Racial/Ethnic Differences Among Tumor-Infiltrating Lymphocytes in Breast Cancer Tumors.

PURPOSE: Tumor-infiltrating lymphocytes (TILs) have emerged as a predictor of breast cancer treatment response and patient outcomes. Current studies investigating racial/ethnic differences in TILs and immune profiles in breast cancer offer varying results. Our study provides some preliminary data in the breast cancer tumor microenvironment where there is a paucity of information, from Asian and Native Hawaiian/Pacific Islander (NHPI) racial/ethnic groups, not well represented in the literature. METHODS: We reviewed 183 cases of women diagnosed with early stage breast cancer who received neoadjuvant treatment at 2 large health systems in Hawaii between 2008 and 2020. We evaluated clinical and demographic information including: age at diagnosis, self-reported race/ethnicity, tumor stage, tumor subtype according to ER, PR, and HER2 receptor status, the amount of TILs and pathologic complete response (pCR). RESULTS: We found a significantly greater amount of TILs in Asians (37.7%, P = .01) and NHPI (37.2%, P = .02) patients compared to White patients on multivariate analysis. We found no significant differences in pCR among the different racial/ethnic groups. CONCLUSIONS: Racial/ethnic differences in the amount of TILs in breast cancer tumors may suggest differences in the breast tumor microenvironment. This may in part contribute to known outcome disparities in these populations and should be further evaluated.

Genomic Landscape of Circulating-Tumor DNA in a Diverse Cohort of Metastatic Breast Cancer Patients.

INTRODUCTION: Breast cancer is the most prevalent cancer and the second leading cause of cancer death among women in the United States. Liquid biopsy is becoming a more commonly accepted method in clinical practice. Thus, there is a need to investigate ways to utilize circulating-tumor DNA (ctDNA) in metastatic breast cancer (mBC). The primary objective of this study was to characterize the genomic landscape of ctDNA in a diverse patient population and across different subtypes of mBC. METHODS: We analyzed the ctDNA profile in patients (n = 45) with mBC who received a Guardant360 liquid biopsy test. Patient demographics, age at diagnosis, race, subtype, and mutations were included in the analysis. RESULTS: The majority of patients (n = 39, 86.7%) had at least one gene alteration detected in their liquid biopsy. We found no statistically significant differences in genomic landscape according to race. However, there were differences seen in tumor genomics according to age and subtype. Postmenopausal patients were more likely to have detectable disease on liquid biopsy compared to premenopausal patients (p = 0.001). Mutations in ESR1 (n = 10) and PIK3CA (n = 8) were more commonly seen in hormone positive (HR+) mBC, where known tailored treatment options are available (i.e., fulvestrant and alpelisib respectively). The most common alterations detected include TP53 (n = 22) followed by PIK3CA (n = 15), ESR1 (n = 11), CCND1 (n = 7), and ERBB2 (n = 7). CONCLUSION: Liquid biopsies are effective tools that can reveal clinically relevant information including mutational status and therapeutic options.

Racial Disparities in Patient-Provider Communication During Telehealth Visits Versus Face-to-face Visits Among Asian and Native Hawaiian and Other Pacific Islander Patients With Cancer: Cross-sectional Analysis.

BACKGROUND: Telehealth visits increase patients' access to care and are often rated as "just as good" as face-to-face visits by oncology patients. Telehealth visits have become increasingly more common in the care of patients with cancer since the advent of the COVID-19 pandemic. Asians and Pacific Islanders are two of the fastest growing racial groups in the United States, but there are few studies assessing patient satisfaction with telemedicine among these two racial groups. OBJECTIVE: Our objective was to compare satisfaction with communication during telehealth visits versus face-to-face visits among oncology patients, with a specific focus on Asian patients and Native Hawaiian and other Pacific Islander (NHOPI) patients. METHODS: We surveyed a racially diverse group of patients who were treated at community cancer centers in Hawaii and had recently experienced a face-to-face visit or telehealth visit. Questions for assessing satisfaction with patient-physician communication were adapted from a previously published study of cancer survivors. Variables that impact communication, including age, sex, household income, education level, and cancer type and stage, were captured. Multivariable logistic models for patient satisfaction were created, with adjustments for sociodemographic factors. RESULTS: Participants who attended a face-to-face visit reported higher levels of satisfaction in all communication measures than those reported by participants who underwent a telehealth encounter. The univariate analysis revealed lower levels of satisfaction during telehealth visits among Asian participants and NHOPI participants compared to those among White participants for all measures of communication (eg, when asked to what degree "[y]our physician listened carefully to you"). Asian patients and NHOPI patients were significantly less likely than White patients to strongly agree with the statement (P<.004 and P<.007, respectively). Racial differences in satisfaction with communication persisted in the multivariate analysis even after adjusting for sociodemographic factors. There were no significant racial differences in communication during face-to-face visits. CONCLUSIONS: Asian patients and NHOPI patients were significantly less content with patient-physician communication during telehealth visits when compared to White patients. This difference among racial groups was not seen in face-to-face visits. The observation that telehealth increases racial disparities in health care satisfaction should prompt further exploration.

Utilizing Liquid Biopsy for Treatment Management in Bone-Dominant Metastatic Breast Cancer: A Case Report.

Breast cancer is the most commonly diagnosed cancer and the second leading cause of cancer death among women in the United States. In clinical practice, the standard method to confirm metastatic disease and tailor treatment is to biopsy a metastatic site. Bone is the most common metastatic site, occurring in up to 70% of patients with advanced breast cancer. Standard-of-care management includes a needle biopsy with histopathological analysis to confirm tumor status and to evaluate for mutations. However, bone biopsies can be technically challenging and are oftentimes painful for patients. Given the challenges in acquisition and analysis of bone samples in metastatic breast cancer (mBC), a liquid biopsy is a less invasive alternative that can reveal clinically relevant alterations. Here, we report two cases of bone-dominant hormone-positive (HR+) mBC, in which circulating tumor DNA (ctDNA) was extracted from blood samples using two different next-generation sequencing (NGS) platforms to identify molecular targets for FDA approved treatment. In both patients, PIK3CA mutations were detected and subsequently started on alpelisib along with aromatase inhibitor or fulvestrant treatment. These cases demonstrate a feasible real-world clinical application to liquid biopsies.

Recruiting Cancer Survivors to a Mobile Mindfulness Intervention in the United States: Exploring Online and Face-to-Face Recruitment Strategies.

Cancer survivorship research faces several recruitment challenges, such as accrual of a representative sample, as well as participant retention. Our study explores patterns in recruited demographics, patient-reported outcomes (PROs), and retention rates for a randomized controlled trial (RCT) utilizing a mobile mindfulness intervention for the well-being of cancer survivors. In total, 123 participants were recruited using traditional and online strategies. Using the chi-square test of independence, recruitment type was compared with demographic and clinical variables, PROs, and retention at Time 2 and Time 3. Online recruitment resulted in almost double the yield compared to traditional recruitment. Online-recruited participants were more often younger, from the continental U.S., Caucasian, diagnosed and treated less recently, at a later stage of diagnosis, diagnosed with blood cancer, without high blood pressure, and with less reported pain. The recruitment method was not significantly associated with retention. Online recruitment may capture a larger, broader survivor sample, but, similar to traditional recruitment, may also lead to selection biases depending on where efforts are focused. Future research should assess the reasons underlying the higher yield and retention rates of online recruitment and should evaluate how to apply a mix of traditional and online recruitment strategies to efficiently accrue samples that are representative of the survivor population.

Spotlight on Trastuzumab Deruxtecan (DS-8201,T-DXd) for HER2 Mutation Positive Non-Small Cell Lung Cancer.

Human epidermal growth factor receptor 2 (HER2) is a proto-oncogene that, when mutated or overexpressed, plays an important role in oncogenesis. The landscape of HER2-positive breast cancer has changed dramatically over the past 2 decades with the FDA approval of a growing number of agents (antibodies, tyrosine kinase inhibitors, and antibody-drug conjugates) targeting the HER2 receptor. HER2 inhibition has also been approved for HER2-positive gastric cancer. HER2 is amplified in 9% and mutated in 3% of lung cancer. Historically, HER2-targeted therapy for lung cancer with trastuzumab, pertuzumab, and trastuzumab emtansine has failed to demonstrate a survival benefit. Trastuzumab deruxtecan (T-DXd) is a novel antibody-drug conjugate with a tetrapeptide linker, which delivers a topoisomerase I inhibitor with a drug-to-antibody ratio of 7~8. The potency of the active payload, as well as its significant bystander effect, resulted in significant anti-tumor activity. The DESTINY-Lung01 trial evaluated T-DXd in HER2-positive non-squamous non-small cell lung cancer (NSCLC) and reported a progression-free survival of 14 months in HER2-mutated NSCLC, earning its breakthrough designation by the FDA. In this review, we will discuss the structural characteristics, pharmacodynamics, and pharmacokinetics of T-DXd. We will also shed light on the preclinical and ongoing clinical trials of T-DXd along with future directions in the management of HER2 positive lung cancer.

Racial and Ethnic Disparities in Rates of Invasive Second Breast Cancer Among Women With Ductal Carcinoma In Situ in Hawai'i.

Importance: Women with ductal carcinoma in situ (DCIS) may develop a subsequent invasive second breast cancer (SBC). Understanding the association of racial and ethnic factors with the development of invasive SBC may help reduce overtreatment and undertreatment of women from minority groups. Objective: To evaluate risk factors associated with developing invasive ipsilateral SBC (iiSBC) and invasive contralateral SBC (icSBC) among women with an initial diagnosis of DCIS who are from racial and ethnic minority populations. Design, Setting, and Participants: This retrospective cohort study used deidentified data from the Hawai'i Tumor Registry of 6221 female Hawai'i residents aged 20 years or older who received a diagnosis of DCIS between January 1, 1973, and December 31, 2017. The 5 most populous ethnic groups were compared (Chinese, Filipino, Japanese, Native Hawaiian, and White). Data analysis was performed from 2020 to 2021. Exposures: Patient demographic and clinical characteristics and the first course of treatment. Main Outcome and Measures: The a priori study outcome was the development of invasive SBC. Logistic regression was used to identify factors associated with invasive SBC. Factors that were significant on unadjusted analyses were included in the adjusted models (ie, age, race and ethnicity, diagnosis year, DCIS histologic characteristics, laterality, hormone status, and treatment). Results: The racial and ethnic distribution of patients with DCIS across the state's most populous groups were 2270 Japanese women (37%), 1411 White women (23%), 840 Filipino women (14%), 821 Native Hawaiian women (13%), and 491 Chinese women (8%). Women of other minority race and ethnicity collectively comprised 6% of cases (n = 388). A total of 6221 women (age range, 20 to ≥80 years) were included in the study; 4817 (77%) were 50 years of age or older, 4452 (72%) received a diagnosis between 2000 and 2017, 2581 (42%) had well or moderately differentiated histologic characteristics, 2383 (38%) had noninfiltrating intraductal DCIS, and 2011 (32%) were treated with mastectomy only. Of these 6221 women, 444 (7%) developed invasive SBC; 190 developed iiSBC (median time to SBC diagnosis, 7.8 years [range, 0.5-30 years]) and 254 developed icSBC (median time to SBC diagnosis, 5.9 years [range, 0.5-28.8 years]). On adjusted analysis, women who developed iiSBC were more likely to be younger than 50 years (adjusted odds ratio [aOR], 1.49; 95% CI, 1.08-2.06), Native Hawaiian (aOR, 3.28; 95% CI, 2.01-5.35), Filipino (aOR, 1.94; 95% CI, 1.11-3.42), Japanese (aOR, 1.58; 95% CI, 1.01-2.48), and untreated (aOR, 2.29; 95% CI, 1.09-4.80). Compared with breast-conserving surgery (BCS) alone, there was a decreased likelihood of iiSBC among women receiving BCS and radiotherapy (aOR, 0.45; 95% CI, 0.27-0.75), BCS and systemic treatment with or without radiotherapy (aOR, 0.40; 95% CI, 0.23-0.69), mastectomy only (aOR, 0.23; 95% CI, 0.13-0.39), and mastectomy and systemic treatment (aOR, 0.57; 95% CI, 0.33-0.96). Women who developed an icSBC were more likely to be Native Hawaiian (aOR, 1.69; 95% CI, 1.10-2.61) or Filipino (aOR, 1.70; 95% CI, 1.10-2.63). Risk of both iiSBC and icSBC decreased in the later years of diagnosis (2000-2017) compared with the earlier years (1973-1999). Conclusions and Relevance: This study suggests that Native Hawaiian and Filipino women who initially received a diagnosis of DCIS were more likely to subsequently develop both iiSBC and icSBC. Japanese women and younger women were more likely to develop iiSBC. Subpopulation disaggregation may help guide clinical treatment and screening decisions for at-risk subpopulations.

Weight changes according to treatment in a diverse cohort of breast cancer patients.

BACKGROUND: Weight changes are common among breast cancer patients. The majority of studies to date have focused on weight gain after a breast cancer diagnosis and its implications on health in survivors. Fewer studies have examined weight loss and its related characteristics. Weight changes have been reported to be influenced by several factors such as age, treatment, stage and pre-diagnostic weight. We evaluated weight changes during key treatment time points in early stage breast cancer patients. METHODS: We characterized 389 female patients diagnosed in Hawaii with early stage breast cancer from 2003 to 2017 in the Multiethnic Cohort (MEC) linked with Kaiser Permanente Hawaii electronic medical record data. We evaluated weight changes from surgery to 4 years post-diagnosis with six time points along a patient's treatment trajectory (chemotherapy, radiation, endocrine, or surgery alone) and annually thereafter, adjusting for age, race/ethnicity and initial body mass index (BMI). RESULTS: We found key time points of significant weight change for breast cancer patients according to their adjuvant treatment. In patients who had surgery alone (S), surgery-radiation (SR), or surgery-endocrine therapy (SE), the majority of patients had stable weight, although this consistently decreased over time. However, the percentages of patients with weight loss and weight gain during this time steadily increased up to 4 years after initial surgery. Weight loss was more common than weight gain by about 2 fold in these treatment groups. For patients with surgery-chemotherapy (SC), there was significant weight loss seen within the first 3 months after surgery, during the time when patients receive chemotherapy. And this weight loss persisted until year 4. Weight gain was less commonly seen in this treatment group. CONCLUSIONS: We identified key time points during breast cancer treatment that may provide a therapeutic window to positively influence outcomes. Tailored weight management interventions should be utilized to promote overall health and long term survivorship.

A cross-sectional study of breast pain in a diverse population of breast cancer patients.

BACKGROUND: Breast cancer is the most common cancer in women, and postoperative breast pain has been reported to be anywhere from 25% to 60%. However, there is sparse data regarding racial/ethnic differences in breast pain among breast cancer patients. METHODS: We performed a cross-sectional anonymous survey of breast cancer patients from the Hawaii Cancer Consortium over a 6-week period between 2019 and 2020. The 237 breast cancer participants were ages 29 to 98, 74% Asian, and mainly from outpatient oncology clinics. We evaluated the prevalence of breast pain in a diverse group of breast cancer patients and characterized the pain using a modified short-form McGill pain questionnaire (sfMPQ). RESULTS: Eighty-fourrespondents(35.4%) reported breast pain. On univariable analysis, we found significant racial/ethnic differences in the amount of breast pain, where Chinese and Japanese participants reported significantly less pain compared to White participants on a 10-point pain scale. We found differences in breast pain according to age and endocrine therapy use as well as survey location, however, no differences were seen according to chemotherapy, radiation, or breast surgery. Based on the sfMPQ, the most common descriptors of breast pain were sensory (throbbing, shooting, and stabbing) compared to affective (tiring-exhausting, sickening, fearful, and punishing-cruel) characteristics. Although they were described as mild and intermittent, in women with breast pain, 33.4% reported the breast pain affected their sleep, 16.7% their work, and 15.4% their sexual activity. CONCLUSIONS: Breast pain is a significant problem in our breast cancer community. This survey assessment has informed our understanding of breast pain in our diverse population. In turn, we are developing culturally appropriate pain management strategies to treat this challenging symptom common in breast cancer survivors.

Telehealth amid the COVID-19 pandemic: perception among Asian, Native Hawaiian and Pacific Islander cancer patients.

Aim: To assess the perception of telehealth visits among a multiracial cancer population during the coronavirus disease 2019 pandemic. Methods: This cross-sectional study was conducted at outpatient cancer clinics in Hawaii between March and August 2020. Patients were invited to participate in the survey either by phone or email. Results: Of the 212 survey respondents, 61.3% were Asian, 23.6% were White and 15.1% were Native Hawaiians or Pacific Islanders. Asians, Native Hawaiians and Pacific Islanders were less likely to desire future telehealth visits compared with Whites. Predictors with regard to preferring future telehealth visits included lower income and hematopoietic cancers. Conclusion: The authors found racial differences in preference for telehealth. Future studies aimed at overcoming these racial disparities are needed to provide equitable oncology care.

If we build it they will come: targeting the immune response to breast cancer.

Historically, breast cancer tumors have been considered immunologically quiescent, with the majority of tumors demonstrating low lymphocyte infiltration, low mutational burden, and modest objective response rates to anti-PD-1/PD-L1 monotherapy. Tumor and immunologic profiling has shed light on potential mechanisms of immune evasion in breast cancer, as well as unique aspects of the tumor microenvironment (TME). These include elements associated with antigen processing and presentation as well as immunosuppressive elements, which may be targeted therapeutically. Examples of such therapeutic strategies include efforts to (1) expand effector T-cells, natural killer (NK) cells and immunostimulatory dendritic cells (DCs), (2) improve antigen presentation, and (3) decrease inhibitory cytokines, tumor-associated M2 macrophages, regulatory T- and B-cells and myeloid derived suppressor cells (MDSCs). The goal of these approaches is to alter the TME, thereby making breast tumors more responsive to immunotherapy. In this review, we summarize key developments in our understanding of antitumor immunity in breast cancer, as well as emerging therapeutic modalities that may leverage that understanding to overcome immunologic resistance.

A phase 2 study of panobinostat with lenalidomide and weekly dexamethasone in myeloma.

Phase 3 studies combining histone deacetylase inhibitors with bortezomib were hampered by gastrointestinal (GI) intolerance, which was not observed when combined with immunomodulatory drugs. This study is a single-center phase 2 study of panobinostat with lenalidomide and dexamethasone (FRD). Twenty-seven relapsed multiple myeloma patients were enrolled. Twenty-two patients (81%) were lenalidomide refractory and 9 (33%), 14 (52%), and 7 (26%) were refractory to pomalidomide, bortezomib, and carfilzomib, respectively. High-risk molecular findings were present in 17 (63%) patients. Responses included 2 complete responses (CRs), 4 very good partial responses (VGPRs), 5 partial responses (PRs), and 9 minimal responses (MRs) for an overall response rate of 41%, clinical benefit rate of 74%, and a disease control rate of 96%. The median progression-free survival (PFS) was 7.1 months. In the 22 lenalidomide-refractory patients, there were 1 CR, 4 VGPRs, 3 PRs, and 7 MRs, with a median PFS of 6.5 months. Median overall survival was not reached. Grade 3/4 toxicities were primarily hematologic. Gene expression profiling of enrollment tumor samples revealed a set of 1989 genes associated with short (<90 days) PFS to therapy. MAGEA1 RNA and protein expression were correlated with short PFS, and laboratory studies demonstrated a role for MAGE-A in resistance to panobinostat-induced cell death. FRD demonstrates durable responses, even in high-risk, lenalidomide-refractory patients, indicating the essential role of panobinostat in attaining responses. MAGEA1 expression may represent a functional biomarker for resistance to panobinostat. In contrast to PANORAMA 1, there were no significant GI toxicities and primarily expected hematologic toxicities. This trial was registered at www.clinicaltrials.gov as #NCT00742027.

Targeting Glutamatergic Signaling and the PI3 Kinase Pathway to Halt Melanoma Progression.

Our group has previously reported that the majority of human melanomas (>60%) express the metabotropic glutamate receptor 1 (GRM1) and that the glutamate release inhibitor riluzole, a drug currently used to treat amyotrophic lateral sclerosis, can induce apoptosis in GRM1-expressing melanoma cells. Our group previously reported that in vitro riluzole treatment reduces cell growth in three-dimensional (3D) soft agar colony assays by 80% in cells with wildtype phosphoinositide 3-kinase (PI3K) pathway activation. However, melanoma cell lines harboring constitutive activating mutations of the PI3K pathway (PTEN and NRAS mutations) showed only a 35% to 40% decrease in colony formation in soft agar in the presence of riluzole. In this study, we have continued our preclinical studies of riluzole and its effect on melanoma cells alone and in combination with inhibitors of the PI3 kinase pathway: the AKT inhibitor, API-2, and the mammalian target of rapamycin (mTOR) inhibitor, rapamycin. We modeled these combinatorial therapies on various melanoma cell lines in 3D and 2D systems and in vivo. Riluzole combined with mTOR inhibition is more effective at halting melanoma anchorage-independent growth and xenograft tumor progression than either agent alone. PI3K signaling changes associated with this combinatorial treatment shows that 3D (nanoculture) modeling of cell signaling more closely resembles in vivo signaling than monolayer models. Riluzole combined with mTOR inhibition is effective at halting tumor cell progression independent of BRAF mutational status. This makes this combinatorial therapy a potentially viable alternative for metastatic melanoma patients who are BRAF WT and are therefore ineligible for vemurafenib therapy.

Chemical genetic screening for compounds that preferentially inhibit growth of methylthioadenosine phosphorylase (MTAP)-deficient Saccharomyces cerevisiae.

Methylthioadenosine phosphorylase (MTAP), a key enzyme in the methionine salvage pathway, is inactivated in a variety of human cancers. Since all human tissues express MTAP, it would be of potential interest to identify compounds that selectively inhibit the growth of MTAP-deficient cells. To determine if MTAP inactivation could be targeted, the authors have performed a differential chemical genetic screen in isogenic MTAP(+) and MTAP(-) Saccharomyces cerevisiae. A low molecular weight compound library containing 30,080 unique compounds was screened for those that selectively inhibit growth of MTAP(-) yeast using a differential growth assay. One compound, containing a 1,3,4-thiadiazine ring, repeatedly showed a differential dose response, with MTAP(-) cells exhibiting a 4-fold shift in IC(50) compared to MTAP(+) cells. Several structurally related derivatives of this compound also showed enhanced growth inhibition in MTAP(-) yeast. These compounds were also examined for growth inhibition of isogenic MTAP(+) and MTAP(-) HT1080 fibrosarcoma cells, and 4 of the 5 compounds exhibited evidence of modest but significant increased potency in MTAP(-) cells. In summary, these studies show the feasibility of differential growth screening technology and have identified a novel class of compounds that can preferentially inhibit growth of MTAP(-) cells.

Isoform-selective chemical inhibition of mDia-mediated actin assembly.

Formins are potent actin assembly factors. Diaphanous formins, including mDia1, mDia2, and mDia3 in mammals, are implicated in mitosis and cytokinesis, but no chemical interactors have been reported. We developed an in vitro screen for inhibitors of actin assembly by mDia1 and identified an inhibitor of mDia1 and mDia2 that does not inhibit mDia3 at the concentrations tested. These results establish the druggability of mDia formins and introduce a first-generation inhibitor.

An isoform-selective, small-molecule inhibitor targets the autoregulatory mechanism of p21-activated kinase.

Autoregulatory domains found within kinases may provide more unique targets for chemical inhibitors than the conserved ATP-binding pocket targeted by most inhibitors. The kinase Pak1 contains an autoinhibitory domain that suppresses the catalytic activity of its kinase domain. Pak1 activators relieve this autoinhibition and initiate conformational rearrangements and autophosphorylation events leading to kinase activation. We developed a screen for allosteric inhibitors targeting Pak1 activation and identified the inhibitor IPA-3. Remarkably, preactivated Pak1 is resistant to IPA-3. IPA-3 also inhibits activation of related Pak isoforms regulated by autoinhibition, but not more distantly related Paks, nor >200 other kinases tested. Pak1 inhibition by IPA-3 in live cells supports a critical role for Pak in PDGF-stimulated Erk activation. These studies illustrate an alternative strategy for kinase inhibition and introduce a highly selective, cell-permeable chemical inhibitor of Pak.