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Purpose:Low-dose tamoxifen reduces breast cancer risk, but remains untested in chest-irradiated cancer survivors—a population with breast cancer risk comparable with BRCA mutation carriers. We hypothesized that low-dose tamoxifen would be safe and efficacious in reducing radiation-related breast cancer risk.Patients and Methods:We conducted an investigator-initiated, randomized, phase IIb, double-blinded, placebo-controlled trial (FDA IND107367) between 2010 and 2016 at 15 U.S. sites. Eligibility included ≥12 Gy of chest radiation by age 40 years and age at enrollment ≥25 years. Patients were randomized 1:1 to low-dose tamoxifen (5 mg/day) or identical placebo tablets for 2 years. The primary endpoint was mammographic dense area at baseline, 1 and 2 years. IGF-1 plays a role in breast carcinogenesis; circulating IGF-1 and IGF-BP3 levels at baseline, 1 and 2 years served as secondary endpoints.Results:Seventy-two participants (low-dose tamoxifen: n = 34, placebo: n = 38) enrolled at a median age of 43.8 years (35–49) were evaluable. They had received chest radiation at a median dose of 30.3 Gy. Compared with the placebo arm, the low-dose tamoxifen arm participants had significantly lower mammographic dense area (P = 0.02) and IGF1 levels (P < 0.0001), and higher IGFBP-3 levels (P = 0.02). There was no difference in toxicity biomarkers (serum bone-specific alkaline phosphatase, lipids, and antithrombin III; urine N-telopeptide cross-links) between the treatment arms. We did not identify any grade 3–4 adverse events related to low-dose tamoxifen.Conclusions:In this randomized trial in chest-irradiated cancer survivors, we find that low-dose tamoxifen is effective in reducing established biomarkers of breast cancer risk and could serve as a risk-reduction strategy.

Background: IDO1 is a mediator of tumor immune suppression through alteration of tryptophan metabolism. Indoximod (1-methyl-tryptophan) is an IDO1 pathway inhibitor. There is preclinical evidence that indoximod acts synergistically with chemotherapy such as taxanes (Uyttenhove, 2003) in an immune dependent fashion. Previous studies demonstrated the safety and activity of indoximod combined with docetaxel in patients with advanced solid tumors, including breast cancer (Soliman, 2014). A phase 2 clinical trial was designed to study the efficacy of indoximod plus taxanes in metastatic breast cancer (MBC) patients (pts). Method: This is a phase II randomized, 1:1 placebo controlled clinical trial, that enrolled MBC pts in multiple centers in the US and Poland. Eligibility criteria included ER+ or ER- HER2- MBC, ability to receive taxane therapy, PS 0-1, normal organ function and absence of autoimmune disease. Pts were randomized to taxane (either weekly paclitaxel 80mg/m2 3 on 1 off or q3wk docetaxel at 75mg/m2 per treating physician’s discretion) + placebo (TP) or taxane + indoximod 1200mg PO BID (TI) as first line treatment for MBC. Primary endpoint was PFS. The sample size of 154 patients was designed to detect a HR of .64 with one sided α=.1 and β=.2 after 95 events. Archival tumor tissue was stained with IHC for IDO1 expression when available. Aperio digital pathology positive pixel algorithm was used for scoring, with manual verification. Median value was used as cut-off for IDO positivity. Results: 164 pts were randomized and treated (85 TI, 79 TP). Demographics and tumor features are shown in table 1. Treatment discontinuation was due to disease progression (60%), adverse events (10%), other (30%). Objective response rate was 40% in TI and 37% in TP arm (p=.74). The median PFS was 6.0 (95% CI, 4.5, 8.1) months in the TI arm and 8.4 (95% CI, 5.6, 9.8) in the TP arm, HR of 1.14 (0.81, 1.60). The median OS was 21.6 months (CI 95%, 16, 39.1) in the TI arm and 21.2 (CI 95%, 19.1, 32.1) in the TP arm. The median follow up was 17.4 (range 0.1, 39.4) months. Grade ≥3 treatment emergent adverse events were observed in 60% of patients in both arms with neutropenia, fatigue, anemia, diarrhea being most common but not significantly different between arms. An exploratory analysis of IDO staining with outcomes in 42 samples (22 in TI and 20 TP) suggested a difference in median PFS in pts with high IDO expression assigned to TI vs. TP (10.3 vs 4 months, p=.047). No other prognostic or predictive associations were observed based on IDO status in the analysis. Conclusions: The combination of indoximod with a taxane in 1st line HER2- MBC was safe and did not result in added toxicity. In an unselected population, no improvement in clinical outcomes was observed for the combination over taxane alone. However, higher tumor IDO expression may select for MBC pts who benefit more from indoximod and should be investigated as a predictive biomarker in future studies. Demographics and tumor featuresIndoximodPlaceboOverallParameterStatistic(N=85)(N=79)(N=164)Age (years)n8579164median (min, max)58 (29,76)57 (29,85)58 (29,85)GenderMalen (%)1 (1.2)2 (2.5)3 (1.8)Femalen (%)84 (98.8)77 (97.5)161 (98.2)RaceWhiten (%)71 (83.5)66 (83.5)137 (83.5)African Americann (%)12 (14.1)10 (12.7)22 (13.4)Asiann (%)1 (1.2)01 (0.6)Othern (%)1 (1.2)3 (3.8)4 (2.4)ECOG status0n (%)41 (48.8)43 (54.4)84 (51.5)1n (%)44 (52.2)36 (44.3)80 (46.6)Hormone Receptor StatusNegativen (%)23 (27.1)23 (29.1)46 (28.0)Positiven (%)62 (72.9)56 (70.9)118 (72.0)Choice of TaxaneDocetaxeln (%)62 (72.9)59 (74.7)121 (73.8)Paclitaxeln (%)23 (27.1)20 (25.3)43 (26.2) Citation Format: Veronica Mariotti, Shou-Ching Tang, Patrick Dillon, Alberto Montero, Andrew Poklepovic, Susan Melin, Ibrahim Nuhad, Petros Nikolinakos, Eugene Kennedy, Hyo Han, Roohi Ismail-Khan, Daniel Bruetman, Oana Danciu, Paul Gilman, Boguslawa Karaszewska, Krzysztof Lesniewski-Kmak, Timothy Panella, Dhimant Patel, Malgorzata Suszko-Kazarnowicz, Fabio Volterra, Hatem Soliman. Results of a phase II double-blinded, randomized, placebo-controlled clinical trial of Indoximod, an Indoleamine-2,3-dioxygenase 1 (IDO1) inhibitor, in combination with Taxane chemotherapy in metastatic breast cancer (MBC) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr PD1-04.

Background Premenopausal women with high-risk hormone receptor (HR)-positive breast cancer often receive ovarian function suppression (OFS) with aromatase inhibitor therapy; however, abrupt menopause induction, together with further decrements in estrogen exposure through aromatase inhibition, may affect cardiovascular microcirculatory function. We examined adenosine-induced changes in left ventricular (LV) myocardial T1, a potential subclinical marker of LV microcirculatory function in premenopausal women undergoing treatment for breast cancer. Methods Twenty-one premenopausal women (14 with HR-positive breast cancer receiving OFS with an aromatase inhibitor and 7 comparator women with triple-negative breast cancer [TNBC] who had completed primary systemic therapy) underwent serial resting and adenosine cardiovascular magnetic resonance imaging measurements of LV myocardial T1 and LV volumes, mass, and ejection fraction. All statistical tests were 2-sided. Results After a median of 4.0 months (range = 3.1-5.7 months), the stress to resting ratio of LV myocardial T1 declined in women with HR-positive breast cancer (−1.3%, 95% confidence interval [CI] = −3.4% to 0.7%) relative to those with TNBC (3.2%, 95% CI = −1.2% to 7.6%, P = .02). After accounting for age, LV stroke volume, LV ejection fraction, diastolic blood pressure, and breast cancer subtype women with HR-positive breast cancer experienced a blunted T1 response after adenosine relative to women with TNBC (difference = −4.7%, 95% CI = −7.3% to −2.1%, Pdifference = .002). Conclusions Over the brief interval examined, women with HR-positive breast cancer receiving OFS with an aromatase inhibitor experienced reductions in adenosine-associated changes in LV myocardial T1 relative to women who received nonhormonal therapy for TNBC. These findings suggest a possible adverse impact on LV myocardial microcirculatory function in premenopausal women with breast cancer receiving hormone deprivation therapy.

Background: Population-based contemporary incidence and survival patterns for breast cancer by receptor status (hormone receptor [HR]; human epidermal growth factor receptor 2 [HER2]) among young US women have not been described. Methods: We identified pre-, peri-, and early postmenopausal women ages 20-29 (n=1,617), 30-39 (n=12,910), 40-49 (n=47,313), and 50-59 (n=68,870) diagnosed with Stage I-III breast cancer from 2010-15 in the Surveillance, Epidemiology and End Results (SEER) database using SEER*Stat version 8.3.5. Of these, respective totals for women with reported HR and non-borderline HER2 status were 1533 (94.8%), 12,225 (94.6%), 44,684 (94.4%), and 64,844 (94.2%). Using this analytic sample, we estimated annual percentage change (APC) in incidence. Restricting the sample to women diagnosed from 2010-14, we estimated four-year survival (maximum available follow-up). Analyses were stratified by age group and receptor status. Results: The proportion of HER2+/HR+ cancer was highest among women 20-29, decreasing with increasing age; that for HER2+/HR- cancer was lower, differing less across age groups (Table 1). For HER2- cancer, the proportion of HER2-/HR+ cancer was lowest for women 20-29 and increased with age; the opposite pattern was observed for HER2-/HR- cancer. Overall, stage I-III breast cancer increased in incidence from 2010-15 for all age groups, with the APC greatest in women 20-29 [2.20](30-39 [1.98], 40-49 [1.91], 50-59 [1.62]). The patterns for the APCs by age and receptor status tended to reflect those for the observed proportions, except those for women with HER2+/HR- cancer, which tended to increase with increasing age (Table 1). Four-year survival estimates for women 20-29, although imprecise, differed by HER2 status, being higher for those with HER2+ than HER2- cancer, and this difference persisted for HR+ and HR- cancers among these women (Table 2). In the other age groups, survival differed by HR status, being higher for women with HR+ than HR- cancer. Conclusions: Using SEER data representative of over one-quarter of the US population, Stage I-III breast cancer has increased among young women in recent years. In particular, HER2+/HR+ and HER2-/HR- cancers were over-represented and estimated to have the highest APCs among women 20-39 compared to those 40-59. Receptor status was observed to influence survival differently across age groups. The differences in four-year survival observed among women 20-29 with HR+ cancers may have implications as we consider anti-estrogen therapy options for these youngest premenopausal women. Table 1:Breast Cancer Frequency and APCReceptorsAge 20-2930-3940-4950-59 N (%) HER2+/HR+331(21.6)2225(18.2)5865(13.1)7706(11.9)HER2+/HR-109(7.1)863(7.0)2254(5.0)3664(5.7)HER2-/HR+733(47.8)6769(55.2)30809(69.0)45693(70.5)HER2-/HR-360(23.5)2398(19.6)5756(12.9)7781(12.0) APCHER2+/HR+5.44.93.94.4HER2+/HR-1.22.14.43.2HER2-/HR+-1.11.51.91.6HER2-/HR-6.50.5-1.1-1.5 Table 2:Four-Year Breast Cancer SurvivalReceptorsAge 20-2930-3940-4950-59 %(SE) HER2+/HR+95.3(1.7)95.5(0.6)96.0(0.4)94.4(0.4)HER2-/HR+95.0(2.9)91.9(1.3)90.8(0.9)90.8(0.7)HER2-/HR+90.6(1.6)93.1(0.4)96.2(0.2)95.6(0.1)HER2-/HR-82.2(2.8)80.3(1.1)82.8(0.7)82.5(0.6)SE: standard error Citation Format: Thomas A, Rhoads A, Pinkerton E, Melin S, Oleson JJ, McNally LR, Hundley WG, Conway K, Lynch CF, Romitti PA. An early look at incidence and survival by HR and HER2 status among young US women with stage I-III breast cancer: SEER 2010-15 [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-08-03.

Background Scalp cooling has demonstrated efficacy in preventing hair loss in women with early stage breast cancer receiving neo/adjuvant chemotherapy. Data from 2 prospective trials (Rugo et al, and Nangia et al, JAMA 2017) led to FDA clearance of 2 automated scalp-cooling devices to prevent chemotherapy induced alopecia (CIA). Although scalp metastases from breast cancer are rare, historical concerns about scalp cooling included a theoretical increase in risk of recurrence in scalp due to reduced delivery of chemotherapy to the scalp. Methods We conducted a multicenter prospective trial evaluating the efficacy and safety of the DigniCap in women with stage I-II breast cancer receiving neo/adjuvant chemotherapy excluding sequential or combination anthracycline/taxanes with concurrent matched controls. The primary endpoint was unblinded patient self-assessment of 5 photographs using the Dean scale to estimate hair loss 4 weeks following the last dose of chemotherapy, with success defined as a Dean score of 0-2 (≤ 50% hair loss); additional endpoints included quality of life (QOL) and both short and long-term safety. Results 106 patients using the scalp cooling device and 16 concurrent controls were enrolled. As previously reported, the use of scalp cooling was associated with less alopecia and improvement in several measures of QOL (Rugo et al, JAMA 2017). 91 patients have follow-up (FU) out to 3 years; 73 with estrogen receptor (ER) positive and 18 with ER negative disease. 5 DigniCap patients have developed recurrent breast cancer in breast (n=1), liver (n=1), bone, liver and breast (n=1), bone, liver, lung, and nodes (1), and bone, breast, GI tract and bladder (n=1). Of 12 control patients with available FU, 1 developed metastases to liver. 2 patients have died of metastatic disease, one in the DigniCap arm and one in the control arm. No new safety signals have been detected. Conclusion Scalp cooling using the DigniCap system in patients with early stage breast cancer receiving taxane based neo/adjuvant chemotherapy is safe and effective. No scalp metastases have been reported 3 years following completion of study treatment. 4 year FU data will be presented. The study was funded by The Lazlo Tauber Family Foundation (UCSF), the Anne Moore Breast Cancer Research Fund (Weil Cornell), and the Friedman Family Foundation (Mount Sinai Beth Israel), as well as partially by Dignitana. Citation Format: Rugo HS, Klein P, Melin SA, Hurvitz SA, Melisko ME, Moore A, D'Agostino, Jr. RB, Deluca A, Cigler T. Long-term safety follow-up of patients with early stage breast cancer treated with scalp cooling on the Dignitana scalp cooling trial [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-17-04.

1553 Background: Cancer survivors receiving potentially cardiotoxic chemotherapy are at increased risk for developing left ventricular (LV) dysfunction. We implemented machine learning (ML) models to predict future LV dysfunction in patients with breast cancer or lymphoma scheduled to receive potentially cardiotoxic chemotherapy. Methods: We utilized prospectively collected data from NIH studies R01HL118740 (supported by the Wake Forest NCORP Research Base (UG1CA189824)) and R01CA167821. Data included measurements of LV function and demographic factors before, during, and 24 months after initiating potentially cardiotoxic chemotherapy. The two datasets were used both separately and collectively in the development of multiple ML models including penalized linear regression, support vector machine, and random forest (RF). A data preprocessing step properly handled missing information, data imbalance, and encoding. Hyperparameter tuning was performed using cross validation of training data. The final models were assessed with a 20% hold-out test dataset. Cardiotoxicity was defined as a pre- to 24-month post cancer treatment decline in LV ejection fraction (LVEF) of > 10% or to an absolute value of < 50%. Results: 276 patients were included in ML models (7% men, 93% women; age 52±13 years). The RF model based on the combined dataset had the best performance with a prediction accuracy, sensitivity, and specificity of 0.94, 0.81, and 0.98, respectively. The most important variables assessed pre-treatment as measured by the Gini impurity factor were in descending order, LVEF, global LV circumferential strain, LV end-systolic volume, body mass index, LV stroke volume, LV end-diastolic volume, and LV mass. Conclusions: Prior to cancer treatment, supervised ML methods such as RF models predicted declines in LVEF of > 10% and/or to absolute values below 50% would occur 24 months after initiating chemotherapy for breast cancer or lymphoma. With further improvement and validation using larger datasets, these models may play an important role in cardio-oncology care during and following cancer treatment.

12072 Background: Statins taken for cardiovascular (CV) indications by breast cancer (BC) and lymphoma survivors during doxorubicin (DOX) treatment may attenuate left ventricular ejection fraction (LVEF) decline, but statin impact among these survivors with no CV indications is unknown. Methods: In 279 patients from 31 cancer centers, we conducted a double blind, placebo-controlled, 24-month randomized trial of 40mg/day atorvastatin among those receiving DOX for BC or lymphoma. At pretreatment, six and 24 months after initiating DOX for BC or lymphoma, we assessed LV volumes, strain, mass, and LVEF (via cardiac magnetic resonance), cognitive function and serum markers of inflammation. Using a linear model adjusted for pretreatment measures, our primary analysis assessed change in LVEF over time by randomization group. Results: Participants were aged 49±12 years; 92% women, 83% white race. The mean pooled LVEF decline from pretreatment to 24 months was 62.2±6.0% to 57.6±6.3% (p < 0.001). Adjusting for pretreatment LVEF, 24-month declines in LVEF averaged 3.5±0.5% and 3.3±0.5% respectively for placebo vs statins (p = 0.83). Both randomized groups were similar for: incidence of > 10% change in LVEF, LV strain, LV mass, cognition and inflammation biomarkers, including among those > 90% study drug compliant (p > 0.05 for all). Conclusions: In BC and lymphoma survivors with no existing indication for statin therapy, prospective statin administration does not appear to impact LVEF declines two years after doxorubicin. Clinical trial information: NCT01988571. [Table: see text]

Importance Indoleamine 2,3-dioxygenase 1 (IDO1) causes tumor immune suppression. The IDO1 pathway inhibitor indoximod combined with a taxane in patients with ERBB2-negative metastatic breast cancer was tested in a prospective clinical trial. Objective To assess clinical outcomes in patients with ERBB2-negative metastatic breast cancer treated with indoximod plus a taxane. Design, setting, and participants This phase 2 double-blinded randomized 1:1 placebo-controlled clinical trial enrolled patients at multiple international centers from August 26, 2013, to January 25, 2016. Eligibility criteria included ERBB2-negative metastatic breast cancer, ability to receive taxane therapy, good performance status, normal organ function, no previous immunotherapy use, and no autoimmune disease. The study was discontinued in June 2017 because of lack of efficacy. Data analysis was performed from February 2019 to April 2020. Interventions A taxane (paclitaxel [80 mg/m2] weekly 3 weeks on, 1 week off, or docetaxel [75 mg/m2] every 3 weeks) plus placebo or indoximod (1200 mg) orally twice daily as first-line treatment. Main outcomes and measures The primary end point was progression-free survival (PFS); secondary end points were median overall survival, objective response rate, and toxic effects. A sample size of 154 patients would detect a hazard ratio of 0.64 with 1-sided α = .1 and β = .2 after 95 events. Archival tumor tissue was stained with immunohistochemistry for IDO1 expression as an exploratory analysis. Results Of 209 patients enrolled, 169 were randomized and 164 were treated (85 in the indoximod arm; 79 in the placebo arm). The median (range) age was 58 (29-85) years; 166 (98.2%) were female, and 135 (79.9%) were White. The objective response rate was 40% and 37%, respectively (indoximod vs placebo) (P = .74). The median (range) follow-up time was 17.4 (0.1-39.4) months. The median PFS was 6.8 months (95% CI, 4.8-8.9) in the indoximod arm and 9.5 months (95% CI, 7.8-11.2) in the placebo arm (hazard ratio, 1.2; 95% CI, 0.8-1.8). Differences between the experimental and placebo arms in median PFS (6.8 vs 9.5 months) and overall survival (19.5 vs 20.6 months) were not statistically significant. Grade 3 or greater treatment-emergent adverse events occurred in 60% of patients in both arms. Conclusions and relevance This randomized clinical trial found that, among patients with ERBB2-negative metastatic breast cancer, addition of indoximod to a taxane did not improve PFS compared with a taxane alone. Trial registration ClinicalTrials.gov Identifier: NCT01792050.

Purpose: Low-dose tamoxifen reduces breast cancer risk, but remains untested in chest-irradiated cancer survivors—a population with breast cancer risk comparable with BRCA mutation carriers. We hypothesized that low-dose tamoxifen would be safe and efficacious in reducing radiation-related breast cancer risk. Patients and Methods: We conducted an investigator-initiated, randomized, phase IIb, double-blinded, placebo-controlled trial (FDA IND107367) between 2010 and 2016 at 15 U.S. sites. Eligibility included ≥12 Gy of chest radiation by age 40 years and age at enrollment ≥25 years. Patients were randomized 1:1 to low-dose tamoxifen (5 mg/day) or identical placebo tablets for 2 years. The primary endpoint was mammographic dense area at baseline, 1 and 2 years. IGF-1 plays a role in breast carcinogenesis; circulating IGF-1 and IGF-BP3 levels at baseline, 1 and 2 years served as secondary endpoints. Results: Seventy-two participants (low-dose tamoxifen: n = 34, placebo: n = 38) enrolled at a median age of 43.8 years (35–49) were evaluable. They had received chest radiation at a median dose of 30.3 Gy. Compared with the placebo arm, the low-dose tamoxifen arm participants had significantly lower mammographic dense area (P = 0.02) and IGF1 levels (P < 0.0001), and higher IGFBP-3 levels (P = 0.02). There was no difference in toxicity biomarkers (serum bone-specific alkaline phosphatase, lipids, and antithrombin III; urine N-telopeptide cross-links) between the treatment arms. We did not identify any grade 3–4 adverse events related to low-dose tamoxifen. Conclusions: In this randomized trial in chest-irradiated cancer survivors, we find that low-dose tamoxifen is effective in reducing established biomarkers of breast cancer risk and could serve as a risk-reduction strategy.

Background Young premenopausal women with breast cancer often experience more aggressive disease biology and poorer survival than older women. Diagnostic and therapeutic advances, including human epidermal growth factor receptor 2 (HER2)-directed therapy, may lessen treatment burden and improve survival for these young women, but contemporary incidence and survival data by HER2 status are limited. Patients and Methods We identified women aged 20-49 years (n = 68,530) diagnosed with stage I-III breast cancer during 2010-2016 from the United States Surveillance, Epidemiology, and End Results 18 registries database. Age-adjusted average annual percent changes in incidence (diagnosis 2010-2016) and 5-year Kaplan-Meier survival curves (diagnosis 2010-2015) were estimated by HER2 and hormone receptor (HR) status and stratified independently by cancer stage and race/ethnicity. Results With increasing age decade, proportions of HER2−/HR+ cancer increased, whereas proportions of HER2+/HR+, HER2+/HR−, and HER2−/HR− decreased. The greatest increases in incidence during 2010-2016 were observed for HER2+ among women aged 20-49 years and HER2−/HR− among women aged 20-29 years. Incidence decreased for HER2−/HR− among women aged 40-49 years. Five-year survival was lowest for HER2−/HR− status compared to other receptor-based subtypes among women aged 20-49 years. HER2+ status was more beneficial for 5-year survival than HR+ status among women aged 20-29 years, with the opposite observed among women aged 30-49 years, particularly those aged 40-49 years. Conclusion HER2+ breast cancer increased among premenopausal women and was also associated with higher early survival within each HR status. HER2−/HR− cancer also increased among women aged 20-29 years and was associated with lower early survival. Our contemporary data provide important insights to help inform preventive and therapeutic strategies for premenopausal women.

Background: Most women consider hair to be an important part of body image. Alopecia is an emotionally traumatic side effect for breast cancer patients undergoing adjuvant chemotherapy. The DigniCap™ Scalp Cooling System is the first scalp cooling system cleared by the US Food and Drug Administration to reduce the likelihood of chemotherapy induced alopecia. Methods: Quality of Life (QOL) data were collected as part of a prospective clinical trial evaluating the clinical performance of scalp cooling in women with early stage BC receiving adjuvant chemotherapy. The study's primary endpoint was hair loss as evaluated by patient self-assessment. Treatment success was defined as ≤ 50% hair loss. QOL was evaluated by the EORTC-QLQ-BR23 (BR23) administered at baseline, last chemotherapy cycle, and one month later. For BR23, 4 response categories were collapsed to 2 categories (Not at all/A little bit and Quite a bit/Very much) for analysis. QOL was compared between those with success vs. failure of scalp cooling. Results: 101 patients were evaluable for the primary endpoint: Success was seen in 67 (66.3%) pts. QOL at study entry was comparable between pts with scalp cooling success or failure for each item in the BR23 questionnaire. Results reported as percentages of patients in each group who answered either quite a bit or very much to body image-related questions on the BR23 questionnaire are displayed in Table 1. BR23 results (% quite a bit/very much) one month after chemotherapyBR23 ItemsTreatment Success % (95% CI)Treatment Failure % (95% CI)Felt physically less attractive18.5% (9.0%, 27.9%)52.2% (31.8%, 72.6%)Felt less feminine15.4% (6.6%, 24.2%)29.1% (19.2%, 59.1%)Found it difficult to see themselves naked13.8% (5.5%, 22.2%)21.7% (4.9%, 38.6%)Felt dissatisfied with their body12.3% (4.3%, 20.3%)26.1% (8.1%, 44.0%) Conclusions: Women with breast cancer using scalp cooling during chemotherapy who had hair preservation experienced improved quality of life, according to self-assessment of body image, compared to women who had significant hair loss. Citation Format: Cigler T, Melin SA, Klein P, Hurvitz SA, Melisko M, Moore A, Park GD, Bageman E, Ver Hoeve ES, Rugo HS. Body image in women with breast cancer using a scalp cooling system to reduce chemotherapy induced alopecia [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P5-11-17.

Introduction: African Americans (AA) present more frequently with triple negative breast cancer (TN) and other aggressive breast cancer subtypes. Invasive lobular (ILC) breast cancer most commonly presents as estrogen receptor (ER)+, progesterone receptor (PR)+ and HER2-, though less frequently the more aggressive ER- or PR- luminal, TN or HER2+ subtypes occur. For women presenting with ILC 2010-2013, we report by race, differences in disease subtype, grade and stage at presentation and 2-year outcomes. Methods: We conducted a retrospective cohort analysis using Surveillance, Epidemiology and End Results Program. Women diagnosed with first primary malignant lobular breast cancer from 2010-2013 were included. Subtypes were categorized into four exclusive groups: ER+ and PR+ HER2-, ER+ or PR+ HER2-, TN and HER2+. Two-year survival was compared across race, and a multivariate cox model assessed overall survival. Results: ILC occurred less frequently in non-whites (Table 1). AA and other non-whites were younger at diagnosis than whites (p Conclusion: In this large, recent ILC cohort there were significant racial disparities in disease biology at presentation, with non-whites having more aggressive ILC subtypes, but only AAs having higher grade ILC. Short-term survival outcomes were inferior for AAs. Whether AAs presenting with advanced stage disease more frequently is due to biology or access to care is unknown. Further study of disease biology and healthcare delivery disparities could offer improved outcomes for AAs with ILC. Table 1: ILC Characteristics by Race WhiteAA Other non-white N13,5571,445 957 ILC - % diagnoses per race category9.67.2 5.8 Rate of ILC (per 100,000 women of that race)10.56.4 4.4 Median Age6461 60 %%OR*p%OR*pSubtype ER+ and PR+ HER2-80.978.30.850.01977.00.790.003ER+ or PR+ HER2-12.914.41.140.10615.31.220.036TN1.52.11.440.0642.11.400.158HER2+4.75.11.090.4735.61.210.186Stage I40.536.4 39.0 Table 2: Multivariate Cox Model for 2-year Survival HRp95% CIRace Whiteref AA1.320.0101.071.64Other non-white0.580.0080.380.87Subtype ER+ and PR+ HER2-ref ER+ or PR+ HER2-1.80 Citation Format: Thomas A, Altekruse S, Avery TP, Melin SA, Howard-McNatt MM, Schroeder MC. African Americans have more aggressive invasive lobular carcinoma subtypes and inferior early outcomes: SEER 2010-2013 [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P5-10-02.

BACKGROUND: Our study aim was to evaluate neuromuscular ultrasound (NMUS) for the assessment of taxane chemotherapy-induced peripheral neuropathy (CIPN), the dose-limiting toxicity of this agent. METHODS: This cross-sectional study of breast cancer patients with taxane CIPN measured nerve cross-sectional area (CSA) by NMUS and compared with healthy historical controls. Correlations were determined between CSA and symptom scale, nerve conduction studies, and intraepidermal nerve fiber density (IENFD). RESULTS: A total of 20 participants reported moderate CIPN symptoms at a median of 3.8 months following the last taxane dose. Sural nerve CSA was 1.2 mm(2) smaller than healthy controls (P ≤ .01). Older age and time since taxane were associated with smaller sural nerve CSA. For each 1 mm(2) decrease in sural nerve CSA, distal IENFD decreased by 2.1 nerve/mm (R(2) 0.30; P = .04). CONCLUSIONS: These data support a sensory predominant taxane neuropathy or neuronopathy and warrant future research on longitudinal NMUS assessment of CIPN.

Introduction: Premenopausal women with high-risk hormone receptor-positive (HR+) breast cancer (BC) undergo abrupt menopause induction with aromatase inhibitor (AI) anti-estrogen therapy and ovarian function suppression (OFS). This treatment improves recurrence-free survival but may increase cardiovascular (CV) risk associated with early hypoestrogenemia as observed in women with non-cancerous reasons for early loss of ovarian function. We sought to identify if OFS+AI therapy is associated with myocardial perfusion changes, a subclinical marker of coronary heart disease. Methods: We evaluated women with paired adenosine cardiovascular magnetic resonance imaging scans at 3-to 6-month intervals using cines and T1 maps in standard short-axis planes. As increased blood flow from vasodilation increases adenosine stress parametric T1 values of the myocardial tissue, the myocardial perfusion reactivity was calculated from the percent increase of stress versus native (pre-stress) T1 maps. Double-blinded post-processing of images was performed in CircleCVI software. Statistical analyses were performed in MATLAB (p0.05). The cardiovascular stress tests identified two HR+ women (14%) with abnormal results during stress imaging who were sent for further cardiovascular evaluations.Conclusions: Women with HR+ BC treated with OFS+AI exhibited a decline in global microcirculatory perfusion during an adenosine cardiac stress test with normal LV functional parameters. Alternatively, triple negative BC patients trended to have an improvement in LV function during the interval with non-significant improvement in myocardial perfusion. This study demonstrates a decline in myocardial perfusion in premenopausal women on OFS+AI therapy, suggesting subclinical coronary artery effects due to early hypoestrogenemia. Future work should confirm these results, identify women at higher risk, and test strategies to mitigate cardiotoxicity in premenopausal women with HR+ BC. Table: Cardiovascular magnetic resonance (CMR) study measures for HR+ BC patients on OFS+ AI therapy and triple negative BC patientsCMR MeasureHormone Receptor-Positive Breast Cancer(n=14)Triple Negative Breast Cancer(n=7)p-value for difference in change by groupBaselineFollow-upp-valueBaselineFollow-upp-valueLV Ejection Fraction, %56 (51, 61)56 (51, 62)0.8255 (50, 60)60 (55, 65)0.060.12EDVindex, mL/m270.6 (63.7, 77.5)69.9 (63.5, 76.3)0.7365.2 (58.0, 72.3)66.8 (51.4, 82.1)0.740.60ESVindex, mL/m231.3 (26.2, 36.5)30.4 (26.2, 34.5)0.3729.4 (23.8, 35.0)27.1 (19.4, 34.8)0.360.55SVindex, mL/m239.3 (34.3, 44.2)39.5 (33.9, 45.1)0.9035.8 (32.3, 39.3)39.7 (31.2, 48.2)0.230.29Myocardial mass index, g/m248.1 (42.7, 53.6)44.6 (40.0, 49.3)0.0843.5 (40.2, 46.8)41.0 (33.3, 48.7)0.420.77Global myocardial perfusion reactivity, %2.8 (1.1, 4.4)1.4 (-0.4, 3.3)0.191.4 (-0.9, 3.7)4.6 (0.9, 8.4)0.130.02Basal SAX myocardial perfusion reactivity, %2.2 (0.7, 3.7)1.4 (0.3, 2.5)0.261.8 (0.2, 3.4)2.1 (-1.7, 5.9)0.850.46Mid SAX myocardial perfusion reactivity, %2.4 (-.3, 5.2)0.5 (-1.5, 2.7)0.221.2 (-1.9, 4.2)3.3 (-0.9, 7.6)0.360.12Apical SAX myocardial perfusion reactivity, %3.4 (1.2, 5.7)2.1 (-1.4, 5.7)0.490.8 (-2.6, 4.1)8.8 (3.7, 13.9) Citation Format: Alexandra Thomas, Ralph B. D'Agostino, Jr., Katherine C. Ansley, Sung Park, Anuj Kotak, Steven M. Sorscher, Susan Melin, Emily H. Douglas, Sujethra Vasu, Paul A. Romitti, William G. Hundley, Jennifer H. Jordan. Global myocardial perfusion is reduced in premenopausal breast cancer patients treated with ovarian function suppression and aromatase inhibitor therapy: An adenosine stress T1 map CMR study [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS13-02.

Background Evidence-based medicine (EBM) is a key aspect of medical training that can be challenging for trainees to learn. Tumour boards (TBs) are multidisciplinary meetings that are often opportunities for trainees to deliver patient case presentations, which is another integral part of medical education; however, TBs are time intensive, typically lack academic structure and may fail to emphasise EBM. Objective To design a systematic approach to improve both trainee satisfaction and the level of evidence cited at typical academic TBs. Methods From 2017 to 2018, Plan-Do-Study-Act (PDSA) methodology was used to develop a systematic approach for medical oncology trainees towards TBs. Statistical testing was used to assess which characteristics of a patient case made it more difficult to apply EBM. Anonymous surveys were distributed to trainees before and after the intervention to assess the educational utility. Results We developed a shared voluntary case database, so that references with higher levels of evidence could be rapidly recalled and applied to similar cases. We then developed EBM-focused review sessions to highlight database trends. Both the database and the review sessions had high participation rates (>90% cases had voluntary data entry), and each were reported to have educational value by trainees. Conclusions A two-step implementation of an easy-to-use case database followed by review sessions focused on high-yield sources of evidence improved trainee satisfaction for TBs, but did not significantly improve the strength of the evidence cited.

Purpose The risk of scalp metastases in patients using scalp cooling for preservation of hair during chemotherapy has been a concern but is poorly described. Methods A systematic review and meta-analysis of longitudinal studies was undertaken to evaluate the effect of scalp cooling versus no scalp cooling on the risk of scalp metastasis in patients treated for breast cancer with chemotherapy. Electronic databases, journal specific, and hand searches of articles identified were searched. Patients were matched based on disease, treatment, lack of metastatic disease, and sex. Results A total of 24 full-text articles were identified for review. Of these articles, ten quantified the incidence of scalp metastasis with scalp cooling over time. For scalp cooling, 1959 patients were evaluated over an estimated mean time frame of 43.1 months. For no scalp cooling, 1238 patients were evaluated over an estimated mean time frame of 87.4 months. The incidence rate of scalp metastasis in the scalp cooling group versus the no scalp cooling group was 0.61% (95% CI 0.32–1.1%) versus 0.41% (95% CI 0.13–0.94%); P = 0.43. Conclusion The incidence of scalp metastases was low regardless of scalp cooling. This analysis suggests that scalp cooling does not increase the incidence of scalp metastases. Electronic supplementary material The online version of this article (doi:10.1007/s10549-017-4185-9) contains supplementary material, which is available to authorized users.

Background: Lymphoma patients exposed to chest RT during adolescence/young adulthood are at increased risk for BC; the cumulative incidence exceeds 20% by age 45 and the BC risk is comparable to that in women with BRCA1 mutations. These findings present an urgent yet unmet need to reduce the risk of BC in RT-exposed lymphoma survivors. The risk of BC is 50% lower in chest RT-exposed survivors who also receive ovarian radiation, suggesting a critical role of endogenous estrogens in RT-related breast carcinogenesis, making tamoxifen (a selective estrogen receptor modulator) an attractive risk-reducing option. Tamoxifen administered at 20 mg/d is effective in BC prevention in other high risk populations, but severe adverse events (SAE: venous thromboembolism, endometrial cancer) have limited its broad use. Previous biomarker trials in the general population have shown that LDTam (5mg/d) is not inferior to tamoxifen at 20 mg/d in reducing BC risk, and is associated with a safer AE profile. Mammographic breast density (MBD) is an established biomarker of BC risk; high MBD is associated with a 4-fold higher risk of BC. We hypothesized that LDTam would be effective in reducing BC risk (using MBD as a primary endpoint) in chest RT-exposed lymphoma survivors. We used an investigator-initiated, multi-institutional, randomized phase IIb, double blind, placebo controlled trial (FDA IND 107367) to test this hypothesis. Methods: Female patients from 13 sites were ≥25y at enrollment, with a history of exposure to chest RT at ≥12 Gy by age 40 for their primary cancer, and were off therapy for ≥6 mo. Subjects with a prior history of BC/DCIS, B/L mastectomy, or baseline MBD Results: A total of 72 patients (LDTam: n=34; placebo: n=38) participated in the trial; primary diagnosis: Hodgkin lymphoma (86%); non-Hodgkin lymphoma (10%); other (3%); median age at diagnosis of primary cancer: 21.5y (IQR, 16-28), and at trial enrollment: 43.8y (35-49); median time from diagnosis of primary cancer to study: 17.0y (12-26). Median chest RT dose: 30.3 Gy (21-37.3); 11% had received pelvic radiation; 39% were post-menopausal at study. Participant characteristics were comparable between the two treatment arms, as was the mean baseline MBD (LDTam: 52.6% vs. placebo: 50.4%, p=0.6). The time*treatment arm effect was statistically significant (LDTam vs. placebo: estimate = -1.7, SE = 0.5, p = 0.001), indicating a significantly lower mean fitted MBD for LDTam (43.9%) vs. placebo (47.3%) at 2y (Figure). This represented a 16.5% relative reduction in MBD on the LDTam arm, corresponding to an estimated 33% lower risk of BC (assuming that reductions in MBD have the same benefit in lymphoma survivors as they do in the general population). There were no grade 3 or 4 AEs related to LDTam. Grade 2 AEs did not differ between treatment arms (LDTam: 44.1% vs. placebo: 36.8%, p=0.6). There was no difference in the prevalence of moderate-to-severe patient-reported outcomes between the treatment arms (Table). Conclusion: Low-dose tamoxifen was associated with a significantly steeper decline in MBD in chest RT-exposed lymphoma survivors, when compared with placebo, and was safe and well-tolerated. This is the first trial demonstrating efficacy of a pharmacologic intervention in reducing a biomarker strongly associated with breast cancer risk in lymphoma survivors with a past history of chest radiation. Disclosures Palomares: Covance: Other: Medical monitoring. Henderson:Seattle Genetics: Research Funding. OffLabel Disclosure: The drug is a low-dose tamoxifen, a selective estrogen receptor modulator. Tamoxifen in standard doses is used to reduce the risk of breast cancer in high risk populations. Tamoxifen in standard or low doses have not been tested before for chest-irradiated cancer survivors to reduce the risk of radiation-related breast cancer.

e13084 Background: Although targeted therapies directed at human epidermal growth factor-2 (HER2) impact breast cancer outcomes, studies have found geographic variation in testing rates. We report population-based patterns of HER2 testing by patient, tumor and geographic characteristics. Methods: Retrospective analysis of Surveillance, Epidemiology, and End Results (SEER) data included women diagnosed 2010-2015 with de novo breast cancer. Women were categorized by age, race, stage, year of diagnosis, and receipt of estrogen receptor (ER), progesterone receptor (PR), and HER2 testing. SEER classified lack of testing with “test ordered, results not in chart” and “test not done.” We report on cases with HER2 “test not done”. Records missing any variables were excluded. County-level measures of socioeconomic status were included for each woman. Univariate and multivariate logistic regressions identified factors associated with testing. Results: Of 281,214 new breast cancer diagnoses, 1.75% had HER2 “test not done”. ER and PR testing were “not done” in 0.57% and 0.74% of cases, respectively. HER2-testing rates improved over time: 2.54% not tested in 2010 and 1.30% in 2015 (p < 0.01). The following characteristics were associated with higher rates of “test not done”: age >70 vs < 50 (OR = 1.33, p < 0.01), blacks vs whites (OR = 1.23, p < 0.01), Stage IV vs I (OR = 2.27, p < 0.01). Regional variation was also seen, with registries reporting HER2 “test not done” ranging from 0.18%-2.89%. On multivariate analysis (Table), HER2 testing was less likely for women age ≥ 70, blacks, Stage IV disease, and those living in counties with high rates of less than high school education. Conclusions: Rates of HER2 testing have increased. However, disparities exist and are associated with age, race, stage, geography, and education. Understanding the cause of these disparities could ultimately enhance access to appropriate therapy and improve disease outcomes. Odds of not having HER2 testing (select results from multivariate analysis). [Table: see text]

e23152 Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting toxicity for breast cancer patients that leads to early treatment discontinuation and worse outcomes. Neuromuscular ultrasound (NMUS) is a non-invasive assessment of peripheral nerves that has not been studied in taxane CIPN. Methods: This cross-sectional study enrolled breast cancer patients with subjective complaints of CIPN symptoms during or after taxane chemotherapy and compared nerve cross-sectional area (CSA) by NMUS with historical values in 120 healthy adults. Findings were correlated with self-reported symptom scale (EORTC-QLQ CIPN20, range 0-72, higher more severe); nerve conduction studies; and skin biopsies for intraepidermal nerve fiber density (IENF). Results: We evaluated 20 participants (mean 55.4 ± 10.5 yrs) with NMUS at 74 nerve sites after median 3.7 months (IQR 1.0-6.1) since last taxane (paclitaxel 10, docetaxel 8, nab-paclitaxel 2). Participants reported moderate-to-severe CIPN symptoms which were predominantly sensory (19.1 ±4.9, max 32) as opposed to motor (15.6 ±5.8, max 32) or autonomic (3.3 ±1.6, max 8). Sural sensory nerve CSA was 1.2 mm2 smaller than in historical controls (4.1 vs. 5.3 mm2, 2-sample t-test p = 0.005) and decreased with more days from last taxane (Spearman’s r -0.46, p = 0.04). Tibial motor nerve was not significantly different from controls (p = 0.35). Median nerve CSA was enlarged at the distal wrist crease entrapment site (12.5 vs 10.1, p = 0.03). Older age was associated with smaller sural CSA (r = -0.72, p < 0.001). When controlling for age and days from last taxane, for each 1mm2 decrease in sural CSA, distal IENF reduced by 2.1 nerve/mm2 (p = 0.04, R2 = 0.30). Conclusions: NMUS showed expected sensory predominant distal axonopathy in taxane CIPN. Evaluation of nerve CSA by non-invasive NMUS may serve as an objective point-of-care assessment to risk-stratify women with taxane CIPN prior to the development of debilitating symptoms. Clinical trial information: NCT03139435. [Table: see text]

The vitamin D hormone, [1,25(OH) 2D, calcitriol], inhibits proliferation and angiogenesis in breast cancer but its therapeutic use is limited by hypercalcemia. Synthetic analogs of 1,25(OH) 2D that are less calcemic, such as paricalcitol (19-nor-1,25-Dihydroxyvitamin D 2), are used to treat hyperparathyroidism associated with chronic kidney disease. We sought to determine the safety and feasibility of taking oral paricalcitol with taxane-based chemotherapy in women with metastatic breast cancer (MBC). Oral paricalcitol was considered safe if it did not result in excessive toxicity, defined as grade 3 or higher serum calcium levels. It was considered feasible if the majority of women could take eight weeks of continuous therapy in the first three months. Serum calcium was monitored weekly and the paricalcitol dose was adjusted based on its calcemic effect. Intact parathyroid hormone (iPTH) was monitored as a marker of paricalcitol activity. Twenty-four women with MBC were enrolled. Twenty women (83%) received eight weeks of continuous therapy. Paricalcitol was well-tolerated with no instances of hypercalcemia grade 2 or greater. Fourteen women (54%) were able to escalate the dose. The dose range of paricalcitol in the first 3 mo was 2-7 ug/day. Serum iPTH levels at baseline were significantly higher in women with serum 25-Hydroxyvitamin D (25-OHD) levels less than 30 ng/ml (96.4 ± 40.9 pg/ml) vs. 46.2 ± 20.3 pg/ml (p = 0 0.001) (iPTH reference 12-72 pg/ml). We conclude that paricalcitol is safe and feasible in women with MBC who are receiving chemotherapy.

Background: Alopecia is a non-life threatening complication of adjuvant CTX for early stage BC. CTX induced hair loss affects quality of life and potentially impacts decisions regarding the risks and benefits of treatment. Scalp cooling (SC), used internationally by thousands of patients (pts) including a growing number in the U.S., is thought to prevent hair loss through decreased follicular metabolic rate and vasoconstriction resulting in reduced delivery and cellular uptake of drugs. The DigniCap™ System is a self-contained SC system with circulating coolant. We sought to evaluate feasibility and efficacy of the DigniCap™ System in pts with stage I BC. Methods: We performed an initial prospective feasibility study before a planned pivotal trial. The primary endpoint was feasibility, defined as 75% HL). Pts assessed their own HL using the Dean's scale, and pt-assessed quality of life, time to and quality of hair re-growth, and impact of HL on treatment decisions were also evaluated. Successful prevention of alopecia was defined as < grade 2 HL by the Dean's scale. Eligibility included stage I disease and excluded use of anthracycline-taxane combination or sequential CTX. Results: 20 pts were enrolled. CTX regimens included: docetaxel and cyclophosphamide (TC) × 4–6 cycles (n = 16), weekly paclitaxel and trastuzumab × 12 (n = 2), and docetaxel, carboplatin, and trastuzumab (TCH) × 6 (n = 2). 19 of 20 pts (95%) completed all CTX using the DigniCap™ System. By IP assessment, 15 pts (75%) had a maximum of ≤ grade 2 HL; 2 pts (10%) and 3 pts (15%) had a maximum grade 3 or 4 HL respectively. By pt assessment, 11 pts (55%) reported ≤ grade 2 HL. 68% and 32% of pts reported grade 1 or 2 toxicity, respectively, including head/scalp pain, feeling chilled, and rash. 85% of pts reported that SC made decisions about CTX easier. At a median follow-up of 15.4 months, no scalp metastases have been observed. Conclusions: Use of the DigniCap™ System is feasible, effective in preventing CTX-induced alopecia in the majority of users, and safe with short-term follow-up in pts with stage I BC. Additional studies should help to define potential causes for cap failure. This is the first prospective US trial to evaluate the effect of SC using an expert IP and blinded photographs to assess extent of alopecia. A larger trial is planned to confirm these results in pts with stage I/II disease. Support for this trial was provided by the Tauber Foundation (UCSF), the Madonia and Cooper Funds (WFBH), and Dignitana. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-12-11.

e22083Background: Chemotherapy-induced peripheral neuropathy (CIPN) occurs in 40% of breast cancer patients receiving taxanes and may lead to early treatment discontinuation. Taxane microtubular hy...

Milataxel is a novel taxane analog, with evidence of enhanced preclinical activity compared to paclitaxel and docetaxel, especially in cell lines that over express P-glycoprotein. Based on preclinical data that milataxel may be active in colorectal cancer (CRC), a phase II study was performed in patients with advanced previously treated CRC.Forty-four eligible patients were entered. Milataxel was administered intravenously every 3 weeks at the dose of 35 mg/m(2). No objective responses were noted, stable disease was seen in three patients. The median time to progression was 1.4 months (95% CI of 1.2-2.4 months). Three subjects developed neutropenic sepsis and two died. The most frequent grade 3/4 adverse events were neutropenia (57%), leukopenia (27%), dehydration (14%), neuropathy (16%), diarrhea (14%) and thrombocytopenia (14%). The pharmacokinetics of milataxel was assessed in five subjects. The mean milataxel elimination half-life was 64 h and the mean area under the plasma concentration-time curve was 1,708 ng h/ml.A syndrome of neutropenic sepsis and diarrhea can be life threatening and close surveillance is needed in patients treated with milataxel at the dose of 35 mg/m(2) every 3 weeks. Clinical activity was not demonstrated in patients with advanced previously treated CRC.

Background The primary objectives of this phase I study were to define a tolerable dose and to describe the toxicity of lenalidomide administered as a daily oral dose for 4 weeks followed by a 2-week rest period (6-week cycle) in patients with solid tumors that were refractory to standard treatment. The secondary objective was to document any antitumor activity. Methods Key eligibility criteria included a performance status of 0–2 and acceptable hematologic, hepatic, and renal function. The dose was escalated from 5 to 10 to 25 mg/day. Nine cycles (54 weeks) were planned unless the patient developed intolerable toxicity or experienced tumor progression. Dose-limiting toxicity was defined as nonhematologic toxicity of grade 3 or higher and hematologic toxicity of grade 4 or higher occurring in cycle 1. Results Overall, 20 patients were enrolled. One patient was ineligible due to a thromboembolic event within the preceding 6 months, but this was not known at enrollment and this patient was included in the analysis. Three, five, and 12 patients were treated with 5, 10, and 25 mg/day, respectively. One patient on 25 mg/day developed grade 3 motor neuropathy in cycle 1, and this was the only dose-limiting toxicity. Moderate dose-dependent and reversible hematologic toxicity was observed. The nonhematologic toxicities were otherwise mild to moderate over multiple cycles of lenalidomide. One patient had a partial response, and three patients had stable disease; three of these patients had non-small cell lung cancer. Conclusion The recommended dose of lenalidomide for further studies in patients with solid tumors is 25 mg/day for 4 weeks followed by a 2-week rest period.

Purpose: Women with metastatic triple negative breast cancer (TNBC) can have a poor prognosis with treatment limited to cytotoxic chemotherapy. The identification of effective therapies that may limit exposure to cytotoxic chemotherapy and lead to prolonged survival is an unmet medical need. We tested an inhibitor of the epidermal growth factor receptor, panitumumab in combination with chemotherapy. Methods: We conducted a single arm clinical trial in women with metastatic or locally advanced TNBC to paclitaxel 80 mg/m2 and carboplatin AUC of 2 on days 1, 8, and 15 and panitumumab 6 mg/kg on days 1 and 15 for a cycle length of 28 days. The objectives were to evaluate the response rate and safety of the combination in comparison to historical controls. Results: Fourteen patients with TNBC were enrolled with a median age of 53 years. The majority of women were African American (64.3%) with visceral metastasis (64.2%). Hematologic toxicities, particularly neutropenia and thrombocytopenia, were a major cause of missed chemotherapy and delayed treatment in this study. The overall response rate (complete and partial response) of the 13 evaluable patients was 46%. The median time to best response was 2.4 months and the median time to disease progression was 3.6 months. We were able to perform the PAM50 analysis on tumors from 7 of our subjects. All the samples tested clustered within the basal-like subtype. Conclusions: In our experience the response rate of carboplatin, paclitaxel and panitumumab was consistent with other reports of response for cytotoxic chemotherapy in metastatic TNBC.

The safety and efficacy of gemcitabine and concurrent radiation to the upper abdomen followed by weekly gemcitabine in patients with resected pancreatic cancer was determined. Patients with resected adenocarcinoma of the pancreas were treated with intravenous gemcitabine administered twice-weekly (40 mg m(-2)) for 5 weeks concurrent with upper abdominal radiation (50.4 Gy in 5(1/2) weeks). At the completion of the chemoradiation, patients without disease progression were given gemcitabine (1000 mg m(-2)) weekly for two cycles. Each cycle consisted of 3 weeks of treatment followed by 1 week without treatment. Forty-seven patients were entered, 46 of whom are included in this analysis. Characteristics: median age 61 years (range 35-79); 24 females (58%); 73% stage T3/T4; and 70% lymph node positive. Grade III/IV gastrointestinal or haematologic toxicities were infrequent. The median survival was 18.3 months, while the median time to disease recurrence was 10.3 months. Twenty-four percent of patients were alive at 3 years. Only six of 34 patients with progression experienced local regional relapse as a component of the first site of failure. These results confirm the feasibility of delivering adjuvant concurrent gemcitabine and radiation to the upper abdomen. This strategy produced good local regional tumour control.

To evaluate the utility of F-FDG-PET in predicting response to concomitant chemoradiation in locally-advanced esophageal cancer.Approximately 25% of esophageal cancer patients experience a pathologic complete response (pCR) to preoperative chemoradiation therapy. Computed tomography, endoscopy, and endoscopic ultrasound are unable to identify patients experiencing a pCR. Growing evidence supports the use of F-FDG-PET in the staging of esophageal cancer in its ability to detect occult metastatic and lymph nodal disease. The identification of patients with a pCR to chemoradiation could potentially spare those patients the morbidity associated with a resection.Eligibility criteria included T3-T4N0M0 or T1-T4N1M0 esophageal cancer. Patients underwent an initial F-FDG-PET before treatment and then repeated 4 to 6 weeks after chemoradiation, prior to the esophagectomy. Chemoradiation consisted of: cisplatinum, 5-fluorouracil, and radiation to a median dose of 50.4 Gy. Pathologic response was determined from a systematic review of the esophagectomy specimens.Sixty-four patients have completed therapy to date. Response was as follows: pCR 27%, pathologic residual microscopic (pCRmicro) 14.5%, partial response 19%, and stable or progressive disease 39.5%. A pretreatment standardized uptake value (SUVmax1hour)or = 15 was associated with an observed 77.8% significant response (pCR + pCRmicro) compared with 24.2% for patients with a pretreatment SUVmax1hour15 (P = 0.005). Significant response was observed in 71.4% of patients with a decrease in SUVmax1houror = 10 compared with 33.3% when the SUVmax1hour decreased10 (P = 0.004).Pretreatment and posttreatment F-FDG-PET can be useful for predicting significant response to chemoradiation in esophageal cancer. These data should be considered in evaluation of patients for esophagectomy after chemoradiation.

Purpose: To determine the impact of 18-F-fluoro-deoxy-D-glucose positron emission tomography (FDG-PET) in the staging and prognosis of patients with locally advanced esophageal cancer (LAEC). Methods and Materials: Between January 2000 and October 2004, all patients with LAEC evaluated in the Department of Radiation Oncology were considered for enrollment into a Phase II trial of preoperative chemoradiation. Entry required a staging whole-body FDG-PET scan. Results: One hundred ten consecutive patients were evaluated; 38 were ineligible for reasons including treatment elsewhere, prior malignancy, or refusal of treatment. After conventional staging (clinical examination, endoscopic ultrasound, and chest/abdominal computerized tomography), 33 patients were ineligible because of metastatic disease or poor performance status. Of the remaining 39 patients, 23 were confirmed to have LAEC after FDG-PET staging and were treated in the Phase II trial (Cohort I). Sixteen patients, however, had FDG-PET findings consistent with occult metastatic disease and were deemed ineligible for the trial but were treated with curative intent (Cohort II). The 2-year survival rate for the 23 patients in Cohort I was 64%, compared with 17% ( p = 0.003) for patients in Cohort II (FDG-PET positive). Conclusions: More than one-third of patients determined to have LAEC with conventional staging were upstaged with the use of FDG-PET. Despite comparable therapy, upstaging with FDG-PET predicts poor 2-year survival.

Purpose: This phase II trial of induction irinotecan/gemcitabine followed by twice-weekly gemcitabine and upper abdominal radiation was initiated to determine the activity of this regimen in patients with unresectable pancreatic cancer. Methods: Patients with locally advanced, nonmetastatic adenocarcinoma of the pancreas received 2 cycles of induction irinotecan (100 mg/m 2 IV) and gemcitabine (1000 mg/m 2 IV) on days 1 and 8 of each 3-week cycle. Following the induction, patients without disease progression received gemcitabine administered twice weekly (40 mg/m 2 /day) for 5 weeks concurrent with upper abdominal radiation (50.4 Gy over 5.5 weeks). Results: From April 2000 to August 2003, 20 patients were entered into this study, 17 of whom were evaluable for treatment response. Characteristics included a median age of 67 years (range, 44-87 years) and 14 men (70%). Grades III and IV hematologic toxicity occurred in 25% and 5% of patients respectively and was primarily thrombocytopenia. No grade IV gastrointestinal toxicities or deaths due to therapy were observed. All therapy was completed in 8 patients, 7 patients were removed due to progression, 2 due to toxicity, 2 refused further treatment, and 1 was removed per the treating physician. The median time to progression and median survival was 5.1 months (95% CI, 3.2-6.7) and 8.8 months (95% CI, 6.4-10.1) respectively. Four patients (20%) were alive at 12 and 18 months. Conclusion: Induction irinotecan/gemcitabine followed by twice-weekly gemcitabine and upper abdominal radiation is feasible in patients with locally advanced pancreatic cancer. This regimen, however, has only modest activity and should not be explored further.

ImportanceChemotherapy-induced alopecia is a common and distressing adverse effect. In previous studies of scalp cooling to prevent chemotherapy-induced alopecia, conclusions have been limited.ObjectivesTo evaluate whether use of a scalp cooling system is associated with a lower amount of hair loss among women receiving specific chemotherapy regimens for early-stage breast cancer and to assess related changes in quality of life.Design, setting, and participantsA prospective cohort study conducted at 5 US medical centers of women with stage I or II breast cancer receiving adjuvant or neoadjuvant chemotherapy regimens excluding sequential or combination anthracycline and taxane (106 patients in the scalp cooling group and 16 in the control group; 14 matched by both age and chemotherapy regimen). The study was conducted between August 2013 and October 2014 with ongoing annual follow-up for 5 years.ExposuresUse of a scalp cooling system. Scalp cooling was initiated 30 minutes prior to each chemotherapy cycle, with scalp temperature maintained at 3°C (37°F) throughout chemotherapy and for 90 minutes to 120 minutes afterward.Main outcomes and measuresSelf-estimated hair loss using the Dean scale was assessed 4 weeks after the last dose of chemotherapy by unblinded patient review of 5 photographs. A Dean scale score of 0 to 2 (≤50% hair loss) was defined as treatment success. A positive association between scalp cooling and reduced risk of hair loss would be demonstrated if 50% or more of patients in the scalp cooling group achieved treatment success, with the lower bound of the 95% CI greater than 40% of the success proportion. Quality of life was assessed at baseline, at the start of the last chemotherapy cycle, and 1 month later. Median follow-up was 29.5 months.ResultsAmong the 122 patients in the study, the mean age was 53 years (range, 28-77 years); 77.0% were white, 9.0% were black, and 10.7% were Asian; and the mean duration of chemotherapy was 2.3 months (median, 2.1 months). No participants in the scalp cooling group received anthracyclines. Hair loss of 50% or less (Dean score of 0-2) was seen in 67 of 101 patients (66.3%; 95% CI, 56.2%-75.4%) evaluable for alopecia in the scalp cooling group vs 0 of 16 patients (0%) in the control group (P

BACKGROUND: Black women can have worse outcomes than white women with breast cancer. We examined survival in black and white women who received neoadjuvant chemotherapy. METHODS: We identified 98 women with stage II or III breast cancer who underwent neoadjuvant chemotherapy. Women with inflammatory breast cancer, T4 disease, or metastases were excluded. Data were analyzed using the Fisher exact test and Kaplan-Meier method. RESULTS: From the cohort, 69 women were included. The median follow-up was 6.2 years. The estrogen receptor status was similar. White women tended to overexpress human epidermal growth factor receptor 2 (HER2) (P 5.091). The pretreatment T stage was T3. All women received similar neoadjuvant chemotherapy. The 5-year progression-free survival was better for white women compared with black women (78% vs 58%, P 5 .05). The 5-year overall survival was similar (P 5 .095). CONCLUSIONS: The pretreatment characteristics of women receiving neoadjuvant chemotherapy were similar. Black women had a worse disease-free survival. The overall survival was the same.

• Fifty-eight patients with either advanced or unresectable squamous cell carcinoma of the head and neck were randomly selected to receive either twice daily radiation alone or twice daily radiation plus concomitant chemotherapy with cisplatin and fluorouracil (5-fluorouracil). There was no advantage in survival or time to progression with the addition of chemotherapy to twice daily radiation for patients with advanced resectable cancers. In the group of patients with unresectable cancers, however, there was a statistically significant advantage to the addition of chemotherapy, both in terms of disease-free survival and date to progression. ( Arch Otolaryngol Head Neck Surg . 1992;118:806-810)

Purpose Cancer survivors exposed to anthracyclines experience an increased risk of cardiovascular (CV) events. We hypothesized that anthracycline use may increase aortic stiffness, a known predictor of CV events. Patients and Methods We performed a prospective, case-control study involving 53 patients: 40 individuals who received an anthracycline for the treatment of breast cancer, lymphoma, or leukemia (cases), and 13 age- and sex-matched controls. Each participant underwent phase-contrast cardiovascular magnetic resonance measures of pulse wave velocity (PWV) and aortic distensibility (AoD) in the thoracic aorta at baseline, and 4 months after initiation of chemotherapy. Four one-way analyses of covariance models were fit in which factors known to influence thoracic aortic stiffness were included as covariates in the models. Results At the 4-month follow-up visit, aortic stiffness remained similar to baseline in the control participants. However, in the participants receiving anthracyclines, aortic stiffness increased markedly (relative to baseline), as evidenced by a decrease in AoD (P < .0001) and an increase in PWV (P < .0001). These changes in aortic stiffness persisted after accounting for age, sex, cardiac output, administered cardioactive medications, and underlying clinical conditions known to influence aortic stiffness, such as hypertension or diabetes (P < .0001). Conclusion A significant increase in aortic stiffness occurs within 4 months of exposure to an anthracycline which was not seen in an untreated control group. These results indicate that previously regarded cardiotoxic cancer therapy adversely increases thoracic aortic stiffness, a known independent predictor of adverse cardiovascular events.

9518 Background: Alopecia is an emotionally traumatic side effect for breast cancer (BC) patients (pts) undergoing adjuvant chemotherapy (CTX). The DigniCap System is the first scalp cooling system...

Early clinical studies combining irinotecan (CPT-11, Camptosar) and gemcitabine (Gemzar) have yielded encouraging results. Gemcitabine administered via a twice-weekly schedule results in an enhanced radiation-sensitizing effect. This multi-institution phase II trial of induction irinotecan/gemcitabine followed by twice-weekly gemcitabine and upper abdominal radiation has been initiated to determine the activity of this regimen in patients with unresectable pancreatic cancer. Patients received two cycles of induction irinotecan (100 mg/ m2 IV) and gemcitabine (1,000 mg/m2 IV) on days 1 and 8 of each 3-week cycle. Following the induction therapy, patients without disease progression received twice-weekly gemcitabine at 40 mg/m2 and radiation. Nine patients have been enrolled in the study to date. Median patient age was 71 years (range: 65-85 years). The major toxicity observed thus far was grade 3/4 neutropenia. Grade 3/4 nonhematologic toxicity was rarely observed and included dehydration (12%) and diarrhea (12%), which were likely related to the irinotecan. No treatment-related deaths have occurred. These preliminary data suggest that this regimen is well tolerated. Although the data are limited, tumor progression during the induction chemotherapy has not been observed thus far (radiographically or biochemically [CA-19-9]).

Purpose: Metastatic triple negative breast cancer is an unmet need in oncology. A targeted therapy for triple negative breast cancer has not been found so metastases are treated with chemotherapy as a single agent or in combination. The epidermal growth factor receptor (EGFR) is frequently over-expressed in triple negative breast cancer. This EGFR receptor can be targeted with agents such as cetuximab or panitumumab. We designed a single-arm clinical trial to investigate the activity of panitumumab in combination with carboplatin and paclitaxel in women with triple negative breast cancer. Patients and Methods: Patients with metastatic disease and who had received no greater than one prior chemotherapy regimen were eligible for the study. Patients received paclitaxel 80mg/m^2 and carboplatin with AUC 2 on days 1, 8, and 15. In addition they received panitumumab 6mg/kg on days 1 and 15. The primary endpoint was overall response rate. We evaluated patients for toxicity prior to each cycle. We also subtyped the breast tumor specimens using microarray into basal-like, Her-2 enriched, luminal A, luminal B, and normal-like to assess for differential response to therapy among these subtypes. Results: We enrolled 14 patients into the study at two sites (Wake Forest University Baptist Medical Center and Ochsner Medical Center). The average age of enrolled patients was 54.1 years. Nine out of the 14 women were African American and 5 patients were Caucasian. The median number of cycles received by the cohort was 3.5 (1-9) with median time to progression of 98 days. Common grade 3 and 4 adverse events included lymphopenia in 5 patients and neutropenia in 9 patients. Seven participants experienced grade 1/2 mucositis and two participants had grade 3 mucositis. Seven patients experienced grade 1/2 acneiform rash. Response to therapy based on tumor subtype (basal-like, Her-2 enriched, luminal A, luminal B, or normal-like) will also be presented, data in progress. Conclusion: Adding the EGFR inhibitor panitumumab to carboplatin/paclitaxel was a well-tolerated and effective therapy for metastatic triple negative breast cancer. This combination could be most appropriate for certain subtypes of triple negative disease. Citation Format: Stacy Cowherd, Susan Melin, Steven Akman, John Cole, Julia Lawrence. A phase II clinical trial of weekly paclitaxel and carboplatin in combination with panitumumab in metastatic or recurrent breast cancer patients with triple negative disease. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT302. doi:10.1158/1538-7445.AM2014-CT302

Numerous studies have found that increased body size (weight or body mass index) is a risk factor for breast cancer development, recurrence, and death. The detrimental relationship between body size and breast cancer recurrence may be more pronounced among women with estrogen receptor (ER)/progesterone receptor (PR)-negative breast cancer. Considering the limited availability of treatments, and the association between body size and recurrence, alternative treatments are needed for ER/PR-negative breast cancer survivors, particularly overweight survivors. The objective of this pilot study was to examine the feasibility of a 12-week, multi-component meal-replacement weight loss intervention among overweight or obese ER/PR-negative breast cancer survivors; and to obtain preliminary data on changes in anthropometrics, biomarkers, and health-related quality of life (QOL). The 12-week intervention included a portion-controlled diet (including meal replacements) and a multi-component intervention (including behavioral techniques, diet modification, physical activity, and social support). The goal of the intervention was to help participants lose 5% or more of their initial weight by reducing their caloric intake and increasing their physical activity (to at least 15 minutes each day). Paired t-tests assessed changes in continuous measures. Body weight was measured weekly and mixed-model regression analysis assessed change in weight over time. Nineteen ER/PR-negative breast cancer survivors with a mean age of 59 years participated in the study. All but two of the participants completed the 12-week intervention. Women lost an average of 6.3 ± 4.9 kg ( P < 0.001), equivalent to 7.5% of their baseline weight. There were significant reductions in waist circumference ( P = 0.001), percent fat mass ( P < 0.001), total cholesterol ( P = 0.026), and triglycerides ( P = 0.002); and improvements in health-related QOL ( P = 0.017). Findings suggested that a meal-replacement weight loss approach among ER/PR-negative breast cancer survivors was feasible and was well received.

A dvanced carcinomas of the head and neck have a dismal prognosis, with a 15% to 30% 5-year survival rate after conventional radiation and surgery. While distant metastases and intercurrent deaths are a cause of mortality, local control remains a problem. There have been several publications describing various hyperfractionation schedules in head and neck carcinomas, and some report increased local control. 1'2 Head and neck carcinomas are also responsive to chemotherapy (CT). Although a survival benefit from the use of adjuvant CT has not been demonstrated, concurrent CT and radiation treatments have shown a disease-free survival incidence and overall survival benefit in some studi e s . 2-5

We designed a phase II trial to examine the benefit of preoperative hyperfractionated radiation therapy (XRT) and concurrent chemotherapy for patients with locally advanced esophageal cancer (LAEC).The pathologic complete response (pCR) was the primary endpoint to estimate efficacy.Twenty-three patients with LAEC received twice-daily XRT during wk 1 and 5 and once-daily XRT during wk 2-4 (59 Gy). Cisplatin (100 mg/m(2)) was given on d 1, while 5-fluorouracil (1000 mg/m(2)) was given by continuous infusion the first and fifth weeks of the XRT.The pCR for the 19 patients undergoing esophagectomy was 16%. The study was closed at the interim analysis having not met the required minimum pCR rate of 20%. Hematologic toxicities consisted of grades III and IV neutropenia observed in 33% and 14% of patients, respectively. Grade III nausea and vomiting was seen in 38% of patients. One grade V pulmonary toxicity occurred. The median survival was 44.6 mo with 65% of patients alive at 2 yr.The pCR rate in this trial did not meet the predetermined statistical minimum. With the encouraging 2-yr survival, it is not clear that pCR is a reliable surrogate endpoint to discern treatment efficacy.

TPS244 Background: Scalp cooling prevents chemotherapy-induced alopecia by reducing the amount of drug delivered to scalp cells and by decreasing intra-follicular metabolic rate. Several devices exist and are in use world-wide. The most common use a series of gel caps that are time-consuming and cumbersome to use. The DigniCap is a free-standing system that utilizes a circulating coolant in a silicon-based cap and maintains a stable scalp temperature. More than 3200 patients have used this system in Europe, Russia and Japan. The majority were treated for breast or ovarian cancer. Overall success rate assessed by wig use is about 85% and varies by CTX regimen (Dignitana data on file). A review of 2000 patients found minimal toxicity (Breed WP, 2004). Scalp metastases are rare (0.6% in 1593 pts in 6 studies). Improved sense of wellbeing (quality of life and body image) has been documented among pts using scalp cooling (Van den Hurk, 2009). This study is a pilot study intended to evaluate the safety and effi...

e19524 Background: Participant compliance in clinical trials is crucial as noncompliance leads to underestimation of treatment effect and loss of statistical power. Compliance is frequently assesse...

4074 Background: This is a preliminary analysis of a phase II trial addressing the optimal integration of hyperfractionated radiation and concurrent chemotherapy in the pre-operative setting for pa...