Akiko Chiba

Trends in Neoadjuvant Endocrine Therapy Use and Impact on Rates of Breast Conservation in Hormone Receptor-Positive Breast Cancer: A National Cancer Data Base Study

BackgroundThe American College of Surgeons Oncology Group Z1031 trial demonstrated that neoadjuvant endocrine therapy (NET) increased breast-conserving surgery (BCS) rates for postmenopausal patients with clinical tumor stage 2–4c estrogen receptor-positive breast cancer. We evaluated national trends in NET use in relation to the conduct of the Z1031 trial and the impact of NET on the rates of BCS.MethodsUsing the National Cancer Data Basexa0(NCDB), we identified all cT2–4c hormone receptor (HR)-positive breast cancer patients age ≥50xa0years from 2004 to 2012. The time intervals of pre-Z1031 (2004–2006), during Z1031 (2007–2009), and post-Z1031 (2010–2012) were examined, and adjusted analyses were performed using multivariable logistic regression.ResultsOf 77,272 patients, 2294 (3.0xa0%) received NET. Clinical T-stage distribution was 66,885 (86.6xa0%) for cT2, 7318 (9.5xa0%) for cT3, and 3069 (4.0xa0%) for cT4a–c. A small but statistically significant increase in NET use was noted, from 2.7xa0% pre-Z1031 to 3.2xa0% post-Z1031; the adjusted odds ratio (OR) for NET was 1.28 [95xa0% confidence interval (CI) 1.13–1.45; pxa0<xa00.001] for post-Z1031 versus pre-Z1031. NET use varied by clinical T stage, increasing from 1.8xa0% pre-Z1031 to 2.4xa0% post-Z1031 in cT2 patients (pxa0<xa00.001) and from 6.3xa0% pre-Z1031 to 7.4xa0% post-Z1031 in cT3 patients (pxa0=xa00.02). Patients receiving NET were more likely to undergo BCS compared with patients undergoing primary surgery (46.4 vs. 43.9xa0%; pxa0=xa00.02) with an adjusted OR of 1.60 (95xa0% CI 1.46–1.75; pxa0<xa00.001).ConclusionsNET use has increased slowly since the Z1031 trial; however, overall use remains low. NET significantly increased the rates of BCS in patients with HR-positive clinical T2–4c breast cancer. Clinicians should consider NET use for patients with HR-positive breast cancer interested in BCS.

Impact that Timing of Genetic Mutation Diagnosis has on Surgical Decision Making and Outcome for BRCA1/BRCA2 Mutation Carriers with Breast Cancer

BackgroundDeleterious BRCA mutation carriers with breast cancer are at increased risk for additional breast cancer events. This study evaluated the impact that timing of identification of BRCA+ status has on surgical decision and outcome.MethodsThe authors reviewed all BRCA carriers at their institution whose breast cancer was diagnosed between January 1996 and June 2015. Patient surveys, medical records, and institutional databases were used to collect data. Differences in surgical choice were analyzed using the chi-square test, and rates of subsequent breast cancer events were estimated using the Kaplan–Meier method.ResultsThe study investigated 173 BRCA carriers with breast cancer (100 BRCA1, 73 BRCA2). Of the women with known BRCA mutation before surgery and unilateral stages 0 to 3 breast cancer (nxa0=xa063), 12.7xa0% underwent lumpectomy, 4.8xa0% underwent unilateral mastectomy (UM), and 82.5xa0% underwent bilateral mastectomy (BM). These surgical choices differed significantly (pxa0<xa00.0001) from those of patients unaware of their mutation at the time of surgery (nxa0=xa093) (51.6xa0% had lumpectomy, 19.4xa0% had UM, 29xa0% had BM). Of the patients with BRCA mutation identified after surgery who underwent lumpectomy or UM, 36 (59xa0%) of 66 underwent delayed BM. The patients with BRCA+ known before diagnosis presented with significantly lower-stage disease (pxa0=xa00.02) at diagnosis (69xa0% stage 0 or 1) than those whose BRCA mutation was identified after cancer diagnosis (40xa0% stage 0 or 1).ConclusionsThe study findings showed that BRCA mutation status influences surgical decision. The rates of BM were higher for the patients with BRCA mutation known before surgery. Identification of BRCA mutation after surgeryxa0frequently leads to subsequent breast surgery. Genetic testing before surgery is important for patients at elevated risk for BRCA mutation.

Nipple-Sparing Mastectomy: To Spare Or Not To Spare?

The use of nipple-sparing mastectomy for prophylactic and therapeutic purposes has increased in recent years primarily driven by patient desire for improved esthetics. This article aims to critically review indications, oncologic safety, and recent advances in operative techniques. Current strategies for minimizing complications of nipple-sparing mastectomy are discussed including incision choices, adjunct tactics, and our experience.

Serum Vitamin D Levels Affect Pathologic Complete Response in Patients Undergoing Neoadjuvant Systemic Therapy for Operable Breast Cancer

Introduction: There has been increasing interest in the potential benefit of vitamin D in improving breast cancer outcome. Preclinical studies suggest that vitamin D enhances chemotherapy‐induced cell death. We investigated the impact of serum vitamin D levels during neoadjuvant chemotherapy (NAC) on the rates of achieving pathologic complete response (pCR) after breast cancer NAC. Patients and Methods: Patients from 1 of 2 Iowa registries who had serum vitamin D level measured before or during NAC were included. French patients enrolled onto a previous study of the impact of NAC on vitamin D and bone metabolism were also eligible for this study. Vitamin D deficiency was defined as < 20 ng/mL. pCR was defined as no residual invasive disease in breast and lymph nodes. A Firth penalized logistic regression multivariable model was used. Results: The study included 144 women. There was no difference between the French and Iowan cohorts with regard to age at diagnosis (P = .20), clinical stage (P = .22), receptor status (P = .32), and pCR rate (P = .34). French women had lower body mass index (mean 24.8 vs. 28.8, P < .01) and lower vitamin D levels (mean 21.5 vs. 27.5, P < .01) compared to Iowan patients. In multivariable analysis, after adjusting for the effects of cohort, clinical stage, and receptor status, vitamin D deficiency increased the odds of not attaining pCR by 2.68 times (95% confidence interval, 1.12‐6.41, P = .03). Conclusion: Low serum vitamin D levels were associated with not attaining a pCR. Prospective trials could elucidate if maintaining vitamin D levels during NAC, a highly modifiable variable, may be utilized to improve cancer outcomes.

Consumption of Mediterranean versus Western Diet Leads to Distinct Mammary Gland Microbiome Populations

SUMMARY Recent identification of a mammary gland-specific microbiome led to studies investigating bacteria populations in breast cancer. Malignant breast tumors have lower Lactobacillus abundance compared with benign lesions, implicating Lactobacillus as a negative regulator of breast cancer. Diet is a main determinant of gut microbial diversity. Whether diet affects breast microbiome populations is unknown. In a non-human primate model, we found that consumption of a Western or Mediterranean diet modulated mammary gland microbiota and metabolite profiles. Mediterranean diet consumption led to increased mammary gland Lactobacillus abundance compared with Western diet-fed monkeys. Moreover, mammary glands from Mediterranean diet-fed monkeys had higher levels of bile acid metabolites and increased bacterial-processed bioactive compounds. These data suggest that diet directly influences microbiome populations outside the intestinal tract in distal sites such as the mammary gland. Our study demonstrates that diet affects the mammary gland microbiome, establishing an alternative mechanistic pathway for breast cancer prevention.

Temozolomide Enhances Triple-Negative Breast Cancer Virotherapy In Vitro

Triple-negative breast cancer (TNBC) is one of the most aggressive types of cancer, and treatment is limited to chemotherapy and radiation. Oncolytic virotherapy may be a promising approach to treat TNBC. However, oncolytic adenovirus (OAd)-based mono-therapeutic clinical trials have resulted in modest outcomes. The OAd potency could be increased by chemotherapy-induced autophagy, an intracellular degradation system that delivers cytoplasmic constituents to the lysosome. In this study, the ability of alkylating agent temozolomide (TMZ)-induced autophagy to increase OAd replication and oncolysis in TNBC cells was evaluated. Human TNBC MDA-MB-231 and HCC1937 cells and mouse 4T1 cells were infected with an OAd expressing the red fluorescent protein mCherry on the virus capsid (OAdmCherry) alone or in combination with TMZ. TNBC cells treated with OAdmCherry/TMZ displayed greater mCherry and adenovirus (Ad) early region 1A (E1A) expression and enhanced cancer-cell killing compared to OAdmCherry or TMZ alone. The combined therapy-mediated cell death was associated with virus replication and accumulation of the autophagy marker light chain 3 (LC3)-II. Overall, this study provides experimental evidence of TMZ’s ability to increase oncolytic virotherapy in both human and murine TNBC cells.

The impact of obesity on outcomes for patients undergoing mastectomy using the ACS-NSQIP data set

PurposeAccording to the World Health Organization (WHO), 34.7% of females in the United States are obese (BMIxa0≥xa030) in 2014, compared to 32.5% in 2010. The previous research has demonstrated high BMI as an independent risk factor for surgical complications after breast surgery. As more patients become obese, we sought to examine whether increasing obesity had an effect on outcomes of women who underwent a unilateral mastectomy without breast reconstruction.MethodsThe study reviewed the 2007–2012 ACS-NSQIP database and identified all patients who underwent a unilateral mastectomy without reconstruction. Patients were then categorized and compared according to the World Health Organization obesity classification. Data were analyzed for minor complications (e.g., UTI and SSI) and major complications (e.g., renal failure, sepsis, deep vein thrombosis, return to operating room [RTOR], and cardiac arrest).ResultsA total of 7207 women were identified. Median BMI was 27.3xa0kg/m2. From the cohort, 453 patients (6.29%) had a major complication and 173 patients (2.40%) had a minor complication. 53 (0.74%) had bleeding complications, 148 (2.05%) had a surgical site infection (SSI), 352 (4.88%) RTOR, and 7 (0.01%) died within 30xa0days. Major complications (pxa0=xa00.005) and minor complications (pxa0<xa00.001) significantly increased as BMI increased. SSI and RTOR had increasing trends, but were not statistically significant.ConclusionsThis study characterizes the risk of complications in women undergoing unilateral mastectomies and shows that increasing obesity is associated with major and minor postoperative complications. Our finding highlights the need for personalized preoperative risk assessment and counseling of obese patients.

Optoacoustic imaging identifies ovarian cancer using a microenvironment targeted theranostic wormhole mesoporous silica nanoparticle

At the intersection of the newly emerging fields of optoacoustic imaging and theranostic nanomedicine, promising clinical progress can be made in dismal prognosis of ovarian cancer. An acidic pH targeted wormhole mesoporous silica nanoparticle (V7-RUBY) was developed to serve as a novel tumor specific theranostic nanoparticle detectable using multispectral optoacoustic tomographic (MSOT) imaging. We report the synthesis of a small, < 40u202fnm, biocompatible asymmetric wormhole pore mesoporous silica core particle that has both large loading capacity and favorable release kinetics combined with tumor-specific targeting and gatekeeping. V7-RUBY exploits the acidic tumor microenvironment for tumor-specific targeting and tumor-specific release. In vitro, treatment with V7-RUBY containing either paclitaxel or carboplatin resulted in increased cell death at pH 6.6 in comparison to drug alone (pu202f<u202f0.0001). In orthotopic ovarian xenograft mouse models, V7-RUBY containing IR780 was specifically detected within the tumor 7X and 4X higher than the liver and >10X higher than in the kidney using both multispectral optoacoustic tomography (MSOT) imaging with secondary confirmation using near infrared fluorescence imaging (pu202f<u202f0.0004). The V7-RUBY system carrying a cargo of either contrast agent or an anti-neoplastic drug has the potential to become a theranostic nanoparticle which can improve both diagnosis and treatment of ovarian cancer.

Applying dynamic contrast enhanced MSOT imaging to intratumoral pharmacokinetic modeling

Examining the dynamics of an agent in the tumor microenvironment can offer critical insights to the influx rate and accumulation of the agent. Intratumoral kinetic characterization in the in vivo setting can further elicudate distribution patterns and tumor microenvironment. Dynamic contrast-enhanced Multispectral Optoacoustic Tomographic imaging (DCE-MSOT) acquires serial MSOT images with the administration of an exogenous contrast agent over time. We tracked the dynamics of a tumor-targeted contrast agent, HypoxiSense 680 (HS680), in breast xenograft mouse models using MSOT. Arterial input function (AIF) approach with MSOT imaging allowed for tracking HS680 dynamics within the mouse. The optoacoustic signal for HS680 was quantified using the ROI function in the ViewMSOT software. A two-compartment pharmacokinetics (PK) model constructed in MATLAB to fit rate parameters. The contrast influx (kin) and outflux (kout) rate constants predicted are kinu2009=u20091.96u2009×u200910−2u2009s-1 and koutu2009=u20099.5u2009×u200910-3u2009s-1 (Ru2009=u20090.9945).

Abstract 4122: Acidic tumor microenvironment targeted wormhole-shaped mesoporous silica nanoparticles to detect ovarian cancer by multispectral optoacoustic tomography

Purpose: The implementation of the innovative technologies remains the top priority for the development of potential modalities for the diagnosis and treatment of various cancers. Despite all the recent advances, ovarian cancer is considered as a lethal gynecologic malignancy in which vast majority of the cases are diagnosed at the late metastatic stage at which the prognosis is poor. Because of the few apparent early symptoms, significant effort was made for developing efficient methods to identify early progression of the disease. We demonstrated that the bioconjugation of the V7 peptide on 27nm wormhole mesoporous silica nanoparticles (V7-CWMSN) particles specifically release the IR780 imaging probe at the orthotopically implanted early-stage ovarian tumor to detect by multispectral optoacoustic imaging technology (MSOT). Methods: Wormhole mesoporous silica nanoparticles (WMSN) were synthesized by sol-gel chemistry. The WMSN were characterized by dynamic light scattering (DLS) and transmission electron microscopy (TEM). The surface of the WMSN particle was functionalized with pH sensitizer chitosan to obtain CWMSN. The CWMSN particle was loaded with propidium Iodide (PI) or IR780 infrared imaging dye. Further, the conjugation of the CWMSN with V7 pHLIP peptide (V7-CWMSN) developed pH sensitive cargo release from the nanoparticles. Female athymic mice were orthotopically implanted with ES-2 ovarian cancer cells. Following 10 days of orthotopic implantation of the tumor cells, mice were intravenously injected with V7-CWMSN particles containing IR780 dye and were imaged with MSOT. Results: In the current study, we have synthesized the wormhole-shaped mesoporous silica particles (WMSN) with the 27 nm diameter carrying IR780 imaging probes for the detection of early-stage ovarian cancer. The V7 peptide undergoes a conformational change upon contact with the acidic tumor microenvironment. Also, the chitosan crosslinking on the surface of the particles (V7-CWMSN) acts as a gatekeeper that is degradable upon contact with acidic pH tumor to prevent off-target release. As a model for ovarian cancer, we have used athymic mice orthotopically implanted with ovarian cancer cells. This model closely resembles the human ovarian cancer pathophysiology. Our results have demonstrated that the intravenous delivery of V7-CWMSN particles could detect the orthotopically implanted early-stage ovarian tumors (p Conclusion: The development of the distinct nanoformulations with potent imaging technology enables the visualization of early-stage ovarian tumors. Translating these modalities may allow clinicians to identify early-stage malignancies that are currently undetectable through conventional imaging techniques. Citation Format: Abhilash Samykutty, Molly W. McNally, William E. Grizzle, Akiko Chiba, Alexandra Thomas, Lacey R. McNally. Acidic tumor microenvironment targeted wormhole-shaped mesoporous silica nanoparticles to detect ovarian cancer by multispectral optoacoustic tomography [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4122.