Julie R. Nangia

Effect of a Scalp Cooling Device on Alopecia in Women Undergoing Chemotherapy for Breast Cancer: The SCALP Randomized Clinical Trial

Importance Chemotherapy may induce alopecia. Although scalp cooling devices have been used to prevent this alopecia, efficacy has not been assessed in a randomized clinical trial. Objectives To assess whether a scalp cooling device is effective at reducing chemotherapy-induced alopecia and to assess adverse treatment effects. Design, Setting, and Participants Multicenter randomized clinical trial of women with breast cancer undergoing chemotherapy. Patients were enrolled from December 9, 2013, to September 30, 2016. One interim analysis was planned to allow the study to stop early for efficacy. Data reported are from the interim analysis. This study was conducted at 7 sites in the United States, and 182 women with breast cancer requiring chemotherapy were enrolled and randomized. Interventions Participants were randomized to scalp cooling (n = 119) or control (n = 63). Scalp cooling was done using a scalp cooling device. Main Outcomes and Measures The primary efficacy end points were successful hair preservation assessed using the Common Terminology Criteria for Adverse Events version 4.0 scale (grade 0 [no hair loss] or grade 1 [<50% hair loss not requiring a wig] were considered to have hair preservation) at the end of 4 cycles of chemotherapy by a clinician unaware of treatment assignment, and device safety. Secondary end points included wig use and scores on the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire–Core 30, Hospital Anxiety and Depression Scale, and a summary scale of the Body Image Scale. Results At the time of the interim analysis, 142 participants were evaluable. The mean (SD) age of the patients was 52.6 (10.1) years; 36% (n = 51) received anthracycline-based chemotherapy and 64% (n = 91) received taxane-based chemotherapy. Successful hair preservation was found in 48 of 95 women with cooling (50.5%; 95% CI, 40.7%-60.4%) compared with 0 of 47 women in the control group (0%; 95% CI, 0%-7.6%) (success rate difference, 50.5%; 95% CI, 40.5%-60.6%). Because the 1-tailed P value from the Fisher exact test was <.001, which crossed the superiority boundary (P = .0061), the data and safety monitoring board recommended study termination on September 26, 2016. There were no statistically significant differences in changes in any of the scales of quality of life from baseline to chemotherapy cycle 4 among the scalp cooling and control groups. Only adverse events related to device use were collected; 54 adverse events were reported in the cooling group, all grades 1 and 2. There were no serious adverse device events. Conclusions and Relevance Among women with stage I to II breast cancer receiving chemotherapy with a taxane, anthracycline, or both, those who underwent scalp cooling were significantly more likely to have less than 50% hair loss after the fourth chemotherapy cycle compared with those who received no scalp cooling. Further research is needed to assess longer-term efficacy and adverse effects. Trial Registration clinicaltrials.gov Identifier: NCT01986140

TBCRC 019: A Phase II Trial of Nanoparticle Albumin-Bound Paclitaxel with or without the Anti-Death Receptor 5 Monoclonal Antibody Tigatuzumab in Patients with Triple-Negative Breast Cancer

Purpose: Tigatuzumab (TIG), an agonistic anti-DR5 antibody, triggers apoptosis in DR5+ human tumor cells without crosslinking. TIG has strong in vitro/in vivo activity against basal-like breast cancer cells enhanced by chemotherapy agents. This study evaluates activity of TIG and chemotherapy in patients with metastatic triple-negative breast cancer (TNBC). Experimental Design: Randomized 2:1 phase II trial of albumin-bound paclitaxel (nab-PAC) ± TIG in patients with TNBC stratified by prior chemotherapy. Patients received nab-PAC weekly × 3 ± TIG every other week, every 28 days. Primary objective was within-arm objective response rate (ORR). Secondary objectives were safety, progression-free survival (PFS), clinical benefit, and TIG immunogenicity. Metastatic research biopsies were required. Results: Among 64 patients (60 treated; TIG/nab-PAC n = 39 and nab-PAC n = 21), there were 3 complete remissions (CR), 8 partial remissions (PR; 1 almost CR), 11 stable diseases (SD), and 17 progressive diseases (PD) in the TIG/nab-PAC arm (ORR, 28%), and no CRs, 8 PRs, 4 SDs, and 9 PDs in the nab-PAC arm (ORR, 38%). There was a numerical increase in CRs and several patients had prolonged PFS (1,025+, 781, 672, 460, 334) in the TIG/nab-PAC arm. Grade 3 toxicities were 28% and 29%, respectively, with no grade 4–5. Exploratory analysis suggests an association of ROCK1 gene pathway activation with efficacy in the TIG/nab-PAC arm. Conclusions: ORR and PFS were similar in both. Preclinical activity of TIG in basal-like breast cancer and prolonged PFS in few patients in the combination arm support further investigation of anti-DR5 agents. ROCK pathway activation merits further evaluation. Clin Cancer Res; 21(12); 2722–9. ©2015 AACR. See related article by Paoletti et al., p. 2771

Abstract S6-02: TBCRC023: A randomized multicenter phase II neoadjuvant trial of lapatinib plus trastuzumab, with endcorine therapy and without chemotherapy, for 12 vs. 24 weeks in patients with HER2 overexpressing breast cancer

Background: We have previously shown in animal models that combination anti-HER2 therapy leads to complete tumor regression of HER2+ breast cancer (BC). We translated these findings in a neoadjuvant trial of 12 weeks (wks) of L+T (TBCRC006) that demonstrated a meaningful pathologic complete response (pCR) and near pCR (in ER+ tumors) in patients with locally advanced HER2+ BC. In the present trial, we sought to determine whether longer treatment would lead to a higher rate of pCR without the use of chemotherapy by converting near pCR to pCR especially in the ER+ subset. Methods: TBCRC023 (NCT00999804) is a randomized phase II trial combining a Simon Phase 2 design in the experimental arm with a pick-the-winner design, not powered for direct comparison. Women with HER2+ BC measuring 2 cm or larger were eligible and were randomized in a 1:2 ratio to 12 vs. 24 wks of L+T. Letrozole (along with ovarian suppression if premenopausal) was also administered in patients whose tumors were also ER+. Serial tumor biopsies were obtained at baseline, wk 1, wk 12, and at the time of surgery. All evaluable patients were assessed for pCR, defined as no residual invasive carcinoma in the breast. Patients did not undergo surgery, withdrew consent, or received additional neoadjuvant therapy were counted as non-responders. Results: Ninety-seven patients were enrolled (33 in 12-wk arm and 64 in 24-wk arm), of whom 95 were evaluable. Seventy seven percent of patients were white and 18% were black. Twenty percent were of Hispanic ethnicity. Median age was 51 and 55% were postmenopausal. Median tumor size was 5 cm and 65% were ER+. Study treatment was well tolerated with grade 1-2 diarrhea (24% in 12-wk arm, 31% in 24-wk arm) and grade 1-2 acneform rash (12% in 12-wk arm, 19% in 24-wk arm) being the most common toxicities. Grade 3 toxicities were uncommon and were mostly in the 24-wk arm (elevated liver function test: 9%, diarrhea 2%, mucositis 2%), while the 12-wk arm had one grade 3 anemia and the study’s only serious adverse event (acute kidney injury). There were no grade 4 toxicities. The experimental arm completed stage 2 accrual and pCR rate was numerically superior to control, entirely due to better results in ER+ (Table 1), but lower than the expected pCR rate of 36% needed in the planned analysis to conclude in favor of enhanced efficacy with extended therapy. pCR rates were also lower in the control arm than in the previous study. Conclusions: Treatment with L+T (with endocrine therapy in ER+ tumors) for 24 weeks leads to doubling of the pCR rate in women with HER2+ breast cancer without using cytotoxic chemotherapy. This approach is effective and well tolerated and warrants study as part of a de-escalation strategy that may spare some patients the cost and toxicity of chemotherapy. Tissue obtained on this trial will provide a valuable resource to validate correlative findings from our prior studies and discover new biomarkers to help guide proper patient selection for treatment. Citation Format: Mothaffar F Rimawi, Polly A Niravath, Tao Wang, Brent Rexer, Andres Forero, Antonio C Wolff, Rita Nanda, Anna M Storniolo, Ian Krop, Matthew P Goetz, Julie R Nangia, Sao Jiralerspong, Anne C Pavlick, Carolina Gutierrez, Rachel Schiff, Susan G Hilsenbeck, C Kent Osborne. TBCRC023: A randomized multicenter phase II neoadjuvant trial of lapatinib plus trastuzumab, with endcorine therapy and without chemotherapy, for 12 vs. 24 weeks in patients with HER2 overexpressing breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr S6-02.

Denosumab for treatment of breast cancer bone metastases and beyond

Introduction: Bone metastases develop in approximately 70 – 85% of patients with metastatic breast cancer, are incurable and can result in debilitating skeletal complications. Bone-modifying agents to treat breast cancer bone metastases include bisphosphonates. Denosumab is a humanized monoclonal IgG2 antibody targeting receptor activator of NF-κB ligand (RANKL) and provides an alternative therapy for treatment of breast cancer bone metastases. Areas covered: This review provides an overview on denosumab and the RANKL–RANK pathway. Denosumab pharmacokinetics, pharmacodynamics, efficacy, safety and tolerability are discussed. Based on the review of clinical studies, denosumab is efficacious in the treatment of breast cancer bone metastases. Adverse events rates of denosumab are similar to those for bisphosphonates. Preclinical studies have indicated a role of the RANKL–RANK pathway in non-bone-related mechanisms such as mammary gland development and tumorigenesis. Expert opinion: Clinical use of denosumab remains limited and its place in therapy will continue to be defined. Clinical questions, such as the optimal duration of therapy, remain unanswered and need to be addressed.

Jejunal intussusception due to malignant phyllodes tumor of the breast

Phyllodes tumors are rare fibroepithelial neoplasms of the breast; classified as benign, borderline, or malignant based on the mitotic activity, cellular atypia, and stromal overgrowth. Wide surgical excision is the treatment of choice. The most common locations for metastasis are lung, bone, and liver; small intestinal metastasis is extremely rare. Here we present the first patient with jejunal metastases and intussusception due to malignant phyllodes tumor of the breast. Adjuvant treatment of malignant phyllodes tumor needs to be investigated.

CME Part 1: Hair disorders in cancer patients

Cytotoxic chemotherapies, molecularly targeted therapies, immunotherapies, radiotherapy, stem cell transplants, and endocrine therapies may lead to hair disorders, including alopecia, hirsutism, hypertrichosis, and pigmentary and textural hair changes. The mechanisms underlying these changes are varied and remain incompletely understood, hampering the development of preventive or therapeutic guidelines. The psychosocial impact of chemotherapy-induced alopecia has been well documented primarily in the oncology literature; however, the effect of other alterations, such as radiation-induced alopecia, hirsutism, and changes in hair color or texture on quality of life have not been described. This article reviews clinically significant therapy-related hair disorders in oncology patients, including the underlying pathophysiological mechanisms, severity grading scales, patient-reported quality of life questionnaires, management strategies, and future translational research opportunities.

A Randomized Multicenter Phase II Study of Docosahexaenoic Acid in Patients with a History of Breast Cancer, Premalignant Lesions, or Benign Breast Disease

Obesity, a cause of subclinical inflammation, is a risk factor for the development of postmenopausal breast cancer and is associated with poorer cancer outcomes. Docosahexaenoic acid (DHA), an omega-3 fatty acid, possesses anti-inflammatory properties. We hypothesized that treatment with DHA would reduce the expression of proinflammatory genes and aromatase, the rate-limiting enzyme for estrogen biosynthesis, in benign breast tissue of overweight/obese women. A randomized, placebo-controlled, double-blind phase II study of DHA given for 12 weeks to overweight/obese women with a history of stage I–III breast cancer, DCIS/LCIS, Pagets disease, or proliferative benign breast disease was carried out. In this placebo controlled trial, the primary objective was to determine whether DHA (1,000 mg by mouth twice daily) reduced breast tissue levels of TNFα. Secondary objectives included evaluation of the effect of DHA on breast tissue levels of COX-2, IL1β, aromatase, white adipose tissue inflammation, and gene expression by RNA-seq. Red blood cell fatty acid levels were measured to assess compliance. From July 2013 to November 2015, 64 participants were randomized and treated on trial (32 women per arm). Increased levels of omega-3 fatty acids in red blood cells were detected following treatment with DHA (P < 0.001) but not placebo. Treatment with DHA did not alter levels of TNFα (P = 0.71), or other biomarkers including the transcriptome in breast samples. Treatment with DHA was overall well-tolerated. Although compliance was confirmed, we did not observe changes in the levels of prespecified biomarkers in the breast after treatment with DHA when compared with placebo. Cancer Prev Res; 11(4); 203–14. ©2018 AACR. See related editorial by Fabian and Kimler, p. 187

P1-08-04: Obesity, Adjuvant Therapy, and Survival Outcomes in Early-Stage Breast Cancer.

BACKGROUND: Obesity has risen to epidemic proportions and is associated with worse breast cancer (BC) prognosis in most studies. However, the effects of obesity according to adjuvant therapy choice are largely unknown. To address this issue, we examined the relationship between body mass index (BMI), adjuvant therapy, and survival outcomes in a large cohort of early-stage BC patients. METHODS: We retrospectively studied patients from the Baylor Breast Center Tumor Bank treated from 1970–1995. Patients were divided into 3 BMI classes: normal/underweight (N, BMI RESULTS: There were 4,368 patients. Median age was 58. 74% were postmenopausal. 72% had stage I-II disease, 28% stage III. 76% were estrogen receptor (ER)-positive, 24% ER-negative. Patients distributed into BMI classes as follows: N 48%, Ov 30%, Ob 22%. Higher BMI was associated with postmenopausal status and increasing age, tumor size, positive lymph nodes, and stage, as well as a higher likelihood of receiving treatment. Median follow-up was 5 years. Kaplan-Meier analysis showed that TTR was significantly shorter in the Ov and Ob groups as compared to the N group (p=0.019), due to distant (p=0.001) rather than local (p=0.970) recurrences. DFS was also significantly worse in the Ov and Ob groups (p=0.002), as was OS (p=0.001). The Table shows the hazard ratios for the various survival outcomes after adjustment for age, tumor size, nodal status, and treatment groups. For all patients, TTR, DFS, and OS were significantly worse in the Ob vs. N groups. TTR and DFS were significantly worse in the chemo treated Ob vs. N groups. DFS and OS were significantly better in the endo treated Ov vs. N groups. DISCUSSION: In this large cohort of BC patients, survival outcomes (TTR, DFS, OS) were significantly worse in the obese group. This remained true after adjustment for multiple factors. Obesity was associated with worse survival outcomes in the chemo treated (CMF) group. Overweight was associated with better survival outcomes in the endo treated (tamoxifen) group. These results confirm and extend the results of previous studies. Further studies to discover the reasons for these differences in outcomes are underway. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-08-04.

Abstract OT3-02-08: Scalp cooling alopecia prevention trial (SCALP) for patients with early stage breast cancer

Background Adjuvant chemotherapy treats micro-metastatic disease and decreases the risk of breast cancer recurrence. However, it may be associated with distressing side effects, including alopecia. Women with breast cancer rate chemotherapy-induced alopecia as one of the most severe, troublesome, and distressing side effects of chemotherapy. In many countries, scalp cooling has been introduced to prevent or reduce chemotherapy-induced alopecia. The theory is that scalp cooling causes cutaneous vasoconstriction, which reduces blood flow to the hair follicles during peak plasma concentrations of the chemotherapeutic agents and therefore reduces cellular uptake of these agents. It also results in reduced biochemical activity, which makes hair follicles less susceptible to the damage of the chemotherapy agents. Historically success rates are have been variable, but based on non-randomized studies, scalp cooling appears to be effective in preventing chemotherapy-induced alopecia especially in more recent studies. Methods We are conducting a prospective multi-center randomized controlled non-blinded trial to evaluate the safety and efficacy of the Orbis Paxman Hair Loss Prevention System in reducing the incidence of chemotherapy-induced alopecia. Women with stage I-II breast cancer who will receive neoadjuvant or adjuvant anthracycline- or taxane-based chemotherapy, for at least four cycles are eligible. Participants are randomized in a 2:1 ratio to scalp-cooling or no cooling. Scalp-cooling is done using the Orbis Paxman Hair Loss Prevention System prior to, during and after each chemotherapy administration. The primary efficacy endpoints are hair preservation, defined as CTCAE v4 alopecia Citation Format: Nangia JR, Wang T, Rude M, Osborne C, Papish S, Abraham J, Holmes F, Savin M, Paxman R, Hilsenbeck SG, Osborne CK, Rimawi M. Scalp cooling alopecia prevention trial (SCALP) for patients with early stage breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr OT3-02-08.

Abstract OT3-3-01: A multicenter phase II study of docosahexaenoic acid (DHA) in triple negative breast cancer (TNBC) survivors

Background: The development of effective chemopreventive strategies to reduce the risk of TNBC, is a critical unmet need. Obesity is associated with a chronic inflammatory condition in the white adipose tissue of the breast, characterized microscopically by crown-like structures of the breast (CLS-B). The presence and extent of these lesions is associated with a series of proinflammatory mediators, including tumor necrosis factor-α (TNF-α), cyclooxygenase-2 (COX-2), interleukin-1β (IL-1β) and aromatase. Importantly these proinflammatory mediators are known to be involved in breast carcinogenesis. In translational studies to date, the strongest correlations have been seen between CLS-B and TNF-α. Therefore, we aim to evaluate whether treatment with a dietary supplement, DHA, an omega-3 fatty acid, with potent effects on TNF-α, can decrease obesity-related breast inflammation in women. Trial design: This is a randomized phase II placebo-controlled, double-blinded study of DHA in overweight/obese patients (pts), defined as body mass index (BMI) ≥25 with a history of TNBC. Pts will receive DHA or placebo twice daily for 24 weeks and will undergo core biopsies from normal (non-irradiated contralateral) breast tissue before and after the treatment to determine whether DHA can decrease obesity-related breast inflammation. Eligibility: Inclusion criteria: 1) Age ≥ 18. 2) BMI ≥ 25. 3) Completed treatment for stage I-III TNBC ≥ 6 months prior. 4) No clinical evidence of disease. 5) Adequate accessible breast tissue for pre- and post- treatment biopsy, consisting of one breast unaffected by invasive cancer, which has not been radiated or surgically augmented. 6) Adequate organ and bone marrow function. 7) ECOG status ≤2. Exclusion criteria: 1) DHA supplementation. 2) Aspirin/NSAID use in the month preceding and during the trial. 3) Therapeutic anticoagulation. 4) Regular use of statins, steroids, or immunomodulators. Specific aims: The primary objective is to determine whether treatment with DHA for 24 weeks at 1,000 mg twice daily as compared to placebo reduces normal breast tissue levels of TNF-α in overweight/obese pts with a history of TNBC. The secondary objective is to evaluate the effect of DHA on the change from baseline in levels of the following tissue biomarkers: COX-2, IL-1β, aromatase, and CLS-B. Exploratory endpoints include assessment of age as a predictor of CLS-B and inflammatory biomarkers and the evaluation of red blood cell fatty acid levels as a surrogate of DHA compliance. Statistical methods: Percent change in TNF-α mRNA levels in normal breast tissue between DHA and placebo arm will be compared using two-sample t-test. If normality assumptions are violated, a two-sample Wilcoxon rank-sum test will be used. With 30 subjects in each arm, we will have 80% power to detect effect size as small as 0.74 at 0.05 significance level using a two-sided, two-sample, Student t-test. Accrual: A total of 60 evaluable pts will be enrolled. Assuming a 10% dropout rate and 10% non-evaluable rate, up to 76 participants will be randomized in this study. This trial is currently enrolling pts. Contact information: For more information on this trial, please visit clinicaltrials.gov (NCT01849250) or contact Ayca Gucalp MD (gucalpa@mskcc.org). Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT3-3-01.