA2-related (OR for BRCA2 = 3.3, 95% CI: 2.4–4.4; P = 4.4 × 10−14), and medullary tumors BRCA1-related (OR for BRCA2 = 0.25, 95% CI: 0.18–0.35; P = 2.3 × 10−15). ER-status of the first breast cancer was predictive of ER-status of asynchronous contralateral breast cancer (P = 0.0004 for BRCA1; P = 0.002 for BRCA2). There were no significant differences in ovarian cancer morphology between BRCA1 and BRCA2 carriers (serous: 67%; mucinous: 1%; endometrioid: 12%; clear-cell: 2%).Conclusions/Impact: Pathologic characteristics of BRCA1 and BRCA2 tumors may be useful for improving risk-prediction algorithms and informing clinical strategies for screening and prophylaxis. Cancer Epidemiol Biomarkers Prev; 21(1); 134–47. ©2011 AACR.

Purpose: Women at familial/genetic ovarian cancer risk often undergo screening despite unproven efficacy. Research suggests each woman has her own CA125 baseline; significant increases above this level may identify cancers earlier than standard 6- to 12-monthly CA125 > 35 U/mL.Experimental Design: Data from prospective Cancer Genetics Network and Gynecologic Oncology Group trials, which screened 3,692 women (13,080 woman-screening years) with a strong breast/ovarian cancer family history or BRCA1/2 mutations, were combined to assess a novel screening strategy. Specifically, serum CA125 q3 months, evaluated using a risk of ovarian cancer algorithm (ROCA), detected significant increases above each subject's baseline, which triggered transvaginal ultrasound. Specificity and positive predictive value (PPV) were compared with levels derived from general population screening (specificity 90%, PPV 10%), and stage-at-detection was compared with historical high-risk controls.Results: Specificity for ultrasound referral was 92% versus 90% (P = 0.0001), and PPV was 4.6% versus 10% (P > 0.10). Eighteen of 19 malignant ovarian neoplasms [prevalent = 4, incident = 6, risk-reducing salpingo-oophorectomy (RRSO) = 9] were detected via screening or RRSO. Among incident cases (which best reflect long-term screening performance), three of six invasive cancers were early-stage (I/II; 50% vs. 10% historical BRCA1 controls; P = 0.016). Six of nine RRSO-related cases were stage I. ROCA flagged three of six (50%) incident cases before CA125 exceeded 35 U/mL. Eight of nine patients with stages 0/I/II ovarian cancer were alive at last follow-up (median 6 years).Conclusions: For screened women at familial/genetic ovarian cancer risk, ROCA q3 months had better early-stage sensitivity at high specificity, and low yet possibly acceptable PPV compared with CA125 > 35 U/mL q6/q12 months, warranting further larger cohort evaluation. Clin Cancer Res; 23(14); 3628–37. ©2017 AACR.

Chromosomal regions with predicted gene expression levels associated with epithelial ovarian cancer risk at P < 2.21E-6 with either ovarian or cross-tissue model.

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Supplementary Materials describing "Inclusion and Exclusion Criteria" for the two studies, a detailed description of the "ROCA methods", "Sample Handling and CA125 Assay Instrumentation", and derivation of standards for "Specificity and Positive Predictive Values" for a cohort of women at increased risk.

Background:BRCA1 and BRCA2 mutation carriers have a lifetime breast cancer risk of 40% to 80%, suggesting the presence of risk modifiers. We previously identified significant associations in genetic variants in the insulin-like growth factor (IGF) signaling pathway. Here, we investigate additional IGF signaling genes as risk modifiers for breast cancer development in BRCA carriers.Methods: A cohort of 1,019 BRCA1 and 500 BRCA2 mutation carriers were genotyped for 99 single-nucleotide polymorphisms (SNP) in 13 genes. Proportional hazards regression was used to model time from birth to diagnosis of breast cancer for BRCA1 and BRCA2 carriers separately. For linkage disequilibrium (LD) blocks with multiple SNPs, an additive genetic model was used. For an SNP analysis, no additivity assumptions were made.Results: Significant associations were found between risk of breast cancer and LD blocks in IGF2 for BRCA1 and BRCA2 mutation carriers (global P values of 0.009 for BRCA1 and 0.007 for BRCA2), HTRA1 for BRCA1 carriers (global P value of 0.005), and MMP3 for BRCA2 carriers (global P = 0.0000007 for BRCA2).Conclusions: We identified significant associations of genetic variants involved in IGF signaling. With the known interaction of BRCA1 and IGF signaling and the loss of PTEN in a majority of BRCA1 tumors, this suggests that signaling through AKT may modify breast cancer risk in BRCA1 carriers.Impact: These results suggest potential avenues for future research targeting the IGF signaling pathway in modifying risk in BRCA1and BRCA2 mutation carriers. Cancer Epidemiol Biomarkers Prev; 20(8); 1690–702. ©2011 AACR.

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Inherited BRCA1/2 mutations confer elevated ovarian cancer risk. Knowledge of factors that can improve ovarian cancer risk assessment in BRCA1/2 mutation carriers is important because no effective early detection for ovarian cancers exists. A cohort of 1,575 BRCA1 and 856 BRCA2 mutation carriers was used to evaluate haplotypes at ATM, BARD1, BRIP1, CTIP, MRE11, NBS1, RAD50, RAD51, and TOPBP1 in ovarian cancer risk. In BRCA1 carriers, no associations were observed with ATM, BARD1, CTIP, RAD50, RAD51, or TOPBP1. At BRIP1, an association was observed for one haplotype with a multiple testing corrected P (Pcorr) = 0.012, although no individual haplotype was significant. At MRE11, statistically significant associations were observed for one haplotype (Pcorr = 0.007). At NBS1, we observed a Pcorr = 0.024 for haplotypes. In BRCA2 carriers, no associations were observed with CTIP, NBS1, RAD50, or TOPBP1. Rare haplotypes at ATM (Pcorr = 0.044) and BARD1 (Pcorr = 0.012) were associated with ovarian cancer risk. At BRIP1, two common haplotypes were significantly associated with ovarian cancer risk (Pcorr = 0.011). At MRE11, we observed a significant haplotype association (Pcorr = 0.012), and at RAD51, one common haplotype was significantly associated with ovarian cancer risk (Pcorr = 0.026). Variants in genes that interact biologically withBRCA1 and/or BRCA2 may be associated with modified ovarian cancer risk in women who carry BRCA1/2 mutations. [Cancer Res 2009;69(14):5801–10]

Supplementary Table 2: Revised 7-14-09 from Modification of Ovarian Cancer Risk by BRCA1/2-Interacting Genes in a Multicenter Cohort of BRCA1/2 Mutation Carriers

Supplementary Table 4 from Modification of Ovarian Cancer Risk by BRCA1/2-Interacting Genes in a Multicenter Cohort of BRCA1/2 Mutation Carriers

Supplementary Table 3 from Modification of Ovarian Cancer Risk by BRCA1/2-Interacting Genes in a Multicenter Cohort of BRCA1/2 Mutation Carriers

Supplementary Methods, Tables 1-3, Figure 1 from Common Breast Cancer Susceptibility Alleles and the Risk of Breast Cancer for BRCA1 and BRCA2 Mutation Carriers: Implications for Risk Prediction

Supplementary Table 2 from Modification of Ovarian Cancer Risk by BRCA1/2-Interacting Genes in a Multicenter Cohort of BRCA1/2 Mutation Carriers

Supplementary Table 1 from Modification of Ovarian Cancer Risk by BRCA1/2-Interacting Genes in a Multicenter Cohort of BRCA1/2 Mutation Carriers

Background BRCA1 and BRCA2 (BRCA) mutation carriers face a high lifetime risk of developing ovarian cancer. Oral contraceptives are protective in this population; however, the impact of other types of contraception (e.g. intrauterine devices, implants, injections) is unknown. We undertook a matched case-control study to evaluate the relationship between type of contraception and risk of ovarian cancer among women with BRCA mutations. Methods A total of 1733 matched pairs were included in this analysis. Women were matched according to year of birth, date of study entry, country of residence, BRCA mutation type and history of breast cancer. Detailed information on hormonal, reproductive and lifestyle exposures were collected from a routinely administered questionnaire. Conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) associated with each contraceptive exposure. Results Ever use of any contraceptive was significantly associated with reduced risk of ovarian cancer (OR = 0.62; 95% CI 0.52–0.75; P < 0.0001), which was driven by significant inverse associations with oral contraceptives (OR = 0.66; 95% CI 0.54–0.79; P < 0.0001) and contraceptive implants (OR = 0.30; 95% CI 0.12–0.73; P = 0.008). We observed a similar effect with use of injections (OR = 0.37; 95% CI 0.10–1.38; P = 0.14), but this did not achieve significance. No significant associations were observed between patterns of intrauterine device use and risk of ovarian cancer. Conclusions These findings support a protective effect of oral contraceptives and implants on risk of ovarian cancer among women with BRCA mutations. The possible protective effect of injections requires further evaluation.

Background: Quality of life (QOL) in breast cancer patients (pts) can be greatly impacted by initial treatment and ongoing therapy, particularly if side effects and symptoms are not well tolerated. The PALLAS trial investigated whether the addition of 2 years of palbociclib (palbo) to adjuvant endocrine therapy (ET) improved invasive disease-free survival (iDFS) over adjuvant ET alone. We report on the main patient-reported outcome (PRO) quality of life (QOL) and symptom severity results of this trial by treatment arm. Methods: PALLAS is an ongoing multicenter, open label phase 3 trial that enrolled hormone receptor positive, HER2-negative, stage II-III breast cancer patients at 406 cancer centers across 21 countries. Patients were randomly assigned (1:1) to either 2 years of palbo (125mg/day, 3 weeks on 1 week off) plus ongoing provider or patient-choice adjuvant ET (palbo+ET) versus ongoing ET alone. The primary study endpoint was iDFS. Treatment with palbo in all pts stopped at the time of the second interim analysis (5/2020) due to futility; all pts then moved to follow up. The PRO analyses were triggered for completion after awareness of the pre-specified 469 iDFS cases in November 2020. Eight PRO endpoints were measured serially (i.e., day 1 of each monthly cycle for the first 3 months, then every 3 months for the first 2 years, and once at year 3). The endpoints were the EORTC QLQ-C30 global health status/QOL score, the Brief Fatigue Inventory score, the modified Brief Pain Inventory severity and pain interference scores, the EORTC QLQ-BR23 alopecia score, and the Breast Cancer Prevention Trial hot flash symptoms, vaginal problems, and musculoskeletal pain scores. Linear mixed models compared the average difference between arms across time points during the initial 2-year treatment period adjusting for cycle 1 day 1 (C1D1) PRO scores, demographic and clinical variables. The average differences between arms (palbo+ET vs ET alone) and the two-sided (1-[0.05/8]) x 100% confidence intervals, adjusted for multiple comparisons, were calculated. Analysis of covariance compared the average between-arm differences by endpoint at 3 years. Results: The PRO intention to collect population included 4688 (81%) of the overall trial pts, and was clinically and demographically representative of the remaining 1073 pts. Each analysis population, with measures at C1D1 and at least 1 post-C1D1 assessment for each PRO endpoint, comprised ≥ 89% of the 4688 pts and the proportions were similar between arms. After adjustment for baseline covariates, on average, no clinically important differences between arms were observed for any of the eight endpoints over the 2 year treatment period (Table 1). All effect sizes were below the pre-specified 0.2 threshold. These PRO results were similar at the 3 year time point. Conclusions: No clinically significant differences in either patient-reported QOL or symptom severity were found, on average, between participants in the two PALLAS treatment arms while either taking palbo+ET or ET alone, or after study-wide termination of palbo. In general, the addition of palbociclib in the adjuvant breast cancer setting did not contribute to increased symptom burden within this survivorship population. Further analyses will examine the relationship between PROs and treatment discontinuation by arm and study time point. Support: AFT, Pfizer, https://acknowledgments.alliancefound.org Table 1.Results of the Patient-Reported QOL and Symptom Severity Analyses Between the Two Treatment Arms During the First 2 Years of PALLASPRO Endpoint *Palbo + ET Adjusted average score (95% CI)ET alone Adjusted average score (95% CI)Average Difference + (Palbo + ET vs ET alone)[99.38% CI] Clinically ++ Important DifferenceEORTC QLQ-C30 Global Health Status/QOL71.7 (71.2, 72.2)74.0 (73.5, 74.5)-2.3 (-3.3, -1.4)**NoBrief Fatigue Inventory Score2.3 (2.2, 2.3)2.1 (2.0, 2.1)0.2 (0.1, 0.3)NoModified Brief Pain Inventory - Severity Score2.3 (2.2, 2.3)2.4 (2.4, 2.5)-0.2 (-0.3, -0.1)NoModified Brief Pain Inventory - Interference Score1.7 (1.6, 1.7)1.7 (1.6, 1.7)0.0 (-0.1, 0.1)NoEORTC QLQ-BR23 Alopecia1.4 (1.4, 1.4)1.3 (1.3, 1.3)0.1 (0.1, 0.1)NoBreast Cancer Prevention Trial - Hot Flash Symptoms1.2 (1.2, 1.3)1.2 (1.2, 1.3)0.0 (-0.1, 0.1)NoBreast Cancer Prevention Trial - Vaginal Problems0.8 (0.8, 0.8)0.8 (0.7, 0.8)0.0 (0.0, 0.1)NoBreast Cancer Prevention Trial - Musculoskeletal Pain1.2 (1.2, 1.2)1.3 (1.3, 1.3)-0.1 (-0.2, 0.0)No* For the EORTC QLQ-C30 Global Health Status/QOL subscale, higher scores indicate better QOL. For all other PRO endpoints, higher scores indicate worse symptom levels. ** The lower bound of the one-sided CI (adjusted for multiple comparisons) was -3.3. Because the lower limit is greater than the pre-specified non-inferiority margin of -3.44, non-inferiority of palbo+ET relative to ET-alone was concluded. The non-inferiority margin corresponds to a 0.2 SD in the EORTC QLQ-C30 global health/QOL score. +The average difference was adjusted for the following baseline covariates: Cycle 1 day 1 score, region (if applicable), age category, first adjuvant ET, race, ethnicity, N-stage, T-stage, histological grade, PgR, prior chemotherapy, ECOG Performance Status. ++Based on each instrument’s published clinically relevant cut-offs, if available. After calculating Cohen’s d treatment effect sizes, (i.e. by dividing the average difference by the ET-alone arm standard deviation from cycle 1 day 1), all effect sizes were below the pre-specified 0.2 threshold, and would not be considered clinically important. Citation Format: Michelle Joy Naughton, David Zahrieh, Michael Gnant, Nicholas Zdenkowski, Julie Lemieux, Jun J Mao, Vesna Bjelic-Radisic, Eileen Shinn, Marija Balic, Christoph Thomssen, Jane Neisel, Manuel Ruiz-Echarri, Sibylle Loibl, Claudine Isaacs, David Cameron, Fernando Manuel Henao Carrasco, Matthew Goetz, Viktor Wette, Gustavo Werutsky, Hope Rugo, Marcus Vetter, Ling-Ming Tseng, Kathy Miller, Florian Fitzal, Juan Miguel Gil Gil, Haeseong Park, Barbro Linderholm, Emilio Bajetta, Zoneddy Dayao, Aleix Prat, Karin Ehrhardt, Otto Metzger, Amal Arahmani, Ernest Law, Ann Partridge, Lisa Carey, Alex Zoroufy, Amylou Dueck, Dominik Hlauschek, Angela DeMichele, Erica Mayer. Quality of life and symptom severity in the PALLAS randomized trial of palbociclib with adjuvant endocrine therapy in early breast cancer (AFT-05) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-10-01.

Background Palbociclib, the first clinically available oral CDK4/6 inhibitor, in combination with endocrine therapy has been approved for HR+/HER2- advanced/metastatic breast cancer (MBC) in the US for more than 6 years. Although clinical trials and growing real-world data have demonstrated safety and effectiveness of palbociclib plus endocrine therapy, data on treatment patterns and effectiveness of palbociclib in minority patients with MBC are limited. This study compared real-world progression free survival (rwPFS) and overall survival (OS) of palbociclib plus letrozole (PB+LE) vs letrozole alone (LE) in Hispanic and African American patients with HR+/HER2- MBC in US routine clinical practices. Methods We conducted a retrospective analysis of patients with MBC from the Flatiron Health longitudinal database, which contains electronic health records from over 280 cancer clinics representing more than 2.2 million actively treated cancer patients in the US. Between February 2015 and February 2019, 151 Hispanic and African American women with HR+/HER2- MBC started PB+LE or LE as first-line therapy. Patients were evaluated from start of PB+LE or LE to May 31, 2019 (Data cutoff date), death, or last visit, whichever came first. rwPFS was defined as months from start of PB+LE or LE to death or disease progression, evaluated based on clinical assessment or radiographic scan/tissue biopsy. Cox proportional-hazards models were used to estimate the relative effectiveness of PB+LE vs LE without and with adjustment of baseline demographics and clinical characteristics. Results Of the 151 eligible patients, 114 (75.5%) were African American, 37 (24.5%) were Hispanic, 76 (50.3%) were treated with PB+LE, and 75 (49.7%) were treated with LE. Median age was 64.5 years in PB+LE patients and 69.0 years in LE patients, respectively. Median follow-up was 2 months longer in PB+LE patients than LE patients (21.7 vs 19.4 months). PB+LE patients were more likely to have ≥2 metastatic sites than LE patients (42.1% vs 34.6%). Median rwPFS was 20.0 months (95%CI = 12.3 - NR) in PB+LE patients and 7.0 months (95%CI=4.6-9.5) in LE patients (HR=0.38, 95%CI=0.25-0.58, p Table. Patient characteristics and effectiveness outcomesVariablePB+LE(N=76)LE alone(N=75)African American, n (%)54 (71.1)60 (80.0)Hispanic, n (%)22 (28.9)15 (20.0)Median age (IQR), years64.5(58.5-71.0)69.0 (59.0-80.0)Metastatic sites≥2, n (%)32 (42.1)26(34.6)Visceral disease, n (%)29 (38.2)29 (38.7)Bone only disease, n (%)29 (38.2)26 (34.7)rwPFS rate at 6 months, %78.052.9rwPFS rate at 12 months, %61.629.4rwPFS rate at 20 months, %49.016.3Median PFS (95%CI), months20.0(12.3-NR)7.0 (4.6-9.5)OS rate at 12 months, %89.373.0OS rate at 24 months, %72.648.7Median OS (95%CI), months24.01 (17.1-NR)NR (33.6-NR)Median follow-up, months (IQR)21.7 (15.3-32.9)19.4 (8.9-30.7)PB+LE= Palbociclib plus letrozole; LE= Letrozole alone; IQR= Interquartile range; NR= Not reached; OS= Overal surval; rwPFS = real-world progression free survival Citation Format: Hope Rugo, Filipa Lynce, Xianchen Liu, Benjamin Li, Lynn McRoy, Claudine Isaacs. Effectiveness of palbociclib plus letrozole vs letrozole in US Hispanic and African American patients with metastatic breast cancer: Flatiron database analysis [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-14-08.

Background: CID occurs in up to 80% of patients with breast cancer who receive trastuzumab (H), pertuzumab (P), and a taxane, with grade 3 experienced by 8-12% of patients. Crofelemer is an extract of the Croton lechleri tree that inhibits luminal chloride efflux, implicated in the HP-related CID. We hypothesized crofelemer would prevent diarrhea in patients with HER2+ breast cancer receiving HP and docetaxel or paclitaxel, with/without carboplatin (THP or TCHP) in the neoadjuvant, adjuvant, or metastatic setting. Clinical trial information: NCT02910219. Methods: Adult patients with HER2+ any stage breast cancer, scheduled to receive at least 3 consecutive cycles of TCHP (docetaxel, carboplatin, trastuzumab and pertuzumab) or THP (trastuzumab and pertuzumab with paclitaxel or docetaxel), normal organ function, PS 0-2, who provided written informed consent were randomized 1:1 to receive crofelemer 125 mg PO 2x/day during cycles 1 and 2 of chemotherapy or no scheduled prophylactic medication. Randomization was stratified according to chemotherapy regimen. The primary endpoint was the incidence of CID of any grade for ≥2 consecutive days assessed by NCI CTCAE v4.0. Provider reported outcomes were collected during clinic visits and prospectively documented in clinical notes. Patient reported outcomes (PRO) were collected from patient diaries. Secondary endpoints were incidence of all grades and grade 3/4 CID by cycle/stratum; time to onset and duration of CID; stool consistency; frequency of break through anti-diarrheal medications use; and FACIT-D total score. Fisher’s exact test was used for comparing binary and categorical variables and summary statistics and Wilcoxon test for ordinal grade variables. The trial was designed to detect a 40% absolute decrease in incidence of CID (from 60% to 20%), two-sided significance level of 0.10. Results: A total of 53 patients were enrolled between 02/21/2017- 08/25/2020 on crofelemer (n=27) or control (n=26) arms. One patient withdrew consent prior to starting protocol procedures and was substituted. Early treatment discontinuation occurred in 7 cases: complications of diarrhea (n=1, control group), chemotherapy regimen changed for other cause than diarrhea (n=4) and non-compliance with trial procedures (n=2). 29 patients had early stage disease treated with TCHP; 23 patients had metastatic disease treated with THP (16 with paclitaxel and 7 with docetaxel). The primary endpoint was not statistically different between the two groups. The incidence of Grade 2 or greater diarrhea was 20.9% vs 26.4% of patients receiving crofelemer or placebo respectively in cycle 1, and 9.5% vs 41.1% in cycle 2 (Table). Results were consistent between provider assessments and patient reported outcomes (PRO). Detailed description of pooled cycle 1-2 data using correlated ordinal model and the additional secondary endpoints will be presented. Conclusions: Although there was no significant difference between crofelemer and control for diarrhea for 2 or more consecutive days in both cycles, there was a clinically meaningful difference between the crofelemer and control groups in maximum within-cycle diarrhea ordinal CTCAE grade diarrhea. These data are supportive for further testing of crofelemer in the ongoing randomized Phase 3 trial OnTARGET (NCT04538625). CycleCTCAE bCrofelemerControlPDiarrhea >= 2 consecutive days a168.069.6NS d265.272.2Maximum diarrhea grade a1Grade 0 c33.321.1NS eGrade 145.852.6Grade 216.721.1Grade 34.25.3Grade 40.00.02Grade 0 c38.117.60.0261 eGrade 152.441.2Grade 29.523.5Grade 30.017.6Grade 40.00.0Maximum diarrhea grade PRO f1Grade 0 c4.08.7NS eGrade 172.039.1Grade 216.043.5Grade 38.08.7Grade 40.00.02Grade 0 c9.10.00.0361 eGrade 181.866.7Grade 24.522.2Grade 34.511.1Grade 40.00.0aProvider assessedbCTCAE: NCI Common Terminology Criteria for Adverse Events v4.0cGrade 0: no diarrheadFisher''s exact testeWilcoxon rank sum testfPRO: Patient reported outcomes Citation Format: Paula R Pohlmann, Deena Graham, Tianmin Wu, Yvonne Ottaviano, Mahsa Mohebtash, Shweta Kurian, Donna McNamara, Filipa Lynce, Robert Warren, Asma Dilawari, Suman Rao, Candace Mainor, Nicole Swanson, Ming Tan, Claudine Isaacs, Sandra M. Swain. Halt-d: A randomized open label phase 2 study of crofelemer for the prevention of chemotherapy induced diarrhea (cid) in patients with breast cancer receiving trastuzumab, pertuzumab, and a taxane [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-18-09.

Background: The PALOMA clinical trials have shown that palbociclib (PAL) plus endocrine therapy (ET) is a safe and effective treatment for HR+/HER2- ABC. However, Black and Hispanic patients are underrepresented in clinical trials and the efficacy and safety of CDK4/6 inhibitors in these populations have not been reported. This post hoc analysis describes the efficacy and safety of PAL + ET in Black and Hispanic patients with HR+/HER2- ABC enrolled in the PALOMA trials. Methods: Postmenopausal patients were treated with letrozole (LET) + PAL on a 125 mg/d, 3/1 weekly schedule or LET alone (PALOMA-1) or LET + placebo (PBO; PALOMA-2) in the 1st line setting. In PALOMA-3, pre/postmenopausal patients were treated with fulvestrant (FUL) + PAL or PBO, with or without a luteinizing hormone releasing hormone agonist, in the ≥1st-line setting. Median progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Treatment-emergent adverse events (AEs) were evaluated according to the National Cancer Institute Common Terminology Criteria for AEs. Results: In PALOMA-2, Black and Hispanic patients comprised 9.8% of the population and had a median age of 58 yrs (PAL + LET arm; n=47) and 54 yrs (PBO + LET arm; n=18). Patients treated with PAL + LET had more visceral disease (62% vs 50%), lung involvement (51% vs 22%), de novo disease (45% vs 22%) and less prior systemics (55% vs 78%) compared to patients treated with PBO + LET. In PALOMA-3, Black and Hispanic patients comprised 9.2% of the population and had a median age of 57 yrs in both the PAL + FUL (n=29) and PBO + FUL (n=19) arms, with baseline characteristics being generally similar between the two arms. PAL+ ET prolonged median PFS in PALOMA-2 and -3 and prolonged median OS in PALOMA-3 compared to PBO + ET (Table 1). In pooled analyses of these patients from PALOMA 1-3 (n=120), the most common grade 3/4 AEs with PAL + ET were neutropenia (57.7%), leukopenia (24.4%), and anemia (3.8%), similar to the rates in the pooled PALOMA 1−3 overall as-treated population (Table 2). None of these grade 3/4 AEs were reported with PBO + ET in the Black/Hispanic subgroup (Table 2). Febrile neutropenia or pulmonary embolism were not reported in either arm. The rate of dose reduction due to AEs was 37.2% with PAL + ET, similar to the rates of dose reduction across the populations in the PALOMA trials (39.4%−42.2%). Conclusion: In Black/Hispanic pts with HR+/HER2- ABC enrolled in the PALOMA-2 and -3 trials, PAL + ET, in the first or greater lines, was an efficacious treatment option with no increased toxicity rates. These findings support the continued use of PAL + ET as a standard of care in these patients. Considering the substantial burden of breast cancer in Black and Hispanic patients, their relatively small representation in the PALOMA trial program highlights the need to increase diversity in clinical trials. Clinical trial identification: Pfizer (NCT00721409, NCT01740427, NCT01942135) Table 1.Median PFS and OS in the ITT population and Black and Hispanic patients from PALOMA-2 and -3Median (95% CI), moHazard Ratioa (95% CI)PAL + ETPBO + ETPAL + ET vs PBO + ETPFSPALOMA-2ITT [n=666]27.6 (22.4-30.3)14.5 (12.3-17.1)0.56 (0.46-0.69)Black and Hispanic [n=65]27.4 (13.8-NE)13.8 (8.1-30.7)0.61 (0.31-1.2)PALOMA-3ITT [n=521]11.2 (9.5-12.9)4.6 (3.5-5.6)0.50 (0.40-0.62)Black and Hispanic [n=48]11.1 (4.5-12.0)1.9 (1.8-5.7)0.56 (0.28-1.14)OSPALOMA-3ITT [n=521]34.8 (28.8-39.9)28.0 (23.5-33.8)0.79 (0.64-0.97)Black and Hispanic [n=48]35.6 (24.0-58.2)21.0 (14.3-35.4)0.48 (0.23-0.97)ET=endocrine therapy; ITT=intent to treat; NE=not estimable; OS=overall survival; PAL=palbociclib; PBO=placebo; PFS=progression free survival.aEstimated from an unstratified Cox proportional hazards model. Table 2.Grade 3/4 treatment emergent adverse events in the overall as-treated population and Black and Hispanic subgroup pooled from the PALOMA trialsPooled PALOMAPooled Black/HispanicAE, No. (%)PAL + ET (n=872)ETa (n=471)PAL + ET (n=78)PBO + ET (n=42)Any AE662 (75.9)110 (23.4)53 (67.9)12 (28.6)Neutropenia570 (65.4)5 (1.1)45 (57.7)0Leukopenia233 (26.7)2 (0.4)19 (24.4)0Anemia40 (4.6)9 (1.9)3 (3.8%)0Thrombocytopenia17 (1.9)1 (0.2)1 (1.3%)1 (2.4)Infections45 (5.2)12 (2.5)1 (1.3%)1 (2.4)AE=adverse event; ET=endocrine therapy; PAL=palbociclib; PBO=placebo.aEndocrine therapy with placebo (PALOMA-2 and 3) and without placebo (PALOMA-1). Citation Format: Claudine Isaacs, Reshma Mahtani, Filipa Lynce, Bethany Sleckman, Aurelio Castrellon, Sujith Kalmadi, Kathy Puyana Theall, Xin Huang, Eustratios Bananis, Hope S. Rugo. Efficacy and safety of palbociclib plus endocrine therapy in Black and Hispanic patients with hormone receptor positive/human epidermal growth factor receptor 2-negative advanced breast cancer (HR+/HER2- ABC) participating in the PALOMA trials [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-18-13.

Background Extending endocrine therapy from 5 to 10 years is recommended for women with invasive estrogen receptor (ER)‐positive breast cancers. We evaluated the benefits and harms of the five additional years of therapy. Methods An established Cancer Intervention and Surveillance Network (CISNET) model used a lifetime horizon with national and clinical trial data on treatment efficacy and adverse events and other‐cause mortality among multiple birth cohorts of U.S. women ages 25–79 newly diagnosed with ER+, non‐metastatic breast cancer. We assumed 100% use of therapy. Outcomes included life years (LYs), quality‐adjusted life years (QALYs), and breast cancer mortality. Results were discounted at 3%. Sensitivity analyses tested a 15‐year time horizon and alternative assumptions. Results Extending tamoxifen therapy duration among women ages 25–49 reduced the lifetime probability of breast cancer death from 11.9% to 9.3% (absolute difference 2.6%). This translates to a gain of 0.77 LYs (281 days)/woman (undiscounted). Adverse events reduce this gain to 0.44 QALYs and after discounting, gains are 0.20 QALYs (73 days)/woman. Extended aromatase inhibitor therapy in women 50–79 had small absolute benefits and gains were offset by adverse events (loss of 0.06 discounted QALYs). There were greater gains with extended endocrine therapy for women with node‐positive versus negative cancers, but only women ages 25–49 and 50–59 had a net QALY gain. All gains were reduced with less than 100% treatment completion. Conclusion The extension of endocrine therapy from 5 to 10 years modestly improved lifetime breast cancer outcomes, but in some women, treatment‐related adverse events may outweigh benefits., Simulation modeling was used to evaluate extended endocrine therapy for women with hormone receptor‐positive non‐metastatic breast cancer. Results indicate that extension of endocrine therapy from 5 to 10 years modestly improves life years in some groups but adverse events may outweigh benefits.

PURPOSE Recent studies, including a meta-analysis of 88 trials, have shown higher than expected rates of recurrence and death in hormone receptor–positive breast cancer. These new findings suggest a need to re-evaluate the use of risk-reducing medication to avoid invasive breast cancer and breast cancer death in high-risk women. METHODS We adapted an established Cancer Intervention and Surveillance Modeling Network model to evaluate the lifetime benefits and harms of risk-reducing medication in women with a ≥ 3% 5-year risk of developing breast cancer according to the Breast Cancer Surveillance Consortium risk calculator. Model input parameters were derived from meta-analyses, clinical trials, and large observational data. We evaluated the effects of 5 years of risk-reducing medication (tamoxifen/aromatase inhibitors) with annual screening mammography ± magnetic resonance imaging (MRI) compared with no screening, MRI, or risk-reducing medication. The modeled outcomes included invasive breast cancer, breast cancer death, side effects, false positives, and overdiagnosis. We conducted subgroup analyses for individual risk factors such as age, family history, and prior biopsy. RESULTS Risk-reducing tamoxifen with annual screening (± MRI) decreased the risk of invasive breast cancer by 40% and breast cancer death by 57%, compared with no tamoxifen or screening. This is equivalent to an absolute reduction of 95 invasive breast cancers, and 42 breast cancer deaths per 1,000 high-risk women. However, these drugs are associated with side effects. For example, tamoxifen could increase the number of endometrial cancers up to 11 per 1,000 high-risk women. Benefits and harms varied by individual characteristics. CONCLUSION The addition of risk-reducing medication to screening could further decrease the risk of breast cancer death. Clinical guidelines for high-risk women should consider integrating shared decision making for risk-reducing medication and screening on the basis of individual risk factors.

PURPOSE There is a need for industry-independent decision tools that integrate clinicopathologic features, comorbidities, and genomic information for women with node-negative, invasive, hormone receptor–positive, human epidermal growth factor receptor-2–negative (early-stage) breast cancer. METHODS We adapted an extant Cancer Intervention and Surveillance Modeling Network simulation model to estimate the 10-year risk of distant recurrence, breast cancer–specific mortality, other-cause mortality, and life-years gained with chemoendocrine versus endocrine therapy. We simulated outcomes for 1,512 unique patient subgroups based on all possible combinations of age, tumor size, grade, and comorbidity level; simulations were performed with and without 21-gene recurrence scores (RSs). Model inputs were derived from clinical trials, large US cohort studies, registry, and claims data. External validation was performed by comparing results to observed rates in two independent sources. We highlight results for one scenario where treatment choice may be uncertain. RESULTS Chemoendocrine versus endocrine therapy in a 65-69-year-old woman with a small (≤ 2 cm), intermediate-grade tumor, and mild comorbidities provides a 1.3% absolute reduction in 10-year distant recurrence risk, with 0.23 life-years gained. With these tumor features, a woman like this will have a 28% probability of having an RS 16-20, 18% RS 21-25, and 11% RS 26+. If testing is done, and her RS is 16-20, chemoendocrine therapy reduces 10-year distant recurrence risk to 1%, with 0.20 life-years gained, a similar result as without testing. The absolute benefits would increase to 4.8%-5.5% if the RS was 26+. The model closely reproduced observed rates in both independent data sets. CONCLUSION Our validated clinical decision tool is flexible, readily adaptable to include new therapies, and can support discussions about genomic testing and early breast cancer treatment.

ImportanceThe American Institute for Cancer Research and American Cancer Society regularly publish modifiable lifestyle recommendations for cancer prevention. Whether these recommendations have an impact on high-risk breast cancer survival remains unknown.ObjectiveTo investigate whether adherence to cancer prevention recommendations before, during, and 1 and 2 years after breast cancer treatment was associated with disease recurrence or mortality.Design, Setting, and ParticipantsThe Diet, Exercise, Lifestyles, and Cancer Prognosis Study (DELCaP) was a prospective, observational cohort study designed to assess lifestyles before diagnosis, during treatment, and at 1 and 2 years after treatment completion, implemented ancillary to the Southwest Oncology Group (SWOG) S0221 trial, a multicenter trial that compared chemotherapy regimens in breast cancer. Participants were chemotherapy-naive patients with pathologic stage I to III high-risk breast cancer, defined as node-positive disease with hormone receptor–negative tumors larger than 1 cm or any tumor larger than 2 cm. Patients with poor performance status and comorbidities were excluded from S0221. The study was conducted from January 1, 2005, to December 31, 2010; mean (SD) follow-up time for those not experiencing an event was 7.7 (2.1) years through December 31, 2018. The analyses reported herein were performed from March 2022 to January 2023.ExposureAn aggregated lifestyle index score comprising data from 4 time points and 7 lifestyles, including (1) physical activity, (2) body mass index, (3) fruit and vegetable consumption, (4) red and processed meat intake, (5) sugar-sweetened beverage consumption, (6) alcohol consumption, and (7) smoking. Higher scores indicated healthier lifestyle.Main Outcomes and MeasuresDisease recurrence and all-cause mortality.ResultsA total of 1340 women (mean [SD] age, 51.3 [9.9] years) completed the baseline questionnaire. Most patients were diagnosed with hormone-receptor positive breast cancer (873 [65.3%]) and completed some education beyond high school (954 [71.2%]). In time-dependent multivariable analyses, patients with highest vs lowest lifestyle index scores experienced a 37.0% reduction in disease recurrence (hazard ratio, 0.63; 95% CI, 0.48-0.82) and a 58.0% reduction in mortality (hazard ratio, 0.42; 95% CI, 0.30-0.59).Conclusions and RelevanceIn this observational study of patients with high-risk breast cancer, strongest collective adherence to cancer prevention lifestyle recommendations was associated with significant reductions in disease recurrence and mortality. Education and implementation strategies to help patients adhere to cancer prevention recommendations throughout the cancer care continuum may be warranted in breast cancer.

Background Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors, including palbociclib, are approved to treat hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer (ABC) and are associated with hematologic toxicity. African American women, who are underrepresented in CDK4/6 inhibitor clinical trials, may experience worse neutropenia because of benign ethnic neutropenia. The authors specifically investigated the hematologic safety of palbociclib in African American women with HR-positive/HER2-negative ABC. Methods PALINA was a single-arm, open-label, investigator-initiated study of palbociclib (125 mg daily; 21 days on and 7 days off) plus endocrine therapy (ET) in African American women who had HR-positive/HER2-negative ABC and a baseline absolute neutrophil count ≥1000/mm3 (ClinicalTrials.gov identifier NCT02692755). The primary outcome was the proportion of patients who completed 12 months of therapy without experiencing febrile neutropenia or treatment discontinuation because of neutropenia. Single nucleotide polymorphism analysis was used to assess Duffy polymorphism status. Results Thirty-five patients received ≥1 dose of palbociclib plus ET; 19 had a Duffy null polymorphism (cytosine/cytosine). There were no reports of febrile neutropenia or permanent study discontinuation because of neutropenia. Significantly more patients with the Duffy null versus the wild-type variant had grade 3 and 4 neutropenia (72.2% vs 23.1%; P = .029) and required a palbociclib dose reduction (55.6% vs 7.7%; P = .008). Patients with the Duffy null versus the wild-type variant had lower overall relative dose intensity (mean ± SD, 81.89% ± 15.87 and 95.67% ± 5.89, respectively; P = .0026) and a lower clinical benefit rate (66.7% and 84.6%, respectively). Conclusions These findings suggest that palbociclib is well tolerated in African American women with HR-positive/HER2-negative ABC. Duffy null status may affect the incidence of grade 3 neutropenia, dose intensity, and possibly clinical benefit.

BACKGROUND We proposed that a test for sensitivity to the adjuvant endocrine therapy component of treatment for patients with stage II-III breast cancer (SET2,3) should measure transcription related to estrogen and progesterone receptors (SETER/PR index) adjusted for a baseline prognostic index (BPI) combining clinical tumor and nodal stage with molecular subtype by RNA4 (ESR1, PGR, ERBB2, and AURKA). PATIENTS AND METHODS Patients with clinically high-risk, hormone receptor-positive (HR+), human epidermal growth factor receptor 2 (HER2)-negative (HR+/HER2-) breast cancer received neoadjuvant taxane-anthracycline chemotherapy, surgery with measurement of residual cancer burden (RCB), and then adjuvant endocrine therapy. SET2,3 was measured from pre-treatment tumor biopsies, evaluated first in an MD Anderson Cancer Center (MDACC) cohort (n = 307, 11 years' follow-up, U133A microarrays), cut point was determined, and then independent, blinded evaluation was carried out in the I-SPY2 trial (n = 268, high-risk MammaPrint result, 3.8 years' follow-up, Agilent-44K microarrays, NCI Clinical Trials ID: NCT01042379). Primary outcome measure was distant relapse-free survival. Multivariate Cox regression models tested prognostic independence of SET2,3 relative to RCB and other molecular prognostic signatures, and whether other prognostic signatures could substitute for SETER/PR or RNA4 components of SET2,3. RESULTS SET2,3 added independent prognostic information to RCB in the MDACC cohort: SET2,3 [hazard ratio (HR) 0.23, P = 0.004] and RCB (HR 1.77, P < 0.001); and the I-SPY2 trial: SET2,3 (HR 0.27, P = 0.031) and RCB (HR 1.68, P = 0.008). SET2,3 provided similar prognostic information irrespective of whether RCB-II or RCB-III after chemotherapy, and in both luminal subtypes. Conversely, RCB was most strongly prognostic in cancers with low SET2,3 status (MDACC P < 0.001, I-SPY2 P < 0.001). Other molecular signatures were not independently prognostic; they could effectively substitute for RNA4 subtype within the BPI component of SET2,3, but they could not effectively substitute for SETER/PR index. CONCLUSIONS SET2,3 added independent prognostic information to chemotherapy response (RCB) and baseline prognostic score or subtype. Approximately 40% of patients with clinically high-risk HR+/HER2- disease had high SET2,3 and could be considered for clinical trials of neoadjuvant endocrine-based treatment.

The AURORA US Metastasis Project was established with the goal to identify molecular features associated with metastasis. We assayed 55 females with metastatic breast cancer (51 primary cancers and 102 metastases) by RNA sequencing, tumor/germline DNA exome and low-pass whole-genome sequencing and global DNA methylation microarrays. Expression subtype changes were observed in ~30% of samples and were coincident with DNA clonality shifts, especially involving HER2. Downregulation of estrogen receptor (ER)-mediated cell-cell adhesion genes through DNA methylation mechanisms was observed in metastases. Microenvironment differences varied according to tumor subtype; the ER