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Background: Although immunotherapy has emerged as a therapeutic strategy for many cancers, there are limited studies establishing the safety and efficacy in people living with HIV (PLWH) and cancer. Methods: PLWH and solid tumors or Kaposi sarcoma (KS) receiving antiretroviral therapy and a suppressed HIV viral load received nivolumab at 3 mg/kg every 2 weeks, in two dose deescalation cohorts stratified by CD4 count (stratum 1: CD4 count > 200/µL and stratum 2: CD4 count 100–199/µL). An expansion cohort of 24 participants with a CD4 count > 200/µL was then enrolled. Results: A total of 36 PLWH received nivolumab, including 15 with KS and 21 with a variety of other solid tumors. None of the first 12 participants had dose‐limiting toxicity in both CD4 strata, and five patients (14%) overall had grade 3 or higher immune related adverse events. Objective partial response occurred in nine PLWH and cancer (25%), including in six of 15 with KS (40%; 95% CI, 16.3–64.7). The median duration of response was 9.0 months overall and 12.5 months in KS. Responses were observed regardless of PDL1 expression. There were no significant changes in CD4 count or HIV viral load. Conclusions: Nivolumab has a safety profile in PLWH similar to HIV‐negative subjects with cancer, and also efficacy in KS. Plasma HIV remained suppressed and CD4 counts remained stable during treatment and antiretroviral therapy, indicating no adverse impact on immune function. Trial Registration: ClinicalTrials.gov Identifier: NCT02408861. The anti‐PD1 inhibitor nivolumab may be used safely for treatment of cancer, and has activity in Kaposi sarcoma, in people living with HIV receiving antiretroviral therapy, a suppressed HIV viral load, and CD4 lymphocyte count of at least 100/µL. [ABSTRACT FROM AUTHOR]

Background: The American Joint Committee on Cancer (AJCC) 8th edition pathologic prognostic staging (PPS) incorporates anatomic and biologic factors. The OncotypeDX Breast Recurrence Score (RS) was included based on the initial report of the TAILORx trial, with T1-2N0 hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2−) breast cancer patients who had a RS < 11 staged as PPS 1A. This study examined whether the RS criteria for PPS 1A can be further expanded using patients enrolled in the TAILORx trial. Methods: The TAILORx trial enrolled 10,273 HR+HER2− T1-2N0 patients. Those with incomplete HR-status/grade and T3 disease were excluded for analysis. The recurrence-free interval (RFI) was compared between the patients who did and those who did not fall into the current PPS 1A category using the Kaplan-Meier method. Results: The study enrolled 9535 patients for analysis. The RS was < 11 in 16.1%, 11–17 in 35.9%, 18–25 in 32.4%, and > 25 in 15.6% of the patients. The majority (91.2%) of the patients (including all the T1N0 patients regardless of RS) were PPS 1A, and 8.8% were not-PPS 1A. The median follow-up time was 95 months. The PPS 1A patients had an 8-year RFI of 94.2%, which was similar to that of the patients with a RS of 11–17 who were not-PPS 1A (91.7%; p = 0.07) and better than that of the patients with a RS ≥ 18 who were not-PPS 1A (85.4% for a RS of 18–25, 76.0% for a RS > 25; both p < 0.01). Similar RFI trends were seen in patients who received endocrine therapy or chemotherapy followed by endocrine therapy. Conclusions: Patients with T1-2N0 HR+HER2− breast cancer and a RS < 18 have an RFI similar to that of patients staged as PPS 1A by the current AJCC staging system, regardless of treatment, suggesting that the criteria for PPS 1A can be expanded to include a RS < 18. [ABSTRACT FROM AUTHOR]

Background: The relationship between Ki67 assessed by immunohistochemistry (IHC) and the Oncotype DX Recurrence Score (RS) is unclear. The objective of this study was to determine the correlation between the 21-gene RS and IHC-measured Ki67 with the prognostic classification groups recommended by the International Ki67 Working Group (IKWG).Methods: The authors performed a retrospective chart review of women who had hormone receptor (HR)-positive, human epidermal growth factor receptor 2-negative early breast cancer with zero to three positive lymph nodes and both Ki67 and the 21-gene RS performed at their institution from 2013 to 2021. Patients were categorized into low (≤5%), intermediate (6%-29%), and high Ki67 groups (≥30%) according to IKWG recommendations. Overall agreement and risk-stratified agreement between Ki67 and RS were assessed with the proportion of agreement and the κ statistic.Results: The study included 525 patients with HR-positive breast cancer. Among the 49% of patients with intermediate Ki67 values of 6%-29%, the distribution of low (0-10), intermediate (11-25), and high RS (26-100) was 19%, 66%, and 15%, respectively. There was slight agreement (κ = 0.01-0.20) between Ki67 and RS (κ = 0.027) in the overall population, although this was not significant (p = .1985). There was fair agreement (κ = 0.21-0.40) between high Ki67 and RS values (κ = 0.280; p < .0001). A higher progesterone receptor percentage was associated with lower RS values (p > .0001) but not lower Ki67 values. A positive nodal status and a larger tumor size were associated with higher Ki67 values (p = .0059 and p < .0001) but not with RS.Conclusions: In this group of patients selected to have a 21-gene RS, there was no significant correlation between Ki67 and RS in the overall population, and there was fair agreement between high Ki67 and high RS values.Lay Summary: In patients with early-stage, hormone receptor-positive breast cancer, decisions on adjuvant chemotherapy are based on certain biological features of the cancer and genomic assays such as the Oncotype DX Recurrence Score (RS). The goal of this study was to determine the correlation between Ki67, a marker of proliferation, and the Oncotype DX RS, a 21-gene assay demonstrated to be predictive of an adjuvant chemotherapy benefit in patients with early-stage breast cancer. In 525 patients, the authors did not find a significant correlation between Ki67 and RS. [ABSTRACT FROM AUTHOR]

Purpose: The three CDK4/6 inhibitors (CDK4/6i) approved for use in HR-positive/HER2-negative metastatic breast cancer (MBC), palbociclib, ribociclib, and abemaciclib, are generally well tolerated; however, neutropenia is a common toxicity. Within the general population, neutropenia has been shown to be more common in individuals of African descent. The landmark CDK4/6i trials in MBC lacked racial diversity in their patient populations. We aimed to assess the toxicity profiles of CDK4/6is in a racially diverse population. Methods: We conducted a retrospective study at Montefiore Medical Center in patients with HR-positive/HER2-negative MBC prescribed CDK4/6i as first or subsequent line therapy between January 2015 and April 2020. Baseline characteristics and laboratory data at various treatment timepoints were collected. Results: The final analysis included 182 patients, of whom 46% were Black. Baseline absolute neutrophil count (ANC) was lower in the Black vs. Non-Black cohort (p = 0.001) but the change in ANC from baseline (delta-ANC) was smaller in the Black cohort, and the ANC at different treatment timepoints was similar between groups. There was no difference in the rate of infection or number of dose delays/reductions between racial groups. We did not find any difference in PFS between Black and Non-Black groups, regardless of the presence of CDK4/6i-induced neutropenia. Conclusion: We analyzed toxicity profiles of 182 patients with HR-positive/HER2-negative MBC treated with CDK4/6i. Despite the lower baseline ANC seen in our Black cohort, treatment toxicities were similar between racial groups. Long-term outcomes with CDK4/6i therapy, measured by PFS, were similar between Black vs. Non-Black patients. [ABSTRACT FROM AUTHOR]

Background: Black race is associated with worse outcome in patients with breast cancer. The distant relapse‐free survival (DRFS) between Black and White women with localized breast cancer who participated in National Cancer Institute–sponsored clinical trial was evaluated. Methods: Pooled data were analyzed from 8 National Surgical Adjuvant Breast and Bowel Project (NSABP) trials including 9702 women with localized breast cancer treated with adjuvant chemotherapy (AC, n = 7485) or neoadjuvant chemotherapy (NAC, n = 2217), who self‐reported as Black (n = 1070) or White (n = 8632) race. The association between race and DRFS was analyzed using log‐rank tests and multivariate Cox regression. Results: After adjustment for covariates including age, tumor size, nodal status, body mass index and taxane use, and treatment (AC vs NAC), Black race was associated with an inferior DRFS in estrogen receptor–positive (ER+; hazard ratio [HR], 1.24; 95% CI, 1.05‐1.46; P =.01), but not in ER– disease (HR, 0.97; 95% CI, 0.83‐1.14; P =.73), and significant interaction between race and ER status was observed (P =.03). There was no racial disparity in DRFS among patients with pathologic complete response (pCR) (log‐rank P =.8). For patients without pCR, Black race was associated with worse DRFS in ER+ (HR, 1.67; 95% CI, 1.14‐2.45; P =.01), but not in ER– disease (HR, 0.91; 95% CI, 0.65‐1.28; P =.59). Conclusions: Black race was associated with significantly inferior DRFS in ER+ localized breast cancer treated with AC or NAC, but not in ER– disease. In the NAC group, racial disparity was also observed in patients with residual ER+ breast cancer at surgery, but not in those who had pCR. Lay Summary: Black women with breast cancer have worse outcomes compared with White women.We investigated if this held true in the context of clinical trials that provide controlled treatment setting.Black women with cancer expressing estrogen receptors (ERs) had worse outcome than White women. If breast cancers did not express ERs, there was no racial disparity in outcome.We also observed racial disparity in women who received chemotherapy before their cancer was removed, but only if they had cancer expressing ERs and residual disease on completion of treatment. If the cancer disappeared with presurgical chemotherapy, there was no racial disparity. Data from 8 National Surgical Adjuvant Breast and Bowel Project clinical trials show that Black women have a significantly inferior distant relapse‐free survival in estrogen receptor–positive (ER+) localized breast cancer treated with adjuvant or neoadjuvant chemotherapy, but not in ER– disease. The most significant racial disparity was observed in patients with residual ER+ breast cancer at surgery, but not in those who had a pathologic complete response. [ABSTRACT FROM AUTHOR]

Emerging evidence shows that tumor cells secrete extracellular vesicles (EVs) that carry bioactive cell surface markers, such as programmed death-ligand 1 (PD-L1), which can modulate immune responses and inhibit anti-tumor responses, potentially playing a role in lymphomagenesis and in promoting the growth of these cancers. In this study, we investigated the role of EVs expressing cell surface molecules associated with B cell activation and immune regulation. We measured levels of EVs derived from plasma from 57 subjects with AIDS-related non-Hodgkin lymphoma (AIDS-NHL) enrolled in the AIDS Malignancies Consortium (AMC) 034 clinical trial at baseline and post-treatment with rituximab plus concurrent infusional EPOCH chemotherapy. We found that plasma levels of EVs expressing PD-L1, CD40, CD40L or TNF-RII were significantly reduced after cancer treatment. AIDS-NHL patients with the diffuse large B cell lymphoma (DLBCL) tumor subtype had decreased plasma levels of EVs bearing PD-L1, compared to those with Burkitt's lymphoma. CD40, CD40L and TNF-RII-expressing EVs showed a significant positive correlation with plasma levels of IL-10, CXCL13, sCD25, sTNF-RII and IL-18. Our results suggest that patients with AIDS-NHL have higher levels of EVs expressing PD-L1, CD40, CD40L or TNF-RII in circulation before cancer treatment and that levels of these EVs are associated with levels of biomarkers of microbial translocation and inflammation. [ABSTRACT FROM AUTHOR]

Background: TAILORx (Trial Assigning Individualized Options for Treatment) prospectively assessed fatigue and endocrine symptoms among women with early‐stage hormone receptor–positive breast cancer and a midrange risk of recurrence who were randomized to endocrine therapy (E) or chemotherapy followed by endocrine therapy (CT+E). Methods: Participants completed the Functional Assessment of Chronic Illness Therapy–Fatigue, the Patient‐Reported Outcomes Measurement Information System–Fatigue Short Form, and the Functional Assessment of Cancer Therapy–Endocrine Symptoms at the baseline and at 3, 6, 12, 24, and 36 months. Linear regression was used to model outcomes on baseline symptoms, treatment, and other factors. Results: Participants (n = 458) in both treatment arms reported greater fatigue and endocrine symptoms at early follow‐up in comparison with the baseline. The magnitude of change in fatigue was significantly greater for the CT+E arm than the E arm at 3 and 6 months but not at 12, 24, or 36 months. The CT+E arm reported significantly greater changes in endocrine symptoms from the baseline to 3 months in comparison with the E arm; change scores were not significantly different at later time points. Endocrine symptom trajectories by treatment differed by menopausal status, with the effect larger and increasing for postmenopausal patients. Conclusions: Adjuvant CT+E was associated with greater increases in fatigue and endocrine symptoms at early time points in comparison with E. These differences lessened over time, and this demonstrated early chemotherapy effects more than long‐term ones. Treatment arm differences in endocrine symptoms were more evident in postmenopausal patients. Lay Summary: Participants in TAILORx (Trial Assigning Individualized Options for Treatment) with early‐stage hormone receptor–positive breast cancer and an intermediate risk of recurrence were randomly assigned to endocrine or chemoendocrine therapy.Four hundred fifty‐eight women reported fatigue and endocrine symptoms at the baseline and at 3, 6, 12, 24, and 36 months.Both groups reported greater symptoms at early follow‐up versus the baseline.Increases in fatigue were greater for the chemoendocrine group than the endocrine group at 3 and 6 months but not later.The chemoendocrine group reported greater changes in endocrine symptoms in comparison with the endocrine group at 3 months but not later. Participants in TAILORx (Trial Assigning Individualized Options for Treatment) randomized to chemoendocrine therapy report significant increases in fatigue and endocrine symptoms 3 months after randomization, which decrease through 36 months. Those randomized to endocrine therapy also report increased symptoms from the baseline, although of a lesser magnitude. [ABSTRACT FROM AUTHOR]

Background: E5103 was a study designed to evaluate the efficacy and safety of bevacizumab. It was a negative trial for the end points of invasive disease–free survival and overall survival. The current work examines the tolerability of bevacizumab and other medication exposures with respect to clinical outcomes and patient‐reported outcomes (PROs). Methods: Adverse events (AEs) collected from the Common Terminology Criteria for Adverse Events were summarized to form an AE profile at each treatment cycle. All‐grade and high‐grade events were separately analyzed. The change in the AE profile over the treatment cycle was delineated as distinct AE trajectory clusters. AE‐related and any‐reason early treatment discontinuations were treated as clinical outcome measures. PROs were measured with the Functional Assessment of Cancer Therapy–Breast + Lymphedema. The relationships between the AE trajectory and early treatment discontinuation as well as PROs were analyzed. Results: More than half of all AEs (57.5%) were low‐grade. A cluster of patients with broad and mixed AE (all‐grade) trajectory grades was significantly associated with any‐reason early treatment discontinuation (odds ratio [OR], 2.87; P =.01) as well as AE‐related discontinuation (OR, 4.14; P =.001). This cluster had the highest count of all‐grade AEs per cycle in comparison with other clusters. Another cluster of patients with primary neuropathic AEs in their trajectories had poorer physical well‐being in comparison with a trajectory of no or few AEs (P <.01). A high‐grade AE trajectory did not predict discontinuations. Conclusions: A sustained and cumulative burden of across‐the‐board toxicities, which were not necessarily all recognized as high‐grade AEs, contributed to early treatment discontinuation. Patients with neuropathic all‐grade AEs may require additional attention for preventing deterioration in their physical well‐being. In this secondary data analysis study of patients with breast cancer treated with bevacizumab and chemotherapy, cumulative multiple toxicities, even of low grades, are associated with early treatment discontinuation. Peripheral neuropathy is related to poor self‐reported physical well‐being, and this suggests additional care for patients exhibiting such toxicity. [ABSTRACT FROM AUTHOR]

Background: The prognostic significance of patients with low-risk recurrence score (RS) results in the context of the American Joint Committee on Cancer (AJCC) eighth edition pathologic prognostic staging has not been investigated. We evaluated if expanded RS criteria can be considered for downstaging in AJCC pathologic prognostic staging.Methods: Using Surveillance, Epidemiology, and End Results data, we identified patients with T1-3N0-3M0 hormone receptor-positive, HER2-negative breast cancer treated from 2010 to 2015 with follow-up data through 2016. We evaluated TNM categories, grade, and RS result. The primary outcome measured was 5-year disease-specific survival (DSS) of patients with low-risk RS results not already pathologic prognostic stage IA, determined by T and N categories per AJCC eighth edition. All statistical tests were 2-sided.Results: Of 154 050 patients with median follow-up of 49 months (range = 0-83), RS results were obtained in 60 886 (39.5%): RS was less than 11 in 13 570 (22.3%); 11-17 in 22 719 (37.3%); 18-25 in 16 521 (27.1%); and 26 or higher in 8076 (13.3%). Five-year DSS for pathologic prognostic stage IA patients (n = 114 910, 74.6%) was 98.8%. Among N0-1 patients with a RS less than 18 not staged as pathologic prognostic stage IA by current criteria, 5-year DSS was excellent and not statistically significantly different than for pathologic prognostic stage IA patients (97.2%-99.7%; P > .05). For those with a RS of 18-25, there was a small decrease in DSS for T2N0 (2.3%) and modest decrease for T1-2N1 (4.2%-6.4%) compared with pathologic prognostic stage IA patients (P < .001).Conclusion: Patients with a RS less than 18 have excellent 5-year DSS regardless of T category for N0-1 disease suggesting further modification of the AJCC staging system using this cutoff. [ABSTRACT FROM AUTHOR]

Purpose: Preclinical data demonstrate STAT3 as an important regulator in HER2+ tumors, and disruption of the IL6-JAK2-STAT-S100A8/S100A9 signaling cascade reduces HER2+ cell viability. Ruxolitinib is an FDA approved inhibitor of JAK1 and JAK2. We performed a phase I/II trial investigating the safety and efficacy of the combination of trastuzumab and ruxolitinib in patients with trastuzumab-resistant metastatic HER2+ breast cancer. Methods: Patients with metastatic HER2+ breast cancer progressing on at least 2 lines of HER2-directed therapy were eligible. The phase I portion determined the tolerable dose of ruxolitinib in combination with trastuzumab. The primary objective of the phase II was to assess the progression free survival (PFS) of the combination of ruxolitinib plus trastuzumab compared to historical control. Results: Twenty-eight patients were enrolled, with a median number of prior therapies of 4.5. Ruxolitinib 25 mg twice daily was the recommended phase II dose with no dose limiting toxicities (DLTs). Of 26 evaluable patients in phase II, the median PFS was 8.3 weeks (95% CI 7.1, 13.9). Among the 14 patients with measurable disease, 1 patient had a partial response and 4 patients had stable disease. Most of the adverse events were hematologic. Conclusion: While well tolerated with a strong preclinical rationale, the combination of ruxolitinib and trastuzumab did not lead to an improvement in PFS compared to historical control in patients with trastuzumab-resistant metastatic HER2+ breast cancer. [ABSTRACT FROM AUTHOR]

Multigene expression assays are prognostic for recurrence in hormone-receptor positive 2 (HER-2) negative breast cancer, and, in some cases, predictive of benefit from chemotherapy or extended endocrine therapy. The results of these assays may be used to guide treatment recommendations for early HER-2 negative breast cancer. We review the results of trials establishing the clinical utility of several commercially available gene expression assays. [ABSTRACT FROM AUTHOR]

Purpose: To compare efficacy and safety of capecitabine and lapatinib with or without IMC-A12 (cituxumumab) in patients with HER2-positive metastatic breast cancer (MBC) previously treated with trastuzumab. Patients and methods: Following an initial safety run-in cohort, patients were randomized 1:2 to Arm A (capecitabine and lapatinib) or to Arm B (capecitabine, lapatinib, and cituxumumab). Given the frequency of non-hematologic grade ≥ 3 adverse events in those receiving the three-drug combination in the safety cohort, lapatinib and capecitabine doses were reduced in Arm B only. The primary objective was to determine if the addition of cituxumumab to capecitabine and lapatinib improved progression-free survival (PFS) compared with capecitabine and lapatinib. Secondary objectives included a comparison between arms of other clinical endpoints, safety, change in overall quality of life (QOL) and self-assessed fatigue, rash, diarrhea, and hand-foot syndrome. Results: From July 2008 to March 2012, 68 patients (out of 142 planned) were enrolled and 63 were evaluable, including 8 for the safety run-in and 55 for the randomized cohort. Study enrollment was stopped early due to slow accrual. The addition of cituxumumab to capecitabine and lapatinib did not improve PFS (HR 0.93, 95% CI: 0.52–1.64). Furthermore, no difference in objective response rate or overall survival (OS) was observed. No difference between arms was observed in grade ≥ 3 adverse events, overall QOL change from baseline after 4 cycles of treatment. Conclusion: The addition of cituxumumab to lapatinib and capecitabine did not improve PFS or OS compared with lapatinib and capecitabine in patients with HER2-positive MBC. Clinical trial registry: ClinicalTrials.gov Identifier: NCT00684983 [ABSTRACT FROM AUTHOR]

Background: Early discontinuation is a substantial barrier to the delivery of endocrine therapies (ETs) and may influence recurrence and survival. The authors investigated the association between early discontinuation of ET and social determinants of health, including insurance coverage and the neighborhood deprivation index (NDI), which was measured on the basis of patients' zip codes, in breast cancer. Methods: In this retrospective analysis of a prospective randomized clinical trial (Trial Assigning Individualized Options for Treatment), women with hormone receptor–positive, human epidermal growth factor receptor 2–negative breast cancer who started ET within a year of study entry were included. Early discontinuation was calculated as stopping ET within 4 years of its start for reasons other than distant recurrence or death via Kaplan‐Meier estimates. A Cox proportional hazards joint model was used to analyze the association between early discontinuation of ET and factors such as the study‐entry insurance and NDI, with adjustments made for other variables. Results: Of the included 9475 women (mean age, 55.6 years; White race, 84%), 58.0% had private insurance, whereas 11.7% had Medicare, 5.8% had Medicaid, 3.8% were self‐pay, and 19.1% were treated at international sites. The early discontinuation rate was 12.3%. Compared with those with private insurance, patients with Medicaid (hazard ratio [HR], 1.53; 95% confidence interval [CI], 1.23‐1.92) and self‐pay patients (HR, 1.65; 95% CI, 1.25‐2.17) had higher early discontinuation. Participants with a first‐quartile NDI (highest deprivation) had a higher probability of discontinuation than those with a fourth‐quartile NDI (lowest deprivation; HR, 1.34; 95% CI, 1.11‐1.62). Conclusions: Patients' insurance and zip code at study entry play roles in adherence to ET, with uninsured and underinsured patients having a high rate of treatment nonadherence. Early identification of patients at risk may improve adherence to therapy. Lay Summary: In this retrospective analysis of 9475 women with breast cancer participating in a clinical trial (Trial Assigning Individualized Options for Treatment), Medicaid and self‐pay patients (compared with those with private insurance) and those in the highest quartile of neighborhood deprivation scores (compared with those in the lowest quartile) had a higher probability of early discontinuation of endocrine therapy.These social determinants of health assume larger importance with the expected increase in unemployment rates and loss of insurance coverage in the aftermath of the coronavirus disease 2019 pandemic. Early identification of patients at risk and enrollment in insurance optimization programs may improve the persistence of therapy. Patients' insurance status and geographic residence play important roles in the persistence of endocrine therapy use. Early identification of patients at risk may improve adherence to therapy. [ABSTRACT FROM AUTHOR]

The objective of this study was to evaluate the impact of insurance and neighborhood SES (nSES) on chemotherapy completion and overall mortality among participants in breast cancer clinical trials. The data sources for this study were two adjuvant breast cancer trials (ECOG E1199 and E5103) collectively including 9790 women. Insurance status at trial registration was categorized into private, government (Medicaid, Medicare, and other government type insurance), and self‐pay. An Agency for Healthcare Research Quality (AHRQ) nSES index was calculated using residential zip codes linked to county level data on occupation, income, poverty, wealth, education, and crowding. Logistic regression and Cox Proportional Hazard models estimated odds ratios (OR) for chemotherapy treatment completion and hazard ratios (HR) for mortality, respectively, for insurance status and nSES. The models adjusted for: race, age, tumor size, nodal status, hormone receptor status, and primary surgery. The majority of patients had private insurance at trial registration: E1199: 85.6% (4154/4854) and E5103: 82.4% (3987/4836); median SES index was 53.8 (range: 41.8‐66.8) and 54.1 (range: 44.5‐66.1), respectively. Patients with government insurance were less likely to complete chemotherapy treatment (E1199 OR (95%CI): 0.73 (0.57‐0.94); E5103 0.76 (0.64‐0.91)) and had an increased risk of death (E1199 HR (95%CI): 1.44 (1.22‐1.70); E5103 1.29 (1.06‐1.58)) compared to the privately insured patients. There was no association between nSES and chemotherapy completion or overall mortality. Patients with government insurance at trial registration appeared to face barriers in chemotherapy completion and had a higher overall mortality compared to their privately insured counterparts. [ABSTRACT FROM AUTHOR]

Multigene expression assays are prognostic for recurrence in hormone-receptor positive 2 (HER-2) negative breast cancer, and, in some cases, predictive of benefit from chemotherapy or extended endocrine therapy. The results of these assays may be used to guide treatment recommendations for early HER-2 negative breast cancer. We review the results of trials establishing the clinical utility of several commercially available gene expression assays. [ABSTRACT FROM AUTHOR]

Breast cancer is the second most commonly diagnosed cancer in American women following skin cancer. Despite overall decrease in breast cancer mortality due to advances in treatment and earlier screening, black patients continue to have 40% higher risk of breast cancer related death compared to white patients. This disparity in outcome persists even when controlled for access to care and stage at presentation and has been attributed to differences in tumor subtypes or gene expression profiles. There is emerging evidence that the tumor microenvironment (TME) may contribute to the racial disparities in outcome as well. Here, we provide a comprehensive review of current literature available regarding race-dependent differences in the TME. Notably, black patients tend to have a higher density of pro-tumorigenic immune cells (e.g., M2 macrophages, regulatory T cells) and microvasculature. Although immune cells are classically thought to be anti-tumorigenic, increase in M2 macrophages and angiogenesis may lead to a paradoxical increase in metastasis by forming doorways of tumor cell intravasation called tumor microenvironment of metastasis (TMEM). Furthermore, black patients also have higher serum levels of inflammatory cytokines, which provide a positive feedback loop in creating a pro-metastatic TME. Lastly, we propose that the higher density of immune cells and angiogenesis observed in the TME of black patients may be a result of evolutionary selection for a more robust immune response in patients of African geographic ancestry. Better understanding of race-dependent differences in the TME will aid in overcoming the racial disparity in breast cancer mortality. [ABSTRACT FROM AUTHOR]

Objective: Poly(ADP-ribosyl) polymerases (PARPs) are nuclear enzymes with roles in DNA damage recognition and repair. PARP1 inhibition enhances the effects of DNA-damaging agents like doxorubicin. We sought to determine the recommended phase two dose (RP2D) of veliparib with pegylated liposomal doxorubicin (PLD) in breast and recurrent gynecologic cancer patients.Methods: Veliparib and PLD were administered in a standard phase 1, 3 + 3 dose-escalation design starting at 50 mg veliparib BID on days 1-14 with PLD 40 mg/mg2 on day 1 of a 28-day cycle. Dose escalation proceeded in two strata: A (prior PLD exposure) and B (no prior PLD exposure). Patients underwent limited pharmacokinetic (PK) sampling; an expansion PK cohort was added.Results: 44 patients with recurrent ovarian or triple negative breast cancer were enrolled. Median age 56 years; 23 patients BRCA mutation carriers; median prior regimens four. Patients received a median of four cycles of veliparib/PLD. Grade 3/4 toxicities were observed in 10% of patients. Antitumor activity was observed in both sporadic and BRCA-deficient cancers. Two BRCA mutation carriers had complete responses. Two BRCA patients developed oral squamous cell cancers after completing this regimen. PLD exposure was observed to be higher when veliparib doses were > 200 mg BID.Conclusions: The RP2D is 200 mg veliparib BID on days 1-14 with 40 mg/m2 PLD on day 1 of a 28-day cycle. Anti-tumor activity was seen in both strata. However, given development of long-term squamous cell cancers and the PK interaction observed, efforts should focus on other targeted combinations to improve efficacy. [ABSTRACT FROM AUTHOR]

Background: We used two models to simulate a proposed noninferiority trial of radiotherapy (RT) omission in low-risk invasive breast cancer to illustrate how modeling could be used to predict the trial's outcomes, inform trial design, and contribute to practice debates.Methods: The proposed trial was a prospective randomized trial of no-RT vs RT in women age 40 to 74 years undergoing lumpectomy and endocrine therapy for hormone receptor-positive, human epidermal growth factor receptor 2-negative, stage I breast cancer with an Oncotype DX score of 18 or lower. The primary endpoint was recurrence-free interval (RFI), including locoregional recurrence, distant recurrence, and breast cancer death. Noninferiority required the two-sided 90% confidence interval of the RFI hazard ratio (HR) for no-RT vs RT to be entirely below 1.7. Model inputs included published data. The trial was simulated 1000 times, and results were summarized as percent concluding noninferiority and mean (standard deviation) of hazard ratios for Model GE and Model M, respectively.Results: Noninferiority was demonstrated in 18.0% and 3.7% for the two models. The respective means (SD) of the RFI hazard ratios were 1.8 (0.7) and 2.4 (0.9); most were locoregional recurrences. The mean five-year RFI rates for no-RT vs RT (SD) were 92.7% (2.9%) vs 95.5% (2.2%) and 88.4% (2.0%) vs 94.5% (1.6%). Both models showed little or no difference in breast cancer-specific or overall survival. Alternative definitions of low risk based on combinations of age and grade produced similar results.Conclusions: The proposed trial was unlikely to show noninferiority of omitting radiotherapy even using alternative definitions of low-risk, as the endpoint included local recurrence. Future trials regarding radiotherapy should address absolute reduction in recurrence and impact of type of recurrence on the patient. [ABSTRACT FROM AUTHOR]

Background: Radiotherapy after breast conservation has become the standard of care. Prior meta-analyses on effects of radiotherapy predated availability of gene expression profiling (GEP) to assess recurrence risk and/or did not include all relevant outcomes. This analysis used GEP information with pooled individual-level data to evaluate the impact of omitting radiotherapy on recurrence and mortality.Methods: We considered trials that evaluated or administered radiotherapy after lumpectomy in women with low-risk breast cancer. Women included had undergone lumpectomy and were treated with hormonal therapy for stage I, ER+ and/or PR+, HER2- breast cancer with Oncotype scores no greater than 18. Recurrence-free interval (RFI), type of RFI (locoregional or distant), and breast cancer-specific and overall survival were compared between no radiotherapy and radiotherapy using adjusted Cox models. All statistical tests were two-sided.Results: The final sample included 1778 women from seven trials. Omission of radiotherapy was associated with an overall adjusted hazard ratio of 2.59 (95% confidence interval [CI] = 1.38 to 4.89, P = .003) for RFI. There was a statistically significant increase in any first locoregional recurrence (P = .001), but not distant recurrence events (P = .90), or breast cancer-specific (P = .85) or overall survival (P = .61). Five-year RFI rate was high (93.5% for no radiotherapy vs 97.9% for radiotherapy; absolute reduction = 4.4%, 95% CI = 0.7% to 8.1%, P = .03). The effects of radiotherapy varied across subgroups, with lower RFI rates for those with Oncotype scores of less than 11 (vs 11-18), older (vs younger), and ER+/PR+ status (vs other).Conclusions: Omission of radiotherapy in hormone-sensitive patients with low recurrence risk may lead to a modest increase in locoregional recurrence event rates, but does not appear to increase the rate of distant recurrence or death. [ABSTRACT FROM AUTHOR]

Black race compared to white race is associated with more advanced stage and biologically aggressive breast cancer. Consequently, black patients are more frequently treated with neoadjuvant chemotherapy (NAC) than white patients. However, it is unclear how distant recurrence-free survival (DRFS) of black patients treated with NAC, compares to DRFS of black patients treated with adjuvant chemotherapy (AC). We evaluated the association between race, distant recurrence, and type of chemotherapy (AC or NAC) in localized or locally advanced breast cancer. We evaluated DRFS in 807 patients, including 473 black, 252 white, 56 Hispanic, and 26 women of other or mixed race. The association between AC or NAC and DRFS was examined using multivariate Cox proportional hazard models that included race, age, stage, estrogen receptor (ER) and triple negative (TN) status. When the black and white subjects were pooled for the analysis the features associated with worse DRFS included stage III disease and age < 50 years, but not ER-negative disease, TN disease, the use of NAC, or black race. However, in the analysis stratified by race NAC was associated with worse DRFS compared to AC in black (HR 2.70; 95% CI 1.73-4.22; p < 0.0001), but not in white women (HR 1.29, 95% CI 0.56-2.95; p = 0.36). Black patients treated with NAC had worse DRFS than black patients treated with AC, or white patients treated with either NAC or AC. These findings need to be validated in a large-scale observational study and the effect of NAC on the breast cancer microenvironment in black women needs to be further evaluated. [ABSTRACT FROM AUTHOR]

Drug-drug interactions between cART and chemotherapy may impact HIV and lymphoma control or lead to increased toxicities. No prospective comparative data informs potential harms and benefits. In AMC034, HIV-associated high-grade B-cell NHL patients received DA-EPOCH with rituximab. cART was given with EPOCH or delayed until chemotherapy completion per investigator choice. Pharmacokinetic, immunological, and treatment effects of concurrent cART were evaluated. CD4 counts dropped during EPOCH in both groups but recovered to higher than baseline 6 months post-EPOCH only in the cART group. HIV viral load decreased during chemotherapy in the cART group but increased in the non-cART group. Incidence of grade ≥3 infectious, hematologic, or neurological toxicities was similar. Concurrent cART was not associated with 1-year EFS or OS. cART with EPOCH was well-tolerated and allowed for faster immune recovery. While we did not observe differences in outcome, the preponderance of evidence is in favor of combining cART with chemotherapy. [ABSTRACT FROM AUTHOR]

Purpose: Suberoylanilide hydroxamic acid (SAHA; vorinostat), a small molecule inhibitor of histone deacetylase, attenuates signaling pathways known to confer trastuzumab resistance. A combination of SAHA and trastuzumab may be a promising strategy to improve the efficacy of trastuzumab against breast cancer. In this Phase I/II study, we evaluated the toxicity and response rate after treatment with SAHA and trastuzumab in patients with HER2-overexpressing metastatic breast cancer with trastuzumab-resistant progressive disease. Methods: In Phase I, the SAHA dose was modified in cohorts of 3-6 patients to find the dose level at which 0 or 1 patients experienced a dose-limiting toxicity (DLT) during the first cycle of therapy. In the Phase II study, response to the recommended dose identified in Phase I was based on the response evaluation criteria in solid tumors. Overall survival and time to progression were also evaluated. Results: The recommended dose was determined to be 200 mg twice a day on days 1-14 and IV trastuzumab 6 mg/kg on day 1 of a 21-day cycle ( n = 6). The Phase II study ( n = 10) was terminated when the pre-planned efficacy evaluation found that none of the patients in the primary analysis set responded to combination SAHA and trastuzumab treatment. Conclusions: In patients with HER2-positive metastatic breast cancer who had relapsed or progressed during trastuzumab therapy, we observed no DLTs with SAHA 200 mg twice daily combined with trastuzumab; however, there was insufficient statistical evidence that adding SAHA reversed trastuzumab resistance in these patients. [ABSTRACT FROM AUTHOR]

The article discusses the findings of a study which examines the effectiveness of a neoadjuvant chemotherapy as treatment for breast cancer metastasis through a tumor microenvironment of metastasis (TMEM). The study highlights the use of a fixed tissue and intravital imaging of breast cancer patients tumors. It also notes the development of TMEM inhibitor function in improving the benefits of chemotherapy to breast cancer patients.

Purpose: Racial disparity in breast cancer outcomes exists between African American and white women in the United States. We have evaluated the impact of genetically determined ancestry on disparity in efficacy and therapy-induced toxicity for patients with breast cancer in the context of a randomized, phase III adjuvant trial. Methods: This study compared outcomes between 386 patients of African ancestry (AA) and 2,473 patients of European ancestry (EA) in a randomized, phase III breast cancer trial, ECOG-ACRIN-5103. The primary efficacy end point, invasive disease–free survival (DFS), and clinically significant toxicities were compared, including anthracycline-induced congestive heart failure, taxane-induced peripheral neuropathy (TIPN), and bevacizumab-induced hypertension. Results: Overall, AAs had significantly inferior DFS (P =.002; hazard ratio, 1.5) compared with EAs. This was significant in the estrogen receptor–positive subgroup (P =.03), with a similar, nonsignificant trend for those who had triple-negative breast cancer (P =.12). AAs also had significantly more grades 3 to 4 TIPN (odds ratio [OR], 2.9; P = 2.4 × 10−11) and grades 3 to 4 bevacizumab-induced hypertension (OR, 1.6; P =.02), with a trend for more congestive heart failure (OR, 1.8; P =.08). AAs had significantly more dose reductions in paclitaxel (P = 6.6 × 10−6). In AAs, dose reductions in paclitaxel had a significant negative impact on DFS (P =.03), whereas in EAs, dose reductions did not have an impact on outcome (P =.35). Conclusion: AAs had inferior DFS, with more clinically important toxicities, in ECOG-ACRIN-5103. The altered risk-to-benefit ratio for adjuvant breast cancer chemotherapy should lead to additional research with the focus on the impact of genetic ancestry on both efficacy and toxicity. Strategies to minimize dose reductions in paclitaxel, especially as the result of TIPN, are warranted for this population. [ABSTRACT FROM AUTHOR]

Purpose: Identification of single-gene biomarkers that are prognostic of outcome can shed new insights on the molecular mechanisms that drive breast cancer and other cancers. Methods: Exploratory analysis of 20,464 single-gene messenger RNAs (mRNAs) in the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) discovery cohort indicates that low expression of FGD3 mRNA is prognostic for poor outcome. Prognostic significance of faciogenital dysplasia 3 (FGD3), SUSD3, and other single-gene proliferation markers was evaluated in breast cancer and The Cancer Genome Atlas (TCGA) cohorts. Results: A meta-analysis of Cox regression of FGD3 mRNA as a continuous variable for overall survival of estrogen receptor (ER)–positive samples in METABRIC discovery, METABRIC validation, TCGA breast cancer, and Combination Chemotherapy in Treating Women With Breast Cancer (E2197) cohorts resulted in a combined hazard ratio (HR) of 0.69 (95% CI, 0.63 to 0.75), indicating better outcome with high expression. In the ER-negative samples, the combined meta-analysis HR was 0.72 (95% CI, 0.63 to 0.82), suggesting that FGD3 is prognostic regardless of ER status. The potential of FGD3 as a biomarker for freedom from recurrence was evaluated in the Breast International Group 1-98 (BIG 1-98; Letrozole or Tamoxifen in Treating Postmenopausal Women With Breast Cancer) study (HR, 0.85; 95% CI, 0.76 to 0.93) for breast cancer–free interval. In the Hungarian Academy of Science (HAS) breast cancer cohort, splitting on the median had an HR of 0.49 (95% CI, 0.42 to 0.58) for recurrence-free survival. A comparison of the Stouffer P value in five ER-positive cohorts showed that FGD3 (P = 3.8E-14) outperformed MKI67 (P = 1.06E-8) and AURKA (P = 2.61E-5). A comparison of the Stouffer P value in four ER-negative cohorts showed that FGD3 (P = 3.88E-5) outperformed MKI67 (P =.477) and AURKA (P =.820). Conclusion: FGD3 was previously shown to inhibit cell migration. FGD3 mRNA is regulated by ESR1 and is associated with favorable outcome in six distinct breast cancer cohorts and four TCGA cancer cohorts. This suggests that FGD3 is an important clinical biomarker. [ABSTRACT FROM AUTHOR]

Background. Icrucumab (ICR) and ramucirumab (RAM) bind vascular endothelial growth factor (VEGF) receptors 1 and 2 (VEGFR-1 and -2), respectively. This open-label, randomized phase II study evaluated their efficacy and safety in combination with capecitabine (CAP) in patients with previously treated unresectable, locally advanced or metastatic breast cancer. Methods. Patients were randomly assigned (1:1:1) to receive CAP (1,000 mg/m2 orally twice daily, days 1-14) alone or in combination with RAM (10 mg/kg intravenously [IV], days 1 and 8) (RAM 1 CAP) or ICR (12 mg/kg IV, days 1 and 8) (ICR 1 CAP) every 21 days. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), tumor response, safety, and pharmacokinetics. Results. Of 153 patients randomized, 150 received treatment. Median PFS (95% confidence interval) was 22.1 (12.1-36.1) weeks on RAM 1 CAP, 7.3 (6.3-13.0) weeks on ICR 1 CAP, and 19.0 (12.1-24.3) weeks on CAP (hazard ratios [HRs]: 0.691, p = .1315, RAM 1 CAP versus CAP; 1.480, p = .0851, ICR 1 CAP versus CAP). Median OS was 67.4 weeks on RAM 1 CAP, 62.0 weeks on ICR 1 CAP, and 71.6 weeks on CAP (HRs: 1.833, p = .0283, RAM 1 CAP versus CAP; 1.468, p = .1550, ICR 1 CAP versus CAP). There was no statistically significant difference in PFS or OS between either combination arm and CAP. Treatment-related adverse events more frequent (by ≥10%) on RAM 1 CAP than on CAP were constipation, decreased appetite, headache, epistaxis, and hypertension. Those more frequent (by ≥10%) on ICR 1 CAP than CAP were anemia, increased lacrimation, periorbital edema, nausea, vomiting, peripheral edema, facial edema, dehydration, and dyspnea. Conclusion. Combining RAM or ICR with CAP did not improve PFS in the targeted study population. [ABSTRACT FROM AUTHOR]

The article offers information surveillance after treatment of localized breast cancer. It mentions evidence-based guidelines recommend surveillance after treatment of localized breast cancer including history, physical examination, and annual mammography. It also mentions key elements of the trial include selection of patients with nonmetastatic breast cancer at high clinical risk of recurrence based on classical clinic pathologic features.

The article presents an editorial on the Hippocratic Oath in breast cancer that includes a statement about preventing the disease whenever possible, as prevention if preferable to cure. Topics discussed include the use of chemoprevention which offer preventive effects against cancer well after completion of a typical 5 year course of chemoprevention therapy.

Purpose: To determine the recommended phase II dose (RPTD) of a 96-h continuous intravenous infusion (CIVI) of cyclophosphamide (200, 300, or 400 mg/m2/d) and etoposide (60 or 90 mg/m2/d) when used in conjunction with doxorubicin (12.5 mg/m2/d) (CDE) given every 28 d plus granulocyte-macrophage colony stimulating factor (GM-CSF) in patients with poor prognosis non-Hodgkin's lymphoma (Group A), and the same regimen given every 21 d (Group B).Methods: In Group A, infusional CDE was repeated every 28 d, GM-CSF (250 microg/m2) was given subcutaneously from d 6 until neutrophil recovery, with dose escalation in cohorts of three to six evaluable patients. The RPTD of cyclophosphamide and etoposide established in Group A was then used with CDE given every 3 wk (Group B) with GM-CSF given on d 6-20, and dose escalation was attempted again.Results: In Group A, the RPTD of cyclophosphamide and etoposide were 300 mg/m2/d and 90 mg/m2/d, respectively; prolonged neutropenia was the dose-limiting toxicity. In Group B, use of GM-CSF on d 6-20 did not facilitate dose escalation above the RPTD established in Group A. Complete response occurred in 13/26 patients (50%) with no prior chemotherapy, and in 4/16 patients (25%) who had relapsed after prior chemotherapy.Conclusions: Because of the increase in dose and dose-density afforded by the administration of GM-CSF, the relative dose intensity was increased by twofold for cyclophosphamide (400 vs 200 mg/m2/wk) and etoposide (120 vs 60 mg/m2/wk), and by 1.3-fold for doxorubicin (16.7 vs 12.5 mg/m2/wk). [ABSTRACT FROM AUTHOR]