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PURPOSE Given the heterogeneity and improvement in outcomes for metastatic breast cancer (MBC), we developed a staging system that refines prognostic estimates for patients with metastatic cancer at the time of initial diagnosis, de novo MBC (dnMBC), on the basis of survival outcomes and disease-related variables. METHODS Patients with dnMBC (2010-2016) were selected from the National Cancer Database (NCDB). Recursive partitioning analysis (RPA) was used to group patients with similar overall survival (OS) on the basis of clinical T category, grade, estrogen receptor (ER), progesterone receptor, human epidermal growth factor receptor 2, histology, organ system site of metastases (bone-only, brain-only, visceral), and number of organ systems involved. Three-year OS rates were used to assign a final stage: IVA: >70%, IVB: 50%-70%, IVC: 25 to RESULTS At a median follow-up of 52.9 months, the median OS of the original cohort (N = 42,467) was 35.4 months (95% CI, 34.8 to 35.9). RPA stratified patients into 53 groups with 3-year OS rates ranging from 73.5% to 5.7%; these groups were amalgamated into four stage groups: 3-year OS, A = 73.2%, B = 61.9%, C = 40.1%, and D = 17% (log-rank P < .001). After bootstrapping, the survival outcomes for the four stages remained significantly different (log-rank P < .001). This staging system was then validated using SEER data (N = 20,469) and a separate cohort from the NCDB (N = 7,645) (both log-rank P < .001). CONCLUSION Our findings regarding the heterogeneity in outcomes for patients with dnMBC could guide future revisions of the current American Joint Committee on Cancer staging guidelines for patients with newly diagnosed stage IV disease. Our findings should be independently confirmed.

PURPOSE Chemotherapy has not demonstrated benefit over adjuvant endocrine therapy alone for postmenopausal patients with node-positive breast cancer with a 21-gene breast recurrence score (RS) of 25 or below (RS ≤ 25). We tested whether combined results from RS and the sensitivity to endocrine therapy (SET2,3) index of endocrine-related transcription (SETER/PR) adjusted for baseline prognostic index (BPI) improve prognostic assessment, and whether SET2,3 predicted benefit from anthracycline-based chemotherapy. METHODS A blinded retrospective clinical validation of SET2,3 in two randomized treatment arms from the SWOG S8814 trial comparing adjuvant anthracycline-based chemotherapy followed by tamoxifen endocrine therapy for 5 years, versus tamoxifen alone. SET2,3 assay was calibrated and measured using whole-transcriptome RNA sequence of tumor samples already tested for RS. The primary end point was disease-free survival (DFS). RESULTS There were 106 events in 283 patients over a median follow-up of 8.99 years. Proportional hazards assumptions were met during the first 5 years only. SET2,3 index and RS were not correlated (r = –0.04) and were independently prognostic (SET2,3: hazard ratio [HR], 0.48 per unit; 95% CI, 0.34 to 0.68; P < .001; RS: HR, 1.28 per 10 units; 95% CI, 1.14 to 1.44; P < .001). SET2,3 index did not predict chemotherapy benefit (interaction P = .77). SET2,3 was high in 93/175 (53%) patients with RS ≤ 25 (concordant low-risk), with 5-year DFS 97%. SET2,3 was low in 55/108 (51%) patients with RS > 25 (concordant high-risk), with 5-year DFS 53%. Both components of SET2,3 index were prognostic after adjustment for RS: SETER/PR (HR, 0.65; 95% CI, 0.46 to 0.92) and BPI (HR, 0.45; 95% CI, 0.31 to 0.64). CONCLUSION SET2,3 index was not correlated with RS, demonstrated additive prognostic performance, and was not chemopredictive in this subset of patients from S8814. The SETER/PR and BPI components of SET2,3 each added prognostic information to RS.

PURPOSETo update key recommendations of the American Society of Clinical Oncology/College of American Pathologists estrogen (ER) and progesterone receptor (PgR) testing in breast cancer guideline.METHODSA multidisciplinary international Expert Panel was convened to update the clinical practice guideline recommendations informed by a systematic review of the medical literature.RECOMMENDATIONSThe Expert Panel continues to recommend ER testing of invasive breast cancers by validated immunohistochemistry as the standard for predicting which patients may benefit from endocrine therapy, and no other assays are recommended for this purpose. Breast cancer samples with 1% to 100% of tumor nuclei positive should be interpreted as ER positive. However, the Expert Panel acknowledges that there are limited data on endocrine therapy benefit for cancers with 1% to 10% of cells staining ER positive. Samples with these results should be reported using a new reporting category, ER Low Positive, with a recommended comment. A sample is considered ER negative if < 1% or 0% of tumor cell nuclei are immunoreactive. Additional strategies recommended to promote optimal performance, interpretation, and reporting of cases with an initial low to no ER staining result include establishing a laboratory-specific standard operating procedure describing additional steps used by the laboratory to confirm/adjudicate results. The status of controls should be reported for cases with 0% to 10% staining. Similar principles apply to PgR testing, which is used primarily for prognostic purposes in the setting of an ER-positive cancer. Testing of ductal carcinoma in situ (DCIS) for ER is recommended to determine potential benefit of endocrine therapies to reduce risk of future breast cancer, while testing DCIS for PgR is considered optional. Additional information can be found at www.asco.org/breast-cancer-guidelines .

6568 Background: Treatment with AI therapy for at least five years is recommended to reduce risk of cancer recurrence in postmenopausal women with hormone-positive breast cancer, but up to 50% prematurely discontinue their AI. Prior studies have demonstrated higher rates of nonadherence in older patients. Higher rates of comorbidities are also present in older patients, many of which require treatment with prescription medications. However, in prior studies, the impact of polypharmacy on AI persistence in older women has been variable. We evaluated the relationship between use of prescription and over-the-counter (OTC) medications and AI discontinuation in older women in a randomized controlled trial of AI therapy. Methods: In the Exemestane and Letrozole Pharmacogenetics (ELPh) trial, postmenopausal women with stage 0-III hormone-positive breast cancer were randomized to receive exemestane or letrozole and followed for two years. Prescription medication and OTC supplement usage was prospectively collected. Only enrolled participants at least 65 years of age were included in this analysis. Univariate and multivariable Cox proportional hazards models evaluated the association between baseline prescription medications, OTC medications, initial assigned AI medication, and time to discontinuation of initial AI. Results: 131 women at least 65 years old with baseline medication and OTC supplement information were identified. The average age was 70.4 (SD 5). 58 participants (44%) were randomized to exemestane and 73 (56%) to letrozole. 21% had previously received tamoxifen and 18% received taxane-based chemotherapy. The average number of prescription medications at AI initiation was 4.95, and 127 patients reported taking at least one. The average number of OTC medications was 3.23, and 107 patients reported taking at least one. There was no difference in number of prescription medications or OTC medications by study arm. As previously reported, exemestane was associated with premature discontinuation (HR 1.92 [95%CI 1.06-3.50], p = 0.032). Controlling for AI, the risk of discontinuation decreased by 12% for every additional prescription medication (HR 0.88 [95%CI 0.78-0.99], p = 0.038). OTC medication use was not significantly associated with AI duration. Conclusions: Increased prescription medication usage at AI initiation was associated with decreased risk of premature discontinuation of AI. Further research is needed to evaluate this interaction and identify characteristics that impact AI persistence in older women with breast cancer. Clinical trial information: NCT00228956.

10527 Background: Among patients with early-stage breast cancer, approximately 6-10% have a pathogenic germline variant (PGV) conferring inherited cancer predisposition. In contrast, few studies have explored the frequency and types of PGVs identified in patients with metastatic breast cancer (MBC); therefore, additional data is needed. Methods: From 2011-2020, 278 patients with MBC underwent fresh tumor biopsy and blood sample collection for paired tumor/normal DNA (targeted exome capture with analysis of 1700 genes) and RNA (tumor transcriptome) sequencing through the Michigan Oncology Sequencing (Mi-ONCOSEQ) program. Somatic and germline alterations were annotated and classified according to degree of clinical actionability with results returned to treating oncologists. Retrospective chart review was performed to determine if: 1) a PGV was identified prior to Mi-ONCOSEQ testing, 2) patients met National Comprehensive Cancer Network (NCCN) guideline criteria for genetic testing on the basis of personal or family cancer history and 3) patients received subsequent therapy informed by a PGV. Results: Forty-eight of the 278 patients (17.3%) had at least one PGV identified, with a total of 50 PGVs identified in this cohort. Only twelve of these PGVs (24%) had been identified prior to Mi-ONCOSEQ testing. The most frequent PGVs identified were in CHEK 2 (n = 9, 18%), MUTYH (n = 6, 12%), BRCA 1 (n = 5, 10%), BRCA2 (n = 5, 10%), ATM (n = 4, 8%) and PALB2 (n = 4, 8%). Somatic loss of heterozygosity events (LOH) occurred in 30 of the 50 cases with PGVs identified (60%). LOH events were observed in 83.3% of BRCA1, BRCA2, ATM and PALB2 PGVs, but were less frequently observed with CHEK2 (33.3%) and MUTYH (66.7%). Two hundred sixteen out of 278 patients (77.7%) in this cohort met NCCN criteria for genetic testing, although six patients with a PGV identified (CHEK2: n = 5; MUTYH: n = 1) did not meet NCCN criteria. Twenty-nine PGVs identified (58%) had potential therapeutic relevance and 11 patients (22.9%) received targeted therapy based on the PGV. Conclusions: The frequency of PGVs identified in this cohort is nearly double the frequency reported for patients with early-stage disease, suggesting that certain PGVs may confer worse prognosis. CHEK2, the most frequently identified PGV, was less likely to have an identifiable LOH event. The direct role of CHEK2 PGVs in tumor pathogenesis is uncertain, but other mechanisms of silencing the wild type allele must be considered. Despite the majority of patients meeting NCCN criteria for genetic testing, those with PGVs in CHEK2 were less reliably identified by this mechanism. The majority of PGVs identified were of potential therapeutic relevance, supporting the recommendation for genetic testing in all patients with MBC.

Since the beginning of its guidelines program in 1993, ASCO has continually sought ways to produce a greater number of guidelines while maintaining its commitment to using the rigorous development methods that minimize the biases that threaten the validity of practice recommendations. ASCO is implementing a range of guideline development and implementation innovations. In this article, we describe innovations that are designed to (1) integrate consideration of multiple chronic conditions into practice guidelines; (2) keep more of its guidelines current by applying evolving signals or (more) rapid, for-cause updating approaches; (3) increase the number of high-quality guidelines available to its membership through endorsement and adaptation of other groups’ products; (4) improve coverage of its members’ guideline needs through a new topic nomination process; and (5) enhance dissemination and promote implementation of ASCO guidelines in the oncology practice community through a network of volunteer ambassadors. We close with a summary of ASCO’s plans to facilitate the integration of data from its rapid learning system, CancerLinQ, into ASCO guidelines and to develop tactics through which guideline recommendations can be embedded in clinicians’ workflow in digital form. We highlight the challenges inherent in reconciling the need to provide clinicians with more interactive, point-of-care guidance with ASCO’s abiding commitment to methodologic rigor in guideline development.

Purpose To provide recommendations on appropriate use of breast tumor biomarker assay results to guide decisions on adjuvant systemic therapy for women with early-stage invasive breast cancer. Methods A literature search and prospectively defined study selection sought systematic reviews, meta-analyses, randomized controlled trials, prospective-retrospective studies, and prospective comparative observational studies published from 2006 through 2014. Outcomes of interest included overall survival and disease-free or recurrence-free survival. Expert panel members used informal consensus to develop evidence-based guideline recommendations. Results The literature search identified 50 relevant studies. One randomized clinical trial and 18 prospective-retrospective studies were found to have evaluated the clinical utility, as defined by the guideline, of specific biomarkers for guiding decisions on the need for adjuvant systemic therapy. No studies that met guideline criteria for clinical utility were found to guide choice of specific treatments or regimens. Recommendations In addition to estrogen and progesterone receptors and human epidermal growth factor receptor 2, the panel found sufficient evidence of clinical utility for the biomarker assays Oncotype DX, EndoPredict, PAM50, Breast Cancer Index, and urokinase plasminogen activator and plasminogen activator inhibitor type 1 in specific subgroups of breast cancer. No biomarker except for estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 was found to guide choices of specific treatment regimens. Treatment decisions should also consider disease stage, comorbidities, and patient preferences.

538 Background: Letrozole is a non-steroidal aromatase inhibitor (AI) used to treat hormone receptor positive (HR+) breast cancer. Variability in letrozole efficacy and toxicity may be partially attributable to variable systemic drug exposure, which may be influenced by germline variants in the enzymes responsible for letrozole metabolism, including CYP2A6. The objective of this genome-wide association study (GWAS) was to identify genetic variants that affect steady state letrozole concentrations. Methods: The Exemestane and Letrozole Pharmacogenetics (ELPh) Study randomized 503 post-menopausal patients with HR+ non-metastatic breast cancer to exemestane or letrozole treatment. Germline DNA was collected pre-treatment and blood samples were collected after 1 or 3 months of treatment to measure steady-state letrozole concentration via HPLC/MS. Genome-wide genotyping was conducted on the Infinium Global Screening Array to the Haplotype Reference Panel ( > 2 million variants). The association of each polymorphism with square-root transformed letrozole concentration was tested in self-reported white patients via linear regression using the standard alpha for genome-wide significance (α = 5x10−8) assuming an additive genetic model and correcting for age and body mass index. Results: 228 patients met inclusion criteria and had all necessary data. Each variant allele of rs7937 a patient carried increased their letrozole concentration ~22.9 ng/mL (standard error = 4.01, p = 3.51x10−8, Table) and this variant explained 13% of the variability in letrozole concentrations. rs7937 is located ~50 kB upstream of CYP2A6, and has previously been identified in GWAS of CYP2A6-related phenotypes, including nicotine metabolism and lung cancer. Conclusions: This GWAS confirmed that steady-state letrozole concentrations are partially determined by germline polymorphisms affecting CYP2A6 activity. If letrozole concentrations affect treatment efficacy or toxicity, CYP2A6 genetics may be useful to individualize letrozole dosing to improve clinical outcomes in patients with HR+ breast cancer. [Table: see text]

1001 Background: PARP inhibitors(i) are effective in BRCA-mutation -associated metastatic breast cancer(MBC). However, there are no studies evaluating PARPi + platin chemotherapy in BRCA wild-type(wt) TNBC. Approximately 1/2 of BRCAwt TNBC demonstrate homologous recombination deficiency (HRD) resulting in a BRCA-like phenotype which might render them sensitive to PARPi. S1416 compared the efficacy of cisplatin plus PARPi veliparib (Vel) or placebo (P) in 3 groups of MBC: gBRCA+; BRCA-like; and non-BRCA-like. Methods: Patients (pts) with metastatic TNBC or g BRCA1/2-associated MBC, who had received < 1 line of prior therapy were treated with cisplatin (75mg/m2) plus Vel or P (300 mg po BID days 1-14), every 3 weeks. All pts underwent central gBRCA testing. A priori established multipronged biomarker panel was used to classify BRCAwt pts into BRCA-like and non-BRCA-like groups, and included myChoice HRD score, somatic BRCA1/2 mutations, BRCA1 methylation and non- BRCA1/2 HR germline mutations. Primary end-point was progression-free survival (PFS) in the three pre-defined groups; secondary end-points included objective response rate (ORR), overall survival (OS), toxicity. Results: 323/335 randomized pts were eligible for efficacy evaluation; 31% had received 1 prior chemotherapy for MBC. 248 pts were classified into the three groups: (1) 37 gBRCA+ (2) 101 BRCA-like; (3) 110 non- BRCA-like. Remaining 75 could not be classified due to missing biomarker information. In the gBRCA+ group (which reached 62% of its projected accrual), numerically better PFS was noted with Vel compared to P (HR=0.64; p=0.26) though this difference was not statistically significant. In BRCA-like group improved PFS was noted with Vel vs P (median PFS 5.7 vs 4.3 months HR=0.58; p=0.023, 1 years PFS 20% vs 7%). Numerically better OS (median OS 13.7 vs 12.1 months, HR=0.66; p=0.14) and ORR (45% vs 35%, p=0.38) were noted with Vel vs P in BRCA-like group. Non-BRCA-like group did not show benefit of veliparib for PFS (HR=0.85; p=0.43) neither did the unclassified group (HR=0.97). Grade 3/4 neutropenia (46% vs 19%) and anemia (23% vs 7%) occurred at higher frequency in Vel arm compared to P. Conclusions: Addition of Vel to cisplatin significantly improved PFS and showed a trend towards improved OS for BRCA-like advanced TNBC. Integral biomarkers used in this study identified a subgroup of BRCAwt TNBC who benefited from addition of PARPi to cisplatin; platinum plus PARPi combination should be explored further in BRCA-like TNBC. Clinical trial information: NCT02595905 .

Purpose Increased circulating tumor cells (CTCs; five or more CTCs per 7.5 mL of whole blood) are associated with poor prognosis in metastatic breast cancer (MBC). A randomized trial of patients with persistent increase in CTCs tested whether changing chemotherapy after one cycle of first-line chemotherapy would improve the primary outcome of overall survival (OS). Patients and Methods Patients with MBC who did not have increased CTCs at baseline remained on initial therapy until progression (arm A). Patients with initially increased CTCs that decreased after 21 days of therapy remained on initial therapy (arm B). Patients with persistently increased CTCs after 21 days of therapy were randomly assigned to continue initial therapy (arm C1) or change to an alternative chemotherapy (arm C2). Results Of 595 eligible and evaluable patients, 276 (46%) did not have increased CTCs (arm A). Of those with initially increased CTCs, 31 (10%) were not retested, 165 were assigned to arm B, and 123 were randomly assigned to arm C1 or C2. No difference in median OS was observed between arm C1 and C2 (10.7 and 12.5 months, respectively; P = .98). CTCs were strongly prognostic. Median OS for arms A, B, and C (C1 and C2 combined) were 35 months, 23 months, and 13 months, respectively (P < .001). Conclusion This study confirms the prognostic significance of CTCs in patients with MBC receiving first-line chemotherapy. For patients with persistently increased CTCs after 21 days of first-line chemotherapy, early switching to an alternate cytotoxic therapy was not effective in prolonging OS. For this population, there is a need for more effective treatment than standard chemotherapy.

e12027 Background: Peripheral neuropathy (PN) is a severe, dose-limiting toxicity of paclitaxel that occurs in up to 25% of patients and can lead to permanent loss of balance and manual dexterity. Due to the lack of effective strategies for PN prevention or treatment, there is a critical need to identify predictive risk factors for paclitaxel-induced PN. Vitamin insufficiencies are known risk factors for PN in other disease states. However, the effect of vitamin insufficiency on paclitaxel-induced PN has not been adequately investigated. Methods: Baseline levels of vitamin D and other nutrients (vitamin B, homocysteine, folate) were measured, and PN was assessed weekly in an observational trial of patients receiving paclitaxel 80 mg/m2 for 12 weeks for non-metastatic breast cancer (NCT0233811). Nutrient levels were measured by Michigan Medicine and insufficiency defined by institutional standards (vitamin D insufficiency < 20 ng/mL). In the primary analysis, the maximum increase from baseline in the 8-item sensory subscale (ΔCIPN8) of the EORTC CIPN20, a validated patient-reported PN assessment tool, was compared in nutrient insufficient and sufficient patients. The effect of vitamin insufficiencies on PN-induced treatment disruptions (dose decrease, delay, or discontinuation) was conducted as a secondary analysis. Results: Only vitamin D insufficiency was identified in enough patients for analysis (15/37 = 41%). Vitamin D insufficient patients reported a greater mean (+/- SD) ΔCIPN8 (36.39 ±22.8) than vitamin D sufficient patients (16.29 ±16.3) (p = 0.003). However, the increase in treatment disruption for vitamin D insufficient patients was not significant (OR = 2.98, 95% CI [0.72, 12.34], p = 0.16). Conclusions: Paclitaxel-treated patients who were vitamin D insufficient at baseline had greater increases in patient-reported PN. If validated in larger studies, vitamin D insufficiency may be a clinically translatable, modifiable risk factor that can be used to prevent paclitaxel-induced PN in patients with non-metastatic breast cancer.

503 Background: TAILORx established that endocrine therapy (ET) alone is non-inferior to adjuvant chemotherapy (CT) plus ET in EBC and a 21-gene RS of 11-25, with some benefit if ≤50 years (y) with RS 16-25 (PMID: 29860917). We evaluated whether clinical risk (tumor size & histologic grade) provides additional prognostic information to RS, a secondary trial objective. Methods: Clinical risk by was assessed by Adjuvant! (version 8.0) using MINDACT criteria (PMID 27557300), defined as low clinical risk (LCR - tumor ≤3 cm and low grade, 50). The RS was 26-100 in 9% of LCR and 27% of HCR patients, with similar distributions by age. Although LCR/HCR provided additional prognostic information in each RS category for iDFS, including RS 0-10 (9-year rates 86.7% vs. 75.7% LCR vs. HCR), 11-25 (85.4% vs. 78.9%), and 26-100 (82.0% vs. 70.4%), iDFS rates were similar irrespective of CT (no vs. yes) in the entire RS 11-25 cohort whether LCR (85.8% vs. 85.1%) or HCR (79.8% vs. 77.9%). DRFI rates were also similar irrespective of CT in the RS 11-25 cohort or > 50y group whether LCR (96.0% vs. 96.1% overall; 96.5% vs. 96.0% > 50y) or HCR (92.3% vs. 89.9% overall; 91.7% vs. 90.7% >50y). For women ≤50y, the absolute reduction in distant recurrence from CT with a RS of 16-20 (N=923) was -0.2% (standard error [SE]±2.1%) for LCR vs. 6.5%(SE±4.9%) for HCR (vs. 1.6%[SE±1.9%] overall), whereas for a RS 21-25 (N=492) it was 6.4% (SE±4.9%) for LCR vs. 8.6% (SE±6.2%) for HCR (vs. 6.5%[SE±3.7%] overall). Conclusions: Clinical risk stratification provides additional prognostic information to the 21-gene RS, but not prediction of CT benefit in the overall TAILORx population or those > 50y, and facilitates more refined estimates of absolute CT benefit for women ≤50y with a RS 16-25. (Funded by National Cancer Institute, Komen Foundation, Breast Cancer Research Foundation). Clinical trial information: NCT00310180.

532 Background: Chemotherapy induced peripheral neuropathy (CIPN) is a common, debilitating paclitaxel side effect that has been primarily attributed to cumulative systemic paclitaxel exposure. Paclitaxel dose-adjustment to achieve target systemic exposure decreases but does not eliminate severe CIPN, suggesting some patients are inherently CIPN-sensitive. Ephrin ( EPHA) polymorphisms have been reported to increase CIPN occurrence (Baldwin 2012, Leandro-Garcia 2013, Boora 2016) but replication has been challenging, perhaps due to the inability to isolate CIPN-sensitivity by accounting for systemic exposure differences. The study purpose was to determine if EPHA genetic variants previously associated with CIPN occurrence are associated with CIPN-sensitivity. Methods: PN was assessed at baseline and weekly using the 8-item sensory subscale (CIPN8) of the patient-reported EORTC CIPN20 in patients receiving paclitaxel 80 mg/m2 weekly x 12. EPHA4, EPHA5, EPHA6, and EPHA8 were sequenced in germline DNA. Associations with higher PN-sensitivity were tested for three genetic models (total variants, coding variants, and rs7349683) by incorporating genetics into previously published CIPN8 predictive models that included measured paclitaxel exposure. Significant associations were tested for association with higher risk of PN-related treatment disruption (i.e. dose decrease, delay, or discontinuation). Results: In the 59 included patients, carrying EPHA5 rs7349683 was associated with greater CIPN sensitivity (beta coefficient: 0.40, standard error: 0.14, p = 0.005), indicating these patients had a greater increase in CIPN8 during treatment than would be predicted based on cumulative paclitaxel exposure. Rs7349683 was not associated with increased PN-induced treatment disruption, perhaps due to the low number of events (n = 19). Conclusions: Using a novel approach that isolates CIPN-sensitivity by accounting for measured paclitaxel exposure, our results provide further evidence that EPHA5 rs7349683 may be a promising marker for CIPN. If additional validation studies confirm this association, genetic testing could enable personalized treatment strategies to prevent CIPN in patients with breast cancer.

More than 90% of cancer deaths result from the development of hematogenously disseminated metastasis. The presence of circulating tumor cells (CTCs) in patients with cancer was first reported in 1869. 1 More recently, methods have been developed to detect, isolate, and characterize CTCs in multiple different malignancies that arise in solid organs. 2 The most widely used method, designated CellSearch (Veridex, Raritan, NJ), relies on immunomagnetic capture of CTCs using antibodies against the epithelial cell adhesion molecule (EpCam), which is expressed on the cell surface of many epithelial malignancies, followed by additional characterization with 4,6-diamidino-2-phenylindole staining (to

LBA1 Background: In hormone receptor (HR)-positive, HER2-negative, axillary node (AN)-negative breast cancer, the 21-gene expression assay (Oncotype DX Recurrence Score [RS]) is prognostic for distant recurrence, prognostic for low recurrence with endocrine therapy alone if low (0-10), and predictive of chemotherapy benefit if high (26 or higher). We performed a prospective, randomized trial of endocrine therapy (ET) versus chemoendocrine therapy (CET) in women with a mid-range RS of 11-25. Methods: Eligibility criteria included women 18-75 years of age with HR-positive, HER2-negative, axillary node (AN)-negative breast cancer and tumors 1.1-5.0 cm in size (or 0.6-1.0 cm and int/high grade) and agreed to have chemotherapy assigned or randomized based on the RS. Women with a mid-range RS (11-25) were randomized to receive ET or CET. The primary endpoint was invasive disease-free survival (iDFS), and the trial was designed to show non-inferiority for ET alone by not rejecting equality (hazard ratio [HR] margin up to 1.322 for omission of chemotherapy, 1-sided type I error rate 10%, type II error rate 5%). The target sample size was adjusted to compensate for non-adherence to randomized treatment, and the protocol-specified final analysis was triggered after 835 iDFS events. Results: Of the 10,253 eligible women enrolled between 4/7/06-10/6/10, 6711 (65.5%) had a RS of 11-25 and adequate information. There were 836 iDFS events at final analysis with a median followup of 90 months. ET was non-inferior to CET for iDFS (HR 1.08, 95% confidence intervals [CI] 0.94, 1.24, p=0.26) in the intention-to-treat (ITT) population. ET was also non-inferior for distant recurrence-free interval (DRFI; HR 1.03, p=0.80), recurrence-free interval (RFI; HR 1.12, p=0.28), and overall survival (OS; HR 0.97, p=0.80). Nine year rates were similar for iDFS (83.3% vs. 84.3%), DRFI (94.5% vs. 95.0%), RFI (92.2% vs. 92.9%), and OS (93.9% vs. 93.8%). Recurrence accounted for 338 (41.6%) the first iDFS event, of which 199 (23.8%) were distant recurrences. Treatment interaction tests were significant for age (iDFS p=0.03; RFI p= 0.02), but not menopause, tumor size, grade, or RS (continuous or RS 11-15, 16-20, 21-25). Conclusions: In women with HR-positive, HER2-negative, AN-negative breast cancer and a RS of 11-25, adjuvant ET was not inferior to CET in the ITT analysis. (Funded by NCI, BCRF, and Komen Foundation.) Clinical trial information: NCT00310180.

543Background: Three aromatase inhibitors (AI), the steroid exemestane, and the azoles anastrozole and letrozole, are effective in the treatment of estrogen receptor positive (ER+) breast cancer by preventing biosynthesis of estrogens including estradiol (E2), estrone (E1), and estrone-sulfate (E1S) in postmenopausal women. OATP1B1, encoded by SLCO1B1, transports E1S into the liver for desulfation to active E1. Women carrying the low-expression SLCO1B1 rs4149056 single nucleotide polymorphism (SNP) have higher E1-conjugate levels (Dudenkov Breast Cancer Res Treat 2017). We hypothesized that patients carrying this SNP would have increased E1S at baseline, and this E1S reserve could resupply E1 and E2 resulting in detectable estrogen levels during AI treatment. Methods: Five hundred postmenopausal women with ER+ breast cancer were randomized 1:1 to either exemestane 25 mg/day or letrozole 2.5 mg/day. Plasma estrogen concentrations were measured prior to and after 3 months of AI treatment using LC/MS/MS (LLO...

Purpose Myeloperoxidase (MPO) generates reactive oxygen species and also activates xenobiotics . In a rigorous clinical trial (Southwest Oncology Group SWOG-8897), we examined relationships between genotypes and disease-free survival (DFS) among women treated for breast cancer, as well as those who did not receive adjuvant chemotherapy. Patients and Methods Patients were assigned to risk groups according to standard prognostic features; the low-risk group (n = 753 genotyped) received follow-up only, and the high-risk group (n = 401 genotyped) was randomly assigned to adjuvant cyclophosphamide, methotrexate, and fluorouracil (CMF) or cyclophosphamide, doxorubicin, and fluorouracil (CAF), with or without tamoxifen. DNA from archived normal lymph node tissue was genotyped, and Cox proportional hazard models were used to calculate DFS associated with MPO genotypes. Results Among women in the treatment arm, those with MPO G alleles had more than a two-fold reduction in hazard of recurrence (adjusted hazard ratio [HR] for GA genotypes, 0.51; 95% CI, 0.21 to 0.99; HR for GG genotypes, 0.41; 95% CI, 0.21 to 0.77). Effects were greatest among women who were further randomly assigned to tamoxifen (HR for GA genotypes, 0.28; 95% CI, 0.12 to 0.69; HR for GG genotypes, 0.19; 95% CI, 0.08 to 0.45). There were no significant associations between genotypes and DFS among women in the untreated arm, and relationships between genotypes and DFS did not differ by CAF or CMF. Conclusion These results, observed in two independent study populations, indicate that high-activity MPO genotypes are associated with better survival among women receiving cyclophosphamide-containing therapy, particularly when followed by tamoxifen therapy. MPO can be inhibited and/or upregulated by commonly used drugs; thus, our findings merit further investigation for optimization of therapeutics for breast cancer.

Purpose Amplification and deletion of the TOP2A gene have been reported as positive predictive markers of response to anthracycline-based therapy. We determined the status of the HER2 and TOP2A genes in a large cohort of breast cancer patients treated with adjuvant doxorubicin (A) and cyclophosphamide (C). Patients and Methods TOP2A/CEP17 and HER2/CEP17 fluorescent in situ hybridization (FISH) were performed on tissue microarrays (TMAs) constructed from 2,123 of the 3,125 women with moderate-risk primary breast cancer who received equivalent doses of either concurrent adjuvant chemotherapy with A plus C (n = 1,592) or sequential A followed by C (n = 1,533). Results An abnormal TOP2A genotype was identified for 153 (9.4%) of 1,626 patients (4.0% amplified; 5.4% deleted). An abnormal HER2 genotype was identified for 303 (20.4%) of 1,483 patients (18.8% amplified; 1.6% deleted). No significant differences in either overall survival (OS) or disease-free survival (DFS) were identified for TOP2A. In univariate analysis, OS and DFS rates were strongly and adversely associated only with higher levels of HER2 amplification (ratio ≥ 4.0). Survival was not associated with low-level HER2 amplification (ratio ≥ 2; OS hazard ratio [HR], 1.14; P = .39; DFS HR, 1.07; P = .62), but it was associated for a ratio ≥ 4 (OS HR, 1.45; P = .03; DFS HR, 1.38; P = .033), in which analysis was adjusted for menopausal status, hormone receptor status, treatment, number of positive nodes, and tumor size. Conclusion In this population of patients with early-stage breast cancer who were treated with adjuvant AC chemotherapy, TOP2A abnormalities were not associated with outcome. HER2 high-level amplification was a prognostic marker in anthracycline-treated patients.

Purpose We have demonstrated that patients with HER2-amplified tumors derive more benefit from higher doses of doxorubicin-containing chemotherapy (cyclophosphamide, doxorubicin, and fluorouracil [CAF]). Because topoisomerase IIα (Topo-IIα) is a target for doxorubicin and is coamplified in 20% to 50% of HER2-amplified tumors, we postulated that Topo-IIα copy number might account for the benefit from CAF dose escalation in HER2-positive tumors. To address this hypothesis, we examined Topo-IIα and HER2 copy number, CAF dose, and clinical outcomes in Cancer and Leukemia Group B (CALGB) 8541. Patients and Methods Topo-IIα and HER2 copy number were measured by fluorescent in situ hybridization (FISH) using a triple-probe system, which includes Topo-IIα, HER2, and chromosome 17 (CEP17). Topo-IIα and/or HER2 were classified as amplified (≥ two copies/CEP17, deleted (≤ 0.67 copies/CEP17) and normal copy number (> .67 to < 2.0 copies/CEP17). Results Topo-IIα/HER2/CEP17 measurement was successful in 624 of 687 cases. HER2 was amplified in 117 cases (19%). Topo-IIα was amplified in 41 cases (7%) and deleted in 69 cases (11%). Topo-IIα amplification was highly correlated with HER2 amplification (39 of 41; P < .0001), HER2 by immunohistochemistry, and by dual-probe FISH. Topo-IIα was deleted in both the HER2-amplified (30 of 69; 43%), normal (22 of 69; 32%) and HER2-deleted tumors (17 of 69; 25%). Although Topo-IIα–amplified tumors were nearly always HER2 amplified, these tumors did not receive benefit from increasing the dose of CAF (P = .15). Conclusion The correlative companion study CALGB 8541-150013 does not support the hypothesis that Topo-IIα amplification is the mechanism behind benefit from increased dose of anthracyclines in HER2-positive breast cancer.

Purpose An American Society of Clinical Oncology (ASCO) provisional clinical opinion (PCO), offers timely clinical direction to ASCO's oncologists following publication or presentation of potentially practice-changing data from major studies. This PCO addresses the utility of KRAS gene mutation testing in patients with metastatic colorectal carcinoma to predict response to anti–epidermal growth factor receptor (anti-EGFR) monoclonal antibody (MoAb) therapy with cetuximab or panitumumab (see Note). Clinical Context Recent results from phase II and III clinical trials demonstrate that patients with metastatic colorectal cancer benefit from therapy with monoclonal antibodies directed against the EGFR, when used either as monotherapy or combined with chemotherapy. Retrospective subset analyses of the data from these trials strongly suggest that patients who have KRAS mutations detected in codon 12 or 13 do not benefit from this therapy. Recent Data Five randomized controlled trials of cetuximab or panitumumab have evaluated outcomes for patients with metastatic colorectal carcinoma in relation to KRAS mutational status as no mutation detected (wild type) or abnormal (mutated). Another five single-arm studies have retrospectively evaluated tumor response according to KRAS status. Provisional Clinical Opinion Based on systematic reviews of the relevant literature, all patients with metastatic colorectal carcinoma who are candidates for anti-EGFR antibody therapy should have their tumor tested for KRAS mutations in a CLIA-accredited laboratory. If KRAS mutation in codon 12 or 13 is detected, then patients with metastatic colorectal carcinoma should not receive anti-EGFR antibody therapy as part of their treatment. NOTE. ASCO's provisional clinical opinions (PCOs) reflect expert consensus based on clinical evidence and literature available at the time they are written, and are intended to assist physicians in clinical decision-making and identify questions and settings for further research. Due to the rapid flow of scientific information in oncology, new evidence may have emerged since the time a PCO was submitted for publication. PCOs are not continually updated and may not reflect the most recent evidence. PCOs cannot account for individual variation among patients, and cannot be considered inclusive of all proper methods of care or exclusive of other treatments. It is the responsibility of the treating physician or other health care provider, relying on independent experience and knowledge of the patient, to determine the best course of treatment for the patient. Accordingly, adherence to any PCO is voluntary, with the ultimate determination regarding its application to be made by the physician in light of each patient's individual circumstances. ASCO PCOs describe the use of procedures and therapies in clinical practice and cannot be assumed to apply to the use of these interventions in the context of clinical trials. ASCO assumes no responsibility for any injury or damage to persons or property arising out of or related to any use of ASCO's PCOs, or for any errors or omissions.

Purpose Hot flashes are common and frequently lead to drug discontinuation among women prescribed tamoxifen. We determined whether genetic polymorphisms in estrogen receptors (ESRs) α and β (ESR1 and ESR2, respectively) are associated with tamoxifen-induced hot flashes. Patients and Methods We determined ESR1 PvuII and XbaI and ESR2-02 genotypes in 297 women who were initiating tamoxifen. One-week hot flash diaries were collected to calculate a hot flash score (frequency × severity) before and 1, 4, 8, and 12 months after starting tamoxifen. Results Approximately 80% of 297 participants reported hot flashes before or during the first year of tamoxifen. After 4 months of tamoxifen, premenopausal women who did not receive adjuvant chemotherapy had a four-fold increase in hot flash score (from 5.9 to 23.6; P = .003) compared with a 1.17-fold increase (from 19.6 to 23; P = .34) in those who received chemotherapy. In premenopausal women, increased number of ESR1 PvuII and XbaI CG alleles was associated with higher baseline hot flash scores compared with those who had other haplotypes (P = .0026). At 4 months, postmenopausal women with ESR1 PvuII CC and ESR2-02 GG genotypes had 4.6 times increases in hot flash scores than other postmenopausal women (56 v 12; P = .0007). Women who had the ESR2-02 AA genotype were significantly less likely to experience tamoxifen-induced hot flashes than women who carried at least one ESR-02 G allele (hazard ratio, 0.26; 95% CI, 0.10 to 0.63; P = .001). Conclusion Knowledge of menopausal status, prior chemotherapy, and ESR genotype may help predict which women are most likely to suffer hot flashes during tamoxifen treatment.

Purpose ErbB-2 (human epidermal growth factor receptor 2) overexpression may be predictive of relative resistance and/or sensitivity to specific chemotherapeutic agents. Results from a previous study from the Cancer and Leukemia Group B (CALGB 8541) demonstrated an interaction between ErbB-2 and increasing dose of adjuvant cyclophosphamide, doxorubicin, and fluorouracil (CAF) chemotherapy. Other studies have suggested that evaluation of the phosphorylated/activated form of ErbB-2 might be more precise in defining the impact of ErbB-2 in breast cancer. We have evaluated tumor tissue sections from CALGB 8541 patients to determine whether the interaction of ErbB-2 with CAF dose is dependent on ErbB-2 activation state, and whether phosphorylated ErbB-2 is an adverse prognostic factor in patients treated with CAF. Patients and Methods Patients were randomly assigned to one of three dosing regimens of CAF. Paraffin samples from 992 of 1,572 patients who participated in CALGB 8541 were available. Of the 570 tumors with any staining for ErbB-2, 488 had tissue available for assay for phosphorylated ErbB-2, which was performed by immunohistochemistry. Results Of 910 total assessable cases, 112 of 488 ErbB-2-positive cases (23%) stained positively for phosphorylated ErbB-2. The previously described interaction of dosing regimen of CAF with ErbB-2 was not dependent on phosphorylation status of ErbB-2. Conclusion Monitoring phosphorylation of ErbB-2 with an antiphospho-ErbB-2 antibody did not add further precision to identifying those patients most likely to benefit from increased dose of anthracycline-based adjuvant chemotherapy. Favorable outcomes are observed in ErbB-2-overexpressing patients treated with high-dose CAF regardless of ErbB-2 phosphorylation state.

PurposeTo update the recommendations for the use of tumor marker tests in the prevention, screening, treatment, and surveillance of breast cancer.MethodsFor the 2007 update, an Update Committee composed of members from the full Panel was formed to complete the review and analysis of data published since 1999. Computerized literature searches of MEDLINE and the Cochrane Collaboration Library were performed. The Update Committee's literature review focused attention on available systematic reviews and meta-analyses of published tumor marker studies. In general, significant health outcomes (overall survival, disease-free survival, quality of life, lesser toxicity, and cost-effectiveness) were used for making recommendations.Recommendations and ConclusionsThirteen categories of breast tumor markers were considered, six of which were new for the guideline. The following categories showed evidence of clinical utility and were recommended for use in practice: CA 15-3, CA 27.29, carcinoembryonic antigen, estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2, urokinase plasminogen activator, plasminogen activator inhibitor 1, and certain multiparameter gene expression assays. Not all applications for these markers were supported, however. The following categories demonstrated insufficient evidence to support routine use in clinical practice: DNA/ploidy by flow cytometry, p53, cathepsin D, cyclin E, proteomics, certain multiparameter assays, detection of bone marrow micrometastases, and circulating tumor cells.

Purpose To update the recommendations for the use of tumor marker tests in the prevention, screening, treatment, and surveillance of gastrointestinal cancers. Methods For the 2006 update, an update committee composed of members from the full Panel was formed to complete the review and analysis of data published since 1999. Computerized literature searches of Medline and the Cochrane Collaboration Library were performed. The Update Committee's literature review focused attention on available systematic reviews and meta-analyses of published tumor marker studies. Recommendations and Conclusion For colorectal cancer, it is recommended that carcinoembryonic antigen (CEA) be ordered preoperatively, if it would assist in staging and surgical planning. Postoperative CEA levels should be performed every 3 months for stage II and III disease for at least 3 years if the patient is a potential candidate for surgery or chemotherapy of metastatic disease. CEA is the marker of choice for monitoring the response of metastatic disease to systemic therapy. Data are insufficient to recommend the routine use of p53, ras, thymidine synthase, dihydropyrimidine dehydrogenase, thymidine phosphorylase, microsatellite instability, 18q loss of heterozygosity, or deleted in colon cancer (DCC) protein in the management of patients with colorectal cancer. For pancreatic cancer, CA 19-9 can be measured every 1 to 3 months for patients with locally advanced or metastatic disease receiving active therapy. Elevations in serial CA 19-9 determinations suggest progressive disease but confirmation with other studies should be sought. New markers and new evidence to support the use of the currently reviewed markers will be evaluated in future updates of these guidelines.

Purpose HER2 is a clinically important tumor marker in breast cancer; however, there is controversy regarding which method reliably measures HER2 status. We compared three HER2 laboratory methods: immunohistochemistry (IHC), fluorescence in situ hybridization (FISH) and polymerase chain reaction (PCR), to predict disease-free survival (DFS) and overall survival (OS) after adjuvant doxorubicin-based therapy in node-positive breast cancer patients. Methods This is a Cancer and Leukemia Group B (CALGB) study, using 524 tumor blocks collected from breast cancer patients registered to clinical trial CALGB 8541. IHC employed CB11 and AO-11-854 monoclonal antibodies; FISH used PathVysion HER2 DNA Probe kit; PCR utilized differential PCR (D-PCR) methodology. Results Cases HER2 positive by IHC, FISH and D-PCR were 24%, 17%, and 18%, respectively. FISH and IHC were clearly related (κ = 64.8%). All three methods demonstrated a similar relationship for DFS and OS. By any method, for patients with HER2-negative tumors, there was little or no effect of dose of adjuvant doxorubicin-based therapy. For patients with HER2-positive tumors, all three methods predicted a benefit from dose-intense (high-dose) compared with low- or moderate-dose adjuvant doxorubicin-based therapy. Conclusion FISH is a reliable method to predict clinical outcome following adjuvant doxorubicin-based therapy for stage II breast cancer patients. There is a moderate level of concordance among the three methods (IHC, FISH, PCR). None of the methods is clearly superior. Although IHC-positive/FISH-positive tumors yielded the greatest interaction with dose of therapy in predicting outcome, no combination of assays tested was statistically superior.

In ideal clinical oncology practice, one would like to have a single platform assay that can provide both prognostic (estimates of risk for failure after surgery alone) and predictive (estimate of benefit from specific therapy) information. Despite years of research, only estrogen receptors (ER), progesterone receptors, and HER-2 have been widely accepted for routine use in breast cancer, serving as predictive factors for endocrine and trastuzumab therapy, respectively. Until recently, new markers have been tested one, or at most two, at a time, a process that results in inefficient tissue usage, long delays in analysis, and, if positive, implementation.

Purpose: The mechanisms responsible for prostate cancer androgen independence are diverse. Mutations of the androgen receptor (AR) gene that broaden ligand specificity have been implicated. Bone marrow specimens containing prostate tumor were obtained from men undergoing antiandrogen withdrawal for AR sequence analysis and clinical correlation.Materials and Methods: Eligible men enrolled on a trial of antiandrogen withdrawal had a minimum prostate-specific antigen (PSA) level of 5 ng/dL that was increasing on castration therapy including an antiandrogen. With informed consent, marrow biopsies were obtained to collect prostate tumor. Additional samples were obtained from men enrolled on chemotherapy trials. AR cDNA or DNA was polymerase chain reaction–amplified, cloned, and sequenced. The AR CAG repeat length was recorded.Results: One hundred eighty-four bone marrow biopsies were obtained, and 48 had prostate tumor detected by light microscopy. The ARs from these 48 samples were sequenced. Overall, five (10%) of 48 tumors had mutated ARs. AR point mutations were detected in the hormone-binding domain involved in transcription factor binding. Three mutations were novel in prostate cancer. One tumor sample had a CAG repeat length of 21, compared with germline length of 22 repeats. There was no association between detectability of AR mutations and antiandrogen withdrawal response or survival.Conclusion: These data suggest that AR mutations are present in approximately 10% of patients with prostate cancer who experience treatment failure with hormone therapy that included an antiandrogen. Mutations in the AR likely confer a growth advantage for a subset of progressive prostate cancers. Correlation of AR mutation with antiandrogen withdrawal response or survival could not be made.

Purpose: Bexarotene is a retinoid X receptor–selective retinoid that has preclinical antitumor activity in breast cancer. We evaluated the efficacy and safety of oral bexarotene in the treatment of patients with metastatic breast cancer. Patients and Methods: The following three groups of patients were treated: hormone-refractory, chemotherapy-refractory, and tamoxifen-resistant patients. Patients in the first two groups were treated with bexarotene alone, whereas the tamoxifen-resistant patients received both tamoxifen and bexarotene. Patients in all groups were randomly assigned to receive bexarotene at either 200 or 500 mg/m2/d. Results: One hundred forty-eight patients were randomized; 145 patients were treated. Of 48 hormone-refractory patients, there were two partial responses (6%) and 10 patients with stable disease lasting more than 6 months; of 47 chemotherapy-refractory patients, there were two partial responses (6%) and five patients with stable disease; and of 51 tamoxifen-resistant patients, there was one partial response (3%) and 11 patients with stable disease. All partial responses occurred at the 200-mg/m2/d dose. The projected median time to progression across all of the arms was 8 to 10 weeks. There were no drug-related deaths, and only two patients had drug-related serious adverse events. The most common drug-related adverse events were hypertriglyceridemia (84%), dry skin (34%), asthenia (30%), and headache (27%). There were no cases of pancreatitis. Conclusion: The efficacy of bexarotene in patients with refractory metastatic breast cancer is limited. However, it is an oral agent with minimal toxicity and a unique mechanism of action, which produced clinical benefit in approximately 20% of patients. Future efforts should define populations likely to benefit from this agent.

The application of precision medicine to clinical oncology will evolve as the technology that underlies precision medicine advances. Indeed, as seen in the American Society of Clinical Oncology (ASCO) policy statement update (on genetic and genomic testing for cancer susceptibility) published in this issue, the increase in genetic sequencing capability combined with the decrease in the cost of testing have altered both regulatory policy and clinical practice and have led to this ASCO policy statement update. Over the past few decades, inherited germline genetic differences among individuals that substantially increase a person’s susceptibility to cancerhavebeenidentified.Well-knownexamplesofclinically important genetic variations (more commonly called mutations) are found in genes such as BRCA1/2 (breast cancer), MSH (colon cancer), RB, and P53 (retinoblastoma and Li-Fraumeni syndrome). Commercially and, more recently, noncommercially available tests are frequently ordered for selected individuals who have a reasonably high chance of harboring mutations in these and other genes, to determine if such individuals and their medical team should implement additional risk mitigation strategies beyond standard of care for the screening or prevention of the associated malignancies. The ASCO policy update provides guidance on when these tests should be ordered and how to interpret them. There is no question that these tests have provided clinical benefit to a small segment of our population. Indeed, there have been calls for much wider application of germline genetic susceptibility testing and even a recommendation that all women should have BRCA1/2 testing, regardless of family history. However, the immense heterogeneity of the human genome, both within and across races and ethnicities, gives rise to many genetic variations that are not by themselves necessarily pathogenic. Many mutations still remain indeterminate for their role in carcinogenesis and are called variants of uncertain significance (VUS). Understanding which genetic variations are benign and which are deleterious drivers of disease expression remains an enormous challenge. The large number of mutations classified as VUS, the methodologic weaknesses inherent to the analysis whereby VUS mutations are reclassified as pathogenic or benign mutations, and the unknown but certain existence of unidentified germline mutations that increase cancer susceptibility all contribute to a degree of ambiguity that exists in genetic counseling of patients about the inherited risk of cancer development. Indiscriminate germline testing in the population will identify far more VUS than established deleterious mutations, which leads to major concerns about unnecessary intensive screening and preventive approaches, including prophylactic surgeries, as well as increased anxiety levels among those who carry them. Although the ASCO guidelines panel recognizes these concerns, the panel continues to recommend a relatively cautious and selective approach, albeit one that is expanded from the previous guideline. However, a brave new world is emerging for genetic cancer susceptibility testing. The previous comments relate to analysis of specific genes that are known to be involved in tumor suppression and for which data strongly support identification of deleterious mutations so that affected individuals can take appropriate actions. Over the past decade, many otherputativesusceptibilitygeneshavebeenidentified,andthereis far less evidencethat thesegenes increaseanindividual’srisksubstantiallyoreven at all. Several commercial entities have now begun to include these genes in panel assays that are bundled with genes known to be important, such as BRCA1/2. On the surface, inclusion of these other genes would seem to offer added value. However, because the clinical utility of the information provided is quite uncertain, the results are likely to lead to false alarms for patients and inappropriate clinical actions. The situation is becoming even more complicated. After the first report of cloning of the human genome, rapid technologic advances have led to exponential reductions in the time and cost required to comprehensively sequence an individual’s genetic profile. Such an approach, designated massively parallel sequencing or nextgeneration sequencing (NGS), may supplant single-gene or even multiple-gene panel assays for genetic susceptibility testing. NGS allows simultaneous sequencing of multiple genes that are genetic hot spots with known cancer associations, the whole exome, and even the entire genome of a patient. However, because of the vast heterogeneity of human genetics, the more genomic data is generated, the greater is the uncertainty about the clinical meaning of this data. The abundance of data of undetermined analytic and clinical utility may result in unnecessary patient fear and anxiety as well as, possibly, the adoption of inappropriate risk mitigation strategies. As exciting as these technologies are, one must be cognizant that different technologies for NGS are not identical. The accuracy of NGS is dependent on the multiplicity or redundancy with which the sample is analyzed, known as depth of coverage, and on other factors that are reviewed in the ASCO policy statement. These factors determine the analytic validity of the test. In addition, the clinical validity (whether JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 33 NUMBER 31 NOVEMBER 1 2015

PURPOSE: Increased microvessel density (MVD), a reflection of tumor angiogenesis, is associated with diminished relapse-free and overall survival (OS) in several subsets of breast cancer patients. However, the utility of this assay in node-positive patients treated with adjuvant cyclophosphamide, doxorubicin, and fluorouracil (CAF) has not been well studied. PATIENTS AND METHODS: Immunostaining for factor VIII–related antigen was performed on tissue sections from a subset of node-positive patients who received one of three dose/schedule regimens of CAF during participation in Cancer and Leukemia Group B protocol 8541. Sections from 577 cancers exhibited acceptable tumor and immunostaining quality and were included in the study. Each section was examined quantitatively for MVD as well as nonquantitatively by scoring the presence or absence of a prominent vascular pattern. RESULTS: MVD counts were not associated with relapse-free or OS in univariate analysis. The presence of a prominent plexiform vascular pattern was correlated with decreased OS (P = .0085) in univariate analysis, but this pattern was not an independent prognostic indicator of survival in multivariate analysis. No apparent clinically important interactions between measures of angiogenesis, other prognostic factors, administration of tamoxifen, and chemotherapy dose were observed. CONCLUSION: Assessment of angiogenesis does not provide useful information regarding prognosis in node-positive breast cancer patients treated with adjuvant CAF, nor do these measures predict which patients will benefit from dose intensification or addition of tamoxifen.

1063 Background: Aromatase inhibitors (AI) suppress estrogen biosynthesis and are effective treatments for estrogen receptor (ER)-positive breast cancer. In a prospectively enrolled cohort we observed a subset of post-menopausal women who exhibit high plasma estradiol (E2) concentrations during AI treatment, which could potentially contribute to treatment failure. We tested the hypothesis that incomplete E2 suppression is due to insufficient systemic AI concentrations. Methods: Five hundred post-menopausal women with ER-positive breast cancer were randomized to daily exemestane (Exe) 25 mg or letrozole (Let) 2.5 mg. Plasma E2 was measured using GC/MS/MS (lower limit of quantification (LLOQ) = 1.25 pg/mL) at baseline and after 3 months. Let and Exe plasma concentrations measured after 1 or 3 months were compared with the magnitude of E2 depletion using four complementary statistical procedures to assess associations of drug concentrations with: 1) a binary outcome of E2 suppression below LLOQ (logistic regression), 2) 3-month E2 concentrations (linear regression), 3) absolute change from baseline in E2 concentrations (Spearman correlation), and 4) an ordinal outcome defined by E2: decreased to below LLOQ, decreased but not to LLOQ, stayed the same, or increased from baseline (cumulative logistic regression). Results: 397 patients with E2 and AI concentration measurements were evaluable (Exe n = 199, Let n = 198). Thirty (7.6%) patients (Exe n = 13, Let n = 17) had E2 concentrations above the LLOQ at 3 months (range: 1.42-63.8 pg/mL). Exe and Let concentrations were not associated with achievement of unmeasurable E2 concentrations, on-treatment E2 concentrations, E2 change from baseline, or ordinal groupings of E2 change (all p > 0.05). In a parallel analysis there was no association of estrone-sulfate and drug concentrations (data not shown). Conclusions: Our results suggest that circulating drug concentrations do not explain incomplete E2 suppression in women receiving AI therapy. Additional studies are underway to determine whether age, body mass and genetic variation in the aromatase enzyme influence AI treatment response.

101 Background: Next generation sequencing (NGS) platforms are frequently utilized in the care of patients (pts) with metastatic cancer to identify tumor genomic alterations that may serve as therapeutic targets. Biomarker driven clinical trials, such as NCI-Molecular Analysis for Therapy Choice (MATCH) and Targeted Agent and Profiling Utilization Registry (TAPUR) have augmented clinicians’ ability use this strategy in clinical practice. Methods: From 2011-2015 over 500 adult pts with metastatic solid tumors of diverse lineage underwent biopsy for whole exome and transcriptome sequencing of tumor and matched normal sample through the Michigan Oncology Sequencing Center (Mi-Oncoseq). Genomic alterations identified were reviewed at Precision Medicine Tumor Board and tiered according to their clinical relevance. Alterations were also classified as being identifiable or not identifiable by a commercially available NGS assay such as Oncomine Focus or FoundationOne. Results: Genomic alterations identified by Mi-Oncoseq provided rationale for enrollment in a clinical trial in 72% (n = 360) of cases. The percentage of pts who did receive therapy informed by NGS results increased over time (5% in 2012 versus 11% in 2015). 11% of pts (n = 55) had a pathogenic germline variant (PGV) conferring increased cancer risk identified, none of which were known prior to study entry. Numerous pts had clinically relevant molecular alterations identified by Mi-Oncoseq that would not have been identifiable utilizing targeted NGS assays, including PGVs and activating/deleterious gene fusions. Conclusions: Comprehensive NGS, including DNA and RNA sequencing, readily identifies potentially actionable alterations in the vast majority of pts beyond what is observed with use of targeted NGS platforms. Observed modest increase in utilization of NGS results to direct subsequent therapy over time is due to clinician employment of this strategy earlier in the therapeutic algorithm, increased availability of biomarker driven clinical trials and changes in physician referral patterns. Comprehensive NGS identified many unanticipated PGVs of clinical importance for pts and their families. Clinical trial information: HUM00067928.

e12102 Background: Increased rates of locoregional recurrence have been observed in TNBC despite chemotherapy and radiation (RT). A novel radiosensitizer screen nominated the AR as a promising target for treatment of radioresistant breast cancer, including TNBC. We assessed in vitro activity of SEVI (VT-464), a selective CYP17 lyase and AR inhibitor, as a potential radiosensitizer in AR+ TNBC model. Methods: Clonogenic survival assays were used to determine the intrinsic RT sensitivity of 21 breast cancer cell (BCC) lines. IC50 values were determined for 130 clinically available compounds and correlation coefficients were calculated using IC50 values and SF-2Gy. Gene expression was measured using RNA Seq or qRT-PCR and protein expression was measured using RPPA arrays. AR function was assessed using functional inhibition with SEVI in MDA-MB-453, ACC-460, SUM-185 (all three AR+ TNBC), MDA-MB-231 (AR- TNBC), and T47D (AR- ER+) BCC lines. Double-stranded DNA (dsDNA) break repair was assessed with γH2AX foci counting. Results: Our novel radiosensitizer screen identified the activity of bicalutamide, an AR antagonist, in RT-resistant BCC lines (R2 = 0.46, p-value < 0.01). Heterogeneity in AR expression was identified in human BCC lines. There was a strong correlation between AR RNA expression and protein expression across all BC intrinsic subtypes. AR inhibition using SEVI induced radiation sensitivity in vitro with an enhancement ratio (ER) of 1.24-1.62 in three different AR+ TNBC lines. No such radiosensitization was seen in AR(-) TNBC or ER+, AR(-) BCC lines. Radiosensitization was at least partially dependent on impaired dsDNA break repair with significant delays in dsDNA break repair at 16 and 24 hours in all AR+ TNBC lines examined (p-value < 0.01). Conclusions: Our results implicate the AR as a mediator of radioresistance in breast cancer and support the rationale for developing seviteronel as a novel radiosensitizing agent in AR+ TNBC.

529 Background: Biomarkers of response and resistance to adjuvant chemotherapy for TNBC are needed. Deficiency in DNA damage response (DDR) and repair pathways have been reported in TNBC and may impact response to chemotherapy. Aims: To investigate DNA damage response deficiency (DDRD) molecular signature, BRCA1mRNA expression and Tumor Infiltrating Lymphocytes (TILs) as prognostic markers in TNBC patients treated with adjuvant AC on S9313. Methods: S9313 accrued 3125 early stage BC patients to two alternative schedules of AC with no difference in outcomes between the two arms. We identified 425 (14%) patients with centrally determined TNBC with tissue availability. DDRD signature (44 gene signature, Almac Inc.) and BRCA1expression (NanoString nCounter) were performed on RNA isolated from pre-treatment FFPE tumor tissue. DDRD score was classified in quartiles. TILs evaluation was performed using previously described criteria. Markers were tested for prognostic effect on DFS and OS using Cox regression model with adjustment for randomized treatment assignment. Results: For 425 TNBC patients median age: 45 yrs, and 5 year DFS and OS = 74% and 82%, respectively. DDRD signature was successfully evaluated in 89.6% (381/425) but only 267 (62.8%) met 60% tumor content criterion for inclusion. DDRD score quartiles were associated with DFS (5 year DFS 59% & 82% in the lowest & highest quartiles respectively, p = 0.0005) and OS (5 year OS 74% and 86% in lowest and highest quartiles respectively, p = 0.008). BRCA1 expression and TILs were successfully determined in 78% and 99% samples, respectively. BRCA1expression was not associated with DFS. TILs were associated with DFS (10% increase HR = 0.88; 95% CI 0.79-0.97; p = 0.016) and OS (HR = 0.84; 95% CI 0.74-0.94; p = 0.0005). DDRD score and TILs were highly correlated (Pearson = 0.62). In multivariate model of DFS including TILs and DDRD quartiles, only DDRD remains significant (p = 0.018). Conclusions: DDRD signature was prognostic in TNBC patients treated with AC chemotherapy and has the potential to be used as a selection criterion to identify TNBC patients whose prognosis is sufficiently poor to justify evaluation of alternative treatment.

OBJECTIVE: To update the 1997 clinical practice guidelines for the use of tumor marker tests in the prevention, screening, treatment, and surveillance of breast and colorectal cancers. These guidelines are intended for use in the care of patients outside of clinical trials. OPTIONS: Six tumor markers for colorectal cancer and eight for breast cancer were considered. They could be recommended or not for routine use or for special circumstances. In addition to carcinoembryonic antigen (CEA) and CA 15-3, CA 27.29 was also considered among the serum tumor markers for breast cancer. OUTCOMES: In general, the significant health outcomes identified for use in making clinical practice guidelines (overall survival, disease-free survival, quality of life, lesser toxicity, and cost-effectiveness) were used. EVIDENCE: A computerized literature search from 1994 to March 1999 was performed. VALUES: The same values for use, utility, and levels of evidence were used by the committee. BENEFITS, HARMS, AND COSTS: The same benefit, harms, and costs were used. RECOMMENDATION: Changes were recommended (see Appendix). VALIDATION: The updated recommendations were validated by external review by the American Society of Clinical Oncology’s (ASCO’s) Health Services Research Committee and by ASCO’s Board of Directors. SPONSOR: American Society of Clinical Oncology.

PURPOSE: An association between the overexpression of proto-oncogene HER-2/neu and resistance to tamoxifen in estrogen receptor (ER)–positive primary and metastatic breast cancer has been suggested. We examine a possible interaction between HER-2/neu or p53 expression and tamoxifen effectiveness in patients with ER-positive, node-positive disease treated with cyclophosphamide, doxorubicin, and fluorouracil in a large adjuvant chemotherapy trial (Cancer and Leukemia Group B [CALGB] 8541). Tamoxifen assignment was not randomized—physician discretion was used for premenopausal and postmenopausal women. Trial protocol then specified assignment to postmenopausal women with ER-positive tumors, although not all took tamoxifen. PATIENTS AND METHODS: CALGB 8541 assessed HER-2/neu expression in patients with ER-positive disease by immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH) and amplification by differential polymerase chain reaction (PCR). IHC assessed expression of p53. Univariate and multivariate proportional hazards models assessed tamoxifen–HER-2/neu status interactions and tamoxifen-p53 status interactions. RESULTS: HER-2/neu status was available for 651 patients with ER-positive disease; 650, 608, and 353 patients were assessed by IHC, PCR, and FISH, respectively. Approximately one half received tamoxifen. Reduction in risk of disease recurrence or death resulting from tamoxifen was approximately 37% (32% with overexpression and 39% with normal expression of HER-2/neu; n = 155 by IHC). The tamoxifen–HER-2/neu status interaction was not significant in multivariate analysis of all three HER-2/neu assessment methods. Tamoxifen-p53 interaction did not significantly predict outcome. CONCLUSION: Disease-free and overall survival benefit of tamoxifen in patients with ER-positive, node-positive breast cancer does not depend on HER-2/neu or p53 status. Our data suggest that neither HER-2/neu nor p53 expression should be used to determine assignment of tamoxifen.

PURPOSE: To determine the efficacy, safety, pharmacokinetics, and effect on serum angiogenic growth factors of two dose levels of thalidomide in patients with metastatic breast cancer. PATIENTS AND METHODS: Twenty-eight patients with progressive metastatic breast cancer were randomized to receive either daily 200 mg of thalidomide or 800 mg to be escalated to 1,200 mg. Fourteen heavily pretreated patients were assigned to each dose level. Each cycle consisted of 8 weeks of treatment. Pharmacokinetics and growth factor serum levels were evaluated. RESULTS: No patient had a true partial or complete response. On the 800-mg arm, 13 patients had progressive disease at or before 8 weeks of treatment and one refused to continue treatment. The dose was reduced because of somnolence to 600 mg for five patients and to 400 mg for two and was increased for one to 1,000 mg and for four to 1,200 mg. On the 200-mg arm, 12 patients had progressive disease at or before 8 weeks and two had stable disease at 8 weeks, of whom one was removed from study at week 11 because of grade 3 neuropathy and the other had progressive disease at week 16. Dose-limiting toxicities included somnolence and neuropathy. Adverse events that did not require dose or schedule modifications included constipation, fatigue, dry mouth, dizziness, nausea, anorexia, arrhythmia, headaches, skin rash, hypotension, and neutropenia. Evaluation of circulating angiogenic factors and pharmacokinetic studies failed to provide insight into the reason for the lack of efficacy. CONCLUSION: Single-agent thalidomide has little or no activity in patients with heavily pretreated breast cancer. Further studies that include different patient populations and/or combinations with other agents might be performed at the lower dose levels.

PURPOSE To assess the cardiac effects of two different cumulative doses of adjuvant doxorubicin and radiation therapy (RT) in breast cancer patients. PATIENTS AND METHODS Two hundred ninety-nine breast cancer patients were prospectively randomized to receive either five cycles (CA5) or 10 cycles (CA10) of adjuvant treatment with cyclophosphamide (500 mg/ m2) and doxorubicin (45 mg/m2) administered by intravenous bolus every 21 days. One hundred twenty-two of these patients also received RT. Estimates of the cardiac RT dose-volume were retrospectively categorized as low, moderate, or high. The risk of major cardiac events (congestive heart failure, acute myocardial infarction) was assessable in 276 patients (92%), with a median follow-up time of 6.0 years (range, 0.5 to 19.4). RESULTS The estimated risk (95% confidence interval) of cardiac events per 100 patient-years was significantly higher for CA10 than for CA5 [1.7 (1.0 to 2.8) v 0.5 (0.1 to 1.2); P=.02]. The risk of cardiac events in CA5 patients, irrespective of the cardiac RT dose-volume, did not differ significantly from rates of cardiac events predicted for the general female population by the Framingham Heart Study. In CA10 patients, the incidence of cardiac events was significantly increased (relative risk ratio, 3.6; P < .00003) compared with the Framingham population, particularly in groups that also received moderate and high dose-volume cardiac RT. CONCLUSION Conventional-dose adjuvant doxorubicin as delivered in the CA5 regimen by itself, or in combination with locoregional RT, was not associated with a significant increase in the risk of cardiac events. Higher doses of adjuvant doxorubicin (CA10) were associated with a threefold to fourfold increased risk of cardiac events. This appears to be especially true in patients treated with higher dose-volumes of cardiac RT. Larger studies with longer follow-up periods are needed to confirm these results.

Trastuzumab has been shown to be quite effective in reducing suffering and mortality from breast cancer in both the metastatic and adjuvant settings. With short follow-up, remarkably consistent results across five adjuvant, prospective, randomized clinical trials suggest that trastuzumab may decrease the odds of distant recurrence and mortality by approximately one half and one third, respectively. Dr George Sledge, who discussed the first presentations of the adjuvant trials at the 2005 Annual Meeting of the American Society of Clinical Oncology, proclaimed these results “astonishing,” and we agree (oral communication, May 2005). However, there is a dark side to trastuzumab that may limit its utility in some patients. Although in general, trastuzumab has been extremely well tolerated, a surprisingly high incidence of congestive heart failure (CHF) was observed in the early studies of metastatic disease, especially in patients who were treated concurrently with doxorubicin. With this knowledge, most subsequent trial designs, particularly those in the adjuvant setting, avoided concurrent anthracycline and trastuzumab therapy, and included careful baseline and serial monitoring of cardiac function. Early results from these trials suggest that approximately 5% of all patients treated with adjuvant trastuzumab, either with nonanthracycline chemotherapy such as the taxanes or vinorelbine, or after all chemotherapy is complete, will develop some objective evidence of systolic cardiac dysfunction. Approximately 1% of patients will develop symptomatic CHF. These rates are approximately four to five times higher than in control patients who did not receive trastuzumab, and the absolute difference in echocardiogram or scintigram-detected cardiac dysfunction between trastuzumab-treated and control patients seems to be approximately 3% to 4%. These observations raise several questions. First, given the enormous benefit of trastuzumab, is pre-existing cardiac dysfunction, especially if it is asymptomatic, sufficient reason to withhold the drug? Are the classic risk factors for cardiac disease, such as hypertension, diabetes, and family history, important predictors of trastuzumab-induced CHF? Is trastuzumab-related CHF reversible if the agent is discontinued, and is it safe to reinitiate this potentially life-saving agent if a patient has developed cardiac dysfunction while receiving it previously? Are there ways to avoid or minimize trastuzumab-related cardiac dysfunction? Will the incidence of this complication increase with longer follow-up of women who receive adjuvant trastuzumab? Finally, what is the mechanism of this perplexing toxicity? In the last few years, a substantial number of publications have addressed the cardiac toxicity of trastuzumab in both prospective clinical trials and from individual institutional experiences. In this issue of the Journal of Clinical Oncology, Guarneri et al report their results from a retrospective analysis of 218 metastatic breast cancer patients who received trastuzumab for at least 1 year from 1998 to 2003. In this series, 28% of patients had some type of cardiac event (CE), and 10.9% had grade 3 cardiotoxicity, with one cardiac death. Therefore, coupled with the larger, prospective trials, the results from this study provide additional insight into our questions. Given that all of the clinical trials of trastuzumab have excluded women with obvious pre-existing heart failure, we cannot determine if this condition should preclude a patient’s receiving it; however, until data to the contrary are reported, we believe it should. What about those who apparently have healthy hearts but have received pretrastuzumab anthracyclines, which are incorporated into most adjuvant regimens? In the adjuvant, prospective, randomized clinical trials conducted by the National Surgical Adjuvant Breast and Bowel Project (NSABP B-31) and the Breast Cancer Intergroup of North America, 6.7% of women who had completed four cycles of doxorubicin and cyclophosphamide (AC) were deemed ineligible to proceed to trastuzumab because of left ventricular dysfunction. We agree that this condition of eligibility was prudent. One might wonder if these patients could have been treated with trastuzumab and monitored closely with discontinuation of the drug on evidence of additional decline in cardiac function. In this regard, a cautionary note comes from the NSABP, which has reported that patients in NSABP B-31 with marginal post-AC left ventricular ejection fractions (LVEF) but who were still eligible for trastuzumab had higher rates of subsequent cardiac dysfunction than those who started trastuzumab with normal cardiac parameters. So for now, the presence of LV dysfunction or heart failure symptoms should exclude the addition of trastuzumab. The study by Guarneri et al may provide additional clues to our questions. Although the study was retrospective and limited by a small number of events, careful analysis of Table 1 suggests that several pre-existing factors may predict trastuzumab CEs. For example, it seems that although only 7% of women who received radiation to the right side developed a CE, 26% of those who received radiation to the left side were affected, although these differences did not reach statistical significance. Again considering the limited power, pre-existing diabetes, coronary artery disease, and valvular dysfunction were all associated with apparent higher rates of trastuzumab-related CEs. Curiously, hypertension and older age were not. In the NSABP/Intergroup analysis of adjuvant patients, age and hypertension were risk factors for cardiac dysfunction. Additional analysis of the NSABP trial data suggest that JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 24 NUMBER 25 SEPTEMBER 1 2006

Since the mid-1980s, mortality as a result of breast cancer has been declining in the Western world, due in part to the widespread application of adjuvant systemic therapy. However, for the most part, clinical trials have failed to address the benefit of adjuvant chemotherapy in elderly women. The few efforts to do so have involved what appear to be better tolerated, yet— one hopes— efficacious treatments. In this issue of the Journal of Clinical Oncology, Fargeot et al from the French Adjuvant Study Group (FASOG) report results of a prospective, randomized clinical trial of weekly adjuvant epirubicin compared to no postoperative chemotherapy for estrogen receptor (ER) -positive, node-positive patients over the age of 65 years, all of whom also received tamoxifen, either alone or concurrent with and following epirubicin. The investigators observed a modest but statistically significant improvement in disease-free survival, but no improvement in overall survival for the epirubicin-treated patients. Although this study represents a victory in accruing patients older than 65 years to a prospective chemotherapy trial, one must question whether these benefits are clinically meaningful. Retrospective subgroup analyses of early randomized trials of adjuvant chemotherapy compared to observation alone suggested that older women gain proportionally less benefit than younger women. Subsequently, the Oxford Worldwide Overview of adjuvant systemic therapy demonstrated a stepwise reduction in relative efficacy of adjuvant chemotherapy with advancing age by decade. Several hypotheses have been proposed to explain these observations, including shorter expected life span in general, differential reductions in delivered dose, and possible differences in tumor biology resulting in reduced sensitivity to chemotherapy in elderly patients. Examination of each of these possibilities provides little further insight. The significant survival benefit from adjuvant tamoxifen, even in older women, speaks against the argument that comorbidity and mortality from other causes prevent prolongation of survival due to suppression of breast cancer. Reductions in chemotherapy dose might play a role, since the elderly represent a special population of patients for whom concurrent morbidity could lead to decreased tolerance of toxic regimens. Some investigators have reported higher toxicities from chemotherapy in the elderly, but several studies have suggested that, with careful selection and with certain caveats, fit elderly women tolerate chemotherapy as well as their younger counterparts. Alternatively, the elderly may have tumors that are biologically less responsive to chemotherapy. Studies have demonstrated that untreated and treated prognoses differ by age, as do biologic factors that are known to be important in both prognosis and prediction for systemic therapy in general. Of these, increased expression of ER in older women is the most consistently observed difference. This observation would obviously lead to higher rates of benefit from endocrine therapy, but ER expression alone may also decrease chemosensitivity. Nonetheless, in addition to the present study by Fargeot et al, other large cooperative groups have also reported statistically significant improvement in outcomes in postmenopausal women with the use of chemotherapy plus tamoxifen compared to tamoxifen alone. Of interest, two of these studies—National Surgical Adjuvant Bowel and Breast Project B-16 and Southwest Oncology Group Intergroup 8814—employed doxorubicin-based regimens, raising the possibility that perhaps anthracycline therapy might be more effective in the elderly, hormone-responsive patient than JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 22 NUMBER 23 DECEMBER 1 2004

516Background: HER2 mutation occurs in ~2% of breast cancer (BC). Preclinical models suggested neratinib, an irreversible HER2/EGFR tyrosine kinase inhibitor, could be an effective treatment. This trial was conducted to assess the clinical benefit rate (CBR), defined as complete response (CR), partial response (PR) or stable disease (SD) ≥ 6 months (mo.), for neratinib in patients (pts) with HER2mutMBC (NCT01670877). Methods: This single arm phase II trial employed the Simon’s Optimal 2-stage design (1st stage: n=10, 2nd stage: n=19) to detect CBR of 20% versus the null hypothesis of 5% (80% power, 1-sided alpha 0.05). The primary endpoint is met if ≥ 4 CB is observed. Eligibility required the presence of somatic HER2mut and absent HER2 amplification. Activating HER2mut by in vitro study was required in the 2nd stage. Pts received neratinib 240 mg PO daily (28-day cycle) with prophylactic loperamide. Response was assessed every 2 cycles by RECIST 1.1. Enrollment was stopped early due to a protocol amendme...

505Background: For operable ER+ breast cancer, 5 years of ET with tamoxifen and/or aromatase inhibitors reduces breast cancer mortality in years 0-4 and years 5-14 by about a third. Extending ET past year 5 further reduces risks in years 5-14, but has further side-effects. Knowledge of the effects of prognostic factors on absolute risks of distant recurrence and death in years 5-14 if ET stops at year 5 could help decide whether to extend ET after year 5 for lower-risk patients. Methods: Data on 46,138 individual patients with ER+ disease (diameter T1 or T2 only, pathological nodal status N0, N1-3 or N4-9 only) in trial groups allocated 5 years only of ET yielded the effects on outcomes in years 5-14 of tumor diameter, nodal status and, if available, grade, Ki-67, PR and HER-2 status. Cox regression analyses of each factor were adjusted for age, trial group, and the other factors. Results: In ER+ disease, recurrence rates continued steadily throughout the first 20 years. Distant recurrence rates in years ...

158 Background: Tolerance of AI therapy can be poor due to treatment-emergent toxicities and can lead to early discontinuation (non-persistence). Patients often switch from one AI to another when toxicities develop; however, limited prospective data exist on patients who switch AI. Here we describe the effect of switching from E to L or L to E on tolerance of and persistence with therapy. Methods: Postmenopausal women initiating AI therapy were enrolled on the ELPh trial and randomized to E or L. Those that stopped their AI for self-reported intolerance were offered crossover to alternate AI after a 2-6 week washout. Kaplan-Meier estimates of proportions on AI after 1, 3, and 6 months were assessed during 1st and 2nd AI. Associations between time on 2ndAI and clinicopathologic factors were analyzed using univariable Cox proportional hazards model. To evaluate effect of crossover on patient-reported outcomes, multiple questionnaires, including a pain visual analog scale (VAS), were assessed serially. Results: 83 women, mean age 60 years, 45% prior chemotherapy, and 31% with prior tamoxifen use, participated in the crossover protocol. 71% reported improvement in symptoms a mean 4.72 weeks after discontinuing 1st AI therapy. Median time on 1st AI was 6.8 months (95% CI 5.8-9 months), and on 2nd AI was 11.5 months (6.9-24.2). The probability of persistence at 1, 3, and 6 months for the 1st AI was 94%, 76%, and 55% and for the 2nd AI was 89%, 73%, and 62%, respectively. There was no significant association between duration on 2nd AI and 1st AI (L vs. E), duration on 1st AI, age, body mass index, or prior therapies. The change in pain VAS from baseline to 1 or 3 months was not significantly different during treatment with the 1st or 2ndAI. Conclusions: Although all AI medications have similar mechanisms of activity, nearly two-thirds of patients who are intolerant of one AI are able to maintain therapy for at least 6 months following switch to 2nd AI. Switching is a reasonable approach for women who cannot tolerate 1st AI that may improve persistence with therapy. The mechanisms for intrapatient variation in tolerance warrant further study. Clinical trial information: NCT00228956.