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Radiotherapy has become much better targeted since the 1980s, improving both safety and efficacy. In breast cancer, radiotherapy to regional lymph nodes aims to reduce risks of recurrence and death. Its effects have been studied in randomised trials, some before the 1980s and some after. We aimed to assess the effects of regional node radiotherapy in these two eras.

IMPORTANCE: Whether racial and ethnic disparities in locoregional recurrence (LRR) exist among patients with similar access to care treated in randomized clinical trials is unknown. OBJECTIVE: To examine racial and ethnic differences in LRR among patients with hormone receptor (HR)–positive, human epidermal growth factor receptor 2 (ERBB2 [formerly HER2 or HER2/neu])–negative, node-negative breast cancer enrolled in the Trial Assigning Individualized Options for Treatment (TAILORx). DESIGN, SETTING, AND PARTICIPANTS: This unplanned retrospective post hoc analysis examined a prospective multicenter clinical trial population of women with breast cancer enrolled between 2006 and 2010, with 9 years of follow-up. The TAILORx investigators randomized patients to treatment based on their Oncotype DX recurrence score, including endocrine therapy alone (recurrence score <11), endocrine therapy alone vs chemotherapy followed by endocrine therapy (recurrence score 11-25), or chemotherapy followed by endocrine therapy (recurrence score >25). Patients with unknown race and ethnicity or lack of follow-up were excluded from this analysis. Data analysis was performed between December 2021 and March 2022. MAIN OUTCOME AND MEASURES: Locoregional recurrence was defined as ipsilateral in breast, skin, chest wall, or regional nodal recurrence without concurrent distant recurrence, and was stratified by racial and ethnic group. Unadjusted Kaplan-Meier and adjusted Cox proportional hazards regression models were used for survival analyses. RESULTS: Of the 10 273 women enrolled in TAILORx, this analysis included 9369 with T1-2N0 HR-positive, ERBB2-negative breast cancer. Of these patients, 428 (4.6%) were Asian, 886 (9.4%) were Hispanic, 676 (7.2%) were non-Hispanic Black (hereinafter Black), and 7406 (78.8%) were non-Hispanic White (hereinafter White). Assigned treatment receipt was high, with a 9.3% (n = 870) crossover of treatment groups and a median endocrine therapy duration of longer than 60 months, ranging from 61.1 to 65.9 months, across racial and ethnic groups. A total of 6818 patients (72.6%) received radiation (6474 [96.1%] after breast-conserving surgery and 344 [13.0%] after mastectomy). At a median follow-up of 94.8 months (range, 1-138 months), 8-year LRR rates were 3.6% (95% CI, 1.6%-5.6%) in Asian patients, 3.9% (95% CI, 2.2%-5.4%) in Black patients, 3.1% in Hispanic patients (95% CI, 1.7%-4.5%), and 1.8% (95% CI, 1.5%-2.3%) in White patients (P < .001). In survival analyses adjusted for patient, tumor, and treatment factors, Asian race (hazard ratio, 1.91 [95% CI, 1.12-3.29]) and Black race (1.78 [1.15-2.77]) were independently associated with LRR. In adjusted survival analyses for breast cancer mortality, LRR was independently associated with increased breast cancer mortality (hazard ratio, 5.71 [95% CI, 3.50-9.31]). CONCLUSIONS AND RELEVANCE: In this post hoc analysis, racial and ethnic differences in LRR were observed among patients with T1-2N0 HR-positive, ERBB2-negative breast cancer despite high rates of treatment receipt in this clinical trial population, with the highest LRR rates in Asian and Black patients. Further study is needed to understand whether failure to rescue after LRR may contribute to racial disparities in breast cancer mortality. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00310180

Anthracycline–taxane chemotherapy for early-stage breast cancer substantially improves survival compared with no chemotherapy. However, concerns about short-term and long-term side-effects of anthracyclines have led to increased use of taxane chemotherapy without anthracycline, which could compromise efficacy. We aimed to better characterise the benefits and risks of including anthracycline, and the comparative benefits of different anthracycline–taxane regimens.

Ki67 has potential clinical importance in breast cancer but has yet to see broad acceptance due to inter-laboratory variability. Here we tested an open source and calibrated automated digital image analysis (DIA) platform to: (i) investigate the comparability of Ki67 measurement across corresponding core biopsy and resection specimen cases, and (ii) assess section to section differences in Ki67 scoring. Two sets of 60 previously stained slides containing 30 core-cut biopsy and 30 corresponding resection specimens from 30 estrogen receptor-positive breast cancer patients were sent to 17 participating labs for automated assessment of average Ki67 expression. The blocks were centrally cut and immunohistochemically (IHC) stained for Ki67 (MIB-1 antibody). The QuPath platform was used to evaluate tumoral Ki67 expression. Calibration of the DIA method was performed as in published studies. A guideline for building an automated Ki67 scoring algorithm was sent to participating labs. Very high correlation and no systematic error (p= 0.08) was found between consecutive Ki67 IHC sections. Ki67 scores were higher for core biopsy slides compared to paired whole sections from resections (p≤ 0.001; median difference: 5.31%). The systematic discrepancy between core biopsy and corresponding whole sections was likely due to pre-analytical factors (tissue handling, fixation). Therefore, Ki67 IHC should be tested on core biopsy samples to best reflect the biological status of the tumor.

IMPORTANCE: Racial disparities in survival outcomes among Black women with hormone receptor–positive breast cancer have been reported. However, the association between individual-level and neighborhood-level social determinants of health on such disparities has not been well studied. OBJECTIVE: To evaluate the association between race and clinical outcomes (ie, relapse-free interval and overall survival) adjusting for individual insurance coverage and neighborhood deprivation index (NDI), measured using zip code of residence, in women with breast cancer. DESIGN, SETTING, AND PARTICIPANTS: This was a post hoc analysis of 9719 women with breast cancer in the Trial Assigning Individualized Options for Treatment, a randomized clinical trial conducted from April 7, 2006, to October 6, 2010. All participants received a diagnosis of hormone receptor–positive, ERBB2-negative, axillary node–negative breast cancer. The present data analysis was conducted from April 1 to October 22, 2021. MAIN OUTCOMES AND MEASURES: A multivariate model was developed to evaluate the association between race and relapse-free interval and overall survival adjusting for insurance and NDI level at study entry, early discontinuation of endocrine therapy 4 years after initiation, and clinicopathologic characteristics of cancer. Median follow-up for clinical outcomes was 96 months. RESULTS: A total of 9719 women (4.2% [n = 405] Asian; 7.1% [n = 693] Black; 84.3% [n = 8189] White; 4.4% [n = 403] others/not specified) were included; 9.1% of included women [n = 889] were Hispanic or Latino. Median (SD) age was 56 (9.2) years. In multivariate models, Black race compared with White race was associated with statistically significant shorter relapse-free interval (hazard ratio [HR], 1.39; 95% CI, 1.05-1.84; P = .02) and overall survival (HR, 1.49; 95% CI, 1.10-2.99; P = .009), adjusting for insurance and NDI level at study entry and other factors. Although uninsured status was not associated with clinical outcomes, patients with Medicare (HR, 1.30; 95% CI, 1.01-1.68; P = .04) and Medicaid (HR, 1.44; 95% CI, 1.01-2.05; P = .05) had shorter overall survival compared with those with private insurance. Participants living in neighborhoods in the highest NDI quartile experienced shorter overall survival compared with those in the lowest quartile (HR, 1.34; 95% CI, 1.01-1.77; P = .04), regardless of self-identified race. CONCLUSIONS AND RELEVANCE: The findings of this post hoc analysis of a randomized clinical trial suggest that Black women with breast cancer have significantly shorter relapse-free interval and overall survival compared with White women. Early discontinuation of endocrine therapy, clinicopathologic characteristics, insurance coverage, and NDI do not fully explain the observed disparity. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00310180

Window-of-opportunity trials, during which patients receive short-duration pre-surgical therapies, provide a platform for understanding the therapies’ mechanisms of action, but will require a paradigm shift in trial design, specimen collection and analysis.

Breast MRI depicts ductal carcinoma in situ diagnosed with conventional imaging (mammography with or without US), with a larger median span than mammography, has an additional cancer detection rate of 6.2%, and could assist with wide local excision.

IMPORTANCE: Early discontinuation of adjuvant endocrine therapy (ET) is problematic among breast cancer survivors, with previous studies suggesting that up to 50% of women do not adhere to the recommended full 5 years of ET treatment. OBJECTIVE: To identify the association between early discontinuation of ET in the Trial Assigning Individualized Options for Treatment (TAILORx) and modifiable risk factors, polypharmacy, and types of additional medications such as antidepressants and opioids. DESIGN, SETTING, AND PARTICIPANTS: This post hoc analysis includes a subgroup of 954 patients with breast cancer in TAILORx, a randomized clinical trial conducted from April 7, 2006, to October 6, 2010. All participants received a diagnosis of hormone receptor–positive, ERBB2-negative, axillary node–negative breast cancer and started ET within a year of study entry. Analyses were conducted in the intent-to-treat population. Statistical analysis took place from January 15, 2020, to April 6, 2021. MAIN OUTCOMES AND MEASURES: Participants completed measures on cancer-related health-related quality of life including physical well-being and social well-being prior to initiating ET. Early discontinuation of ET was defined as discontinuation less than 4 years from initiation for reasons other than death or recurrence. Kaplan-Meier estimates were used to calculate discontinuation, and Cox proportional hazards regression joint prediction models were used to analyze the association between rates of adherence to ET with patient-level factors. RESULTS: A total of 954 women (mean [SD] age, 56.6 [8.9] years) were included in this analysis. In a joint model, receipt of chemoendocrine therapy (vs receipt of ET only; hazard ratio [HR], 0.57; 95% CI, 0.35-0.92; P = .02) and age older than 40 years (vs ≤40 years; HR for 41-50 years, 0.39; 95% CI, 0.18-0.85; P = .02; HR for 51-60 years, 0.28; 95% CI, 0.13-0.60; P = .001; HR for 61-70 years, 0.40; 95% CI, 0.18-0.86; P = .02; and HR for >70 years, 0.23; 95% CI, 0.07-0.77; P = .02) were associated with a lower probability of early discontinuation of ET. Adjusted for these factors, a history of depression compared with no history of depression (HR, 1.82; 95% CI, 1.19-2.77; P = .005), worse physical well-being compared with better physical well-being (HR, 2.12; 95% CI, 1.30-3.45; P = .002), and worse social well-being compared with better social well-being (HR, 1.94; 95% CI, 1.20-3.13; P = .006) were individually and significantly associated with a higher probability of early discontinuation of ET. Only antidepressant use at study baseline was associated with early discontinuation (HR, 1.87; 95% CI, 1.23-2.84; P = .003). CONCLUSIONS AND RELEVANCE: In this post hoc analysis of a randomized clinical trial, baseline patient-reported health-related quality of life components, such as poor social well-being, poor physical well-being, and comorbid depression, were significant risk factors for early discontinuation of endocrine therapies. These results support systematic screening for patient-reported outcomes and depressive symptoms to identify women at risk for discontinuation of ET. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00310180

ABSTRACTIntroductionApproximately 10% of all breast cancer cases occur in individuals who have germline pathogenic variants of the BRCA 1, BRCA 2, and other genes associated with impaired DNA damage repair that is associated with an increased risk of breast, ovarian, and other cancers. Inhibitors of poly-ADP ribose polymerase (PARP) induce synthetic lethality in cancer cells harboring such pathogenic variants.Area coveredIn this review, the authors review the mechanisms of action, antitumor activity, and adverse events associated with PARP inhibitors for the treatment of advanced breast cancer. The authors then summarize the area and provide their expert perspectives on the area.Expert opinionTwo PARP inhibitors are approved in metastatic breast cancer, including olaparib and talozaparib. Both agents were approved based on phase III trials demonstrating that they were associated with improved progression-free survival compared with treatment of physician’s choice in patients receiving second-third line therapy for locally advanced, inoperable, or metastatic breast cancer in patients with germline pathogenic BRCA 1 or BRCA2 variants.

Anal cancer is an increasingly common non–AIDS-defining cancer among individuals infected with the human immunodeficiency virus (HIV). It is associated with human papillomavirus (HPV). HPV16 is the most common genotype detected in anal cancers. The HPV types detected in anal cancer are included in the 9-valent vaccine. HPV vaccines have demonstrated efficacy in reducing anal precancerous lesions in HIV-infected individuals. Standard treatment has been fluorouracil and mitomycin (or cisplatin) plus radiation. Continued studies are needed to test new treatment strategies in HIV-infected patients with anal cancer to determine which treatment protocols provide the best therapeutic index.

EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin) is a preferred regimen for HIV-non-Hodgkin lymphomas (HIV-NHLs), which are frequently Epstein-Barr virus (EBV) positive or human herpesvirus type-8 (HHV-8) positive. The histone deacetylase (HDAC) inhibitor vorinostat disrupts EBV/HHV-8 latency, enhances chemotherapy-induced cell death, and may clear HIV reservoirs. We performed a randomized phase 2 study in 90 patients (45 per study arm) with aggressive HIV-NHLs, using dose-adjusted EPOCH (plus rituximab if CD20+), alone or with 300 mg vorinostat, administered on days 1 to 5 of each cycle. Up to 1 prior cycle of systemic chemotherapy was allowed. The primary end point was complete response (CR). In 86 evaluable patients with diffuse large B-cell lymphoma (DLBCL; n = 61), plasmablastic lymphoma (n = 15), primary effusion lymphoma (n = 7), unclassifiable B-cell NHL (n = 2), and Burkitt lymphoma (n = 1), CR rates were 74% vs 68% for EPOCH vs EPOCH-vorinostat (P = .72). Patients with a CD4+ count <200 cells/mm3 had a lower CR rate. EPOCH-vorinostat did not eliminate HIV reservoirs, resulted in more frequent grade 4 neutropenia and thrombocytopenia, and did not affect survival. Overall, patients with Myc+ DLBCL had a significantly lower EFS. A low diagnosis-to-treatment interval (DTI) was also associated with inferior outcomes, whereas preprotocol therapy had no negative impact. In summary, EPOCH had broad efficacy against highly aggressive HIV-NHLs, whereas vorinostat had no benefit; patients with Myc-driven DLBCL, low CD4, and low DTI had less favorable outcomes. Permitting preprotocol therapy facilitated accruals without compromising outcomes. This trial was registered at www.clinicaltrials.gov as #NCT0119384.

EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin) is a preferred regimen for HIV-non-Hodgkin lymphomas (HIV-NHLs), which are frequently Epstein-Barr virus (EBV) positive or human herpesvirus type-8 (HHV-8) positive. The histone deacetylase (HDAC) inhibitor vorinostat disrupts EBV/HHV-8 latency, enhances chemotherapy-induced cell death, and may clear HIV reservoirs. We performed a randomized phase 2 study in 90 patients (45 per study arm) with aggressive HIV-NHLs, using dose-adjusted EPOCH (plus rituximab if CD20+), alone or with 300 mg vorinostat, administered on days 1 to 5 of each cycle. Up to 1 prior cycle of systemic chemotherapy was allowed. The primary end point was complete response (CR). In 86 evaluable patients with diffuse large B-cell lymphoma (DLBCL; n = 61), plasmablastic lymphoma (n = 15), primary effusion lymphoma (n = 7), unclassifiable B-cell NHL (n = 2), and Burkitt lymphoma (n = 1), CR rates were 74% vs 68% for EPOCH vs EPOCH-vorinostat (P= .72). Patients with a CD4+count <200 cells/mm3had a lower CR rate. EPOCH-vorinostat did not eliminate HIV reservoirs, resulted in more frequent grade 4 neutropenia and thrombocytopenia, and did not affect survival. Overall, patients with Myc+DLBCL had a significantly lower EFS. A low diagnosis-to-treatment interval (DTI) was also associated with inferior outcomes, whereas preprotocol therapy had no negative impact. In summary, EPOCH had broad efficacy against highly aggressive HIV-NHLs, whereas vorinostat had no benefit; patients with Myc-driven DLBCL, low CD4, and low DTI had less favorable outcomes. Permitting preprotocol therapy facilitated accruals without compromising outcomes. This trial was registered at www.clinicaltrials.govas #NCT0119384.

IMPORTANCE: A high 21-gene recurrence score (RS) by breast cancer assay is prognostic for distant recurrence of early breast cancer after local therapy and endocrine therapy alone, and for chemotherapy benefit. OBJECTIVE: To describe clinical outcomes for women with a high RS who received adjuvant chemotherapy plus endocrine therapy in the TAILORx trial, a population expected to have a high distant recurrence rate with endocrine therapy alone. DESIGN, SETTING, AND PARTICIPANTS: In this secondary analysis of data from a multicenter randomized clinical trial, 1389 women with hormone receptor–positive, ERBB2-negative, axillary node-negative breast cancer, and a high RS of 26 to 100 were prospectively assigned to receive adjuvant chemotherapy in addition to endocrine therapy. The analysis was conducted on May 12, 2019. INTERVENTIONS: The adjuvant chemotherapy regimen was selected by the treating physician. MAIN OUTCOMES AND MEASURES: Freedom from recurrence of breast cancer at a distant site, and freedom from recurrence, second primary cancer, and death (also known as invasive disease-free survival [IDFS]). RESULTS: Among the 9719 eligible women, with a mean age of 56 years (range 23-75 years), 1389 (14%) had a recurrence score of 26 to 100, of whom 598 (42%) had an RS of 26 to 30 and 791 (58%) had an RS of 31 to 100. The most common chemotherapy regimens included docetaxel/cyclophosphamide in 589 (42%), an anthracycline without a taxane in 334 (24%), an anthracycline and taxane in 244 (18%), cyclophosphamide/methotrexate/5-fluorouracil in 52 (4%), other regimens in 81 (6%), and no chemotherapy in 89 (6%). At 5 years, the estimated rate of freedom from recurrence of breast cancer at a distant site was 93.0% (standard error [SE], 0.8%), freedom of recurrence of breast cancer at a distant and/or local regional site 91.0% (SE, 0.8%), IDFS 87.6% (SE, 1.0%), and overall survival 95.9% (SE, 0.6%). CONCLUSIONS AND RELEVANCE: The estimated rate of freedom from recurrence of breast cancer at a distant site in women with an RS of 26 to 100 treated largely with taxane and/or anthracycline-containing adjuvant chemotherapy regimens plus endocrine therapy in the prospective TAILORx trial was 93% at 5 years, an outcome better than expected with endocrine therapy alone in this population. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00310180

IMPORTANCE: There is tremendous interest in using immunotherapy to treat breast cancer, as evidenced by the more than 290 clinical trials ongoing at the time of this narrative review. The objective of this review is to describe the current status of immunotherapy in breast cancer, highlighting its potential in both early-stage and metastatic disease. OBSERVATIONS: After searching ClinicalTrials.gov on April 24, 2018, and PubMed up to June 30, 2018, to identify breast cancer immunotherapy trials, we found that immune checkpoint blockade (ICB) is the most investigated form of immunotherapy in breast cancer. Use of ICB as monotherapy has achieved objective responses in patients with breast cancer, with higher rates seen when administered in earlier lines of therapy. For responding patients, those responses are durable. More recent data suggest clinical efficacy when ICB is given in combination with chemotherapy. Ongoing studies are evaluating combination strategies pairing ICB with additional chemotherapeutic agents, targeted therapy, vaccines, and local ablative therapies to enhance response. To date, robust predictive biomarkers for response to ICB have not been established. CONCLUSIONS AND RELEVANCE: It is anticipated that combination therapy strategies will be the way forward for immunotherapy in breast cancer, with an improved understanding of tumor, microenvironment, and host factors informing treatment combination decisions. Thoughtful study design incorporating appropriate end points and correlative studies will be critical in identifying optimal strategies for enhancing the immune response against breast tumors.

IMPORTANCE: Advanced diagnostics, such as magnetic resonance imaging (MRI) and gene expression profiles, are potentially useful to guide targeted treatment in patients with ductal carcinoma in situ (DCIS). OBJECTIVES: To examine the proportion of patients who converted to mastectomy after MRI and the reasons for those conversions and to measure patient adherence to radiotherapy guided by the 12-gene DCIS score. DESIGN, SETTING, AND PARTICIPANTS: Analysis of a prospective, cohort, nonrandomized clinical trial that enrolled women with DCIS on core biopsy who were candidates for wide local excision (WLE) from 75 institutions from March 25, 2015, to April 27, 2016, through the Eastern Cooperative Oncology Group–American College of Radiology Imaging Network trial E4112. INTERVENTIONS: Participants underwent breast MRI before surgery, and subsequent management incorporated MRI findings for choice of surgery. The DCIS score was used to guide radiotherapy recommendations among women with DCIS who had WLE as the final procedure and had tumor-free excision margins of 2 mm or greater. MAIN OUTCOMES AND MEASURES: The primary end point was to estimate the conversion rate to mastectomy and the reason for conversion. RESULTS: Of 339 evaluable women (mean [SD] age, 59.1 [10.1] years; 262 [77.3%] of European descent) eligible for WLE before MRI, 65 (19.2%; 95% CI, 15.3%-23.7%) converted to mastectomy. Of these 65 patients, conversion was based on MRI findings in 25 (38.5%), patient preference in 25 (38.5%), positive margins after attempted WLE in 10 (15.4%), positive genetic test results in 3 (4.6%), and contraindication to radiotherapy in 2 (3.1%). Among the 285 who had WLE performed after MRI as the first surgical procedure, 274 (96.1%) achieved successful breast conservation. Of 171 women eligible for radiotherapy guided by DCIS score (clear margins, absence of invasive disease, and score obtained), the score was low (&lt;39) in 82 (48.0%; 95% CI, 40.6%-55.4%) and intermediate-high (≥39) in 89 (52.0%; 95% CI, 44.6%-59.4%). Of these 171 patients, 159 (93.0%) were adherent with recommendations. CONCLUSIONS AND RELEVANCE: Among women with DCIS who were WLE candidates based on conventional imaging, multiple factors were associated with conversion to mastectomy. This study may provide useful preliminary information required for designing a planned randomized clinical trial to determine the effect of MRI and DCIS score on surgical management, radiotherapy, overall resource use, and clinical outcomes, with the ultimate goal of achieving greater therapeutic precision. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02352883

Increasing the dose intensity of cytotoxic therapy by shortening the intervals between cycles, or by giving individual drugs sequentially at full dose rather than in lower-dose concurrent treatment schedules, might enhance efficacy.

HIV-associated lymphomas (HALs) have high rates of latent infection by gammaherpesviruses (GHVs). We hypothesized that proteasome inhibition would induce lytic activation of GHVs and inhibit HIV infectivity via preservation of cytidine deaminase APOBEC3G, improving lymphoma control. We tested this oncolytic and antiviral strategy by using bortezomib combined with ifosfamide, carboplatin, and etoposide (ICE) alone or with rituximab (ICE/R) in relapsed/refractory HAL. A 3+3 dose-escalation design was used with a 7-day lead-in period of single-agent bortezomib. Bortezomib was administered intravenously on days 1 and 8 of each cycle at 1 of 4 dose levels: 0.7, 1.0, 1.3, or 1.5 mg/m2. ICE began day 8 of cycle 1 and day 1 of subsequent cycles. Rituximab was included on day 1 of cycles 2 to 6 for CD20+lymphomas. Twenty-three patients were enrolled. The maximum tolerated dose of bortezomib was not reached. Grade 4 toxicities attributable to bortezomib were limited to myelosuppression. Responses occurred in 17 (77%) of 22 patients receiving any protocol therapy. The 1-year overall survival was 57%. After bortezomib alone, both patients with Kaposi sarcoma herpesvirus (KSHV)–positive lymphoma had more than a 1-log increase in KSHV viral load. In 12 patients with Epstein-Barr virus (EBV)–positive lymphoma, median values of EBV viral load increased. Undetectable HIV viremia at baseline in the majority of patients limited evaluation of HIV inhibition. APOBEC3G levels increased in 75% of evaluable patients. Bortezomib combined with ICE/R in patients with relapsed/refractory HAL is feasible with response and survival comparing favorably against previously reported second-line therapies. Changes in GHV viral loads and APOBEC3G levels trended as hypothesized. This trial was registered at www.clinicaltrials.govas #NCT00598169.

HIV-associated lymphomas (HALs) have high rates of latent infection by gammaherpesviruses (GHVs). We hypothesized that proteasome inhibition would induce lytic activation of GHVs and inhibit HIV infectivity via preservation of cytidine deaminase APOBEC3G, improving lymphoma control. We tested this oncolytic and antiviral strategy by using bortezomib combined with ifosfamide, carboplatin, and etoposide (ICE) alone or with rituximab (ICE/R) in relapsed/refractory HAL. A 3+3 dose-escalation design was used with a 7-day lead-in period of single-agent bortezomib. Bortezomib was administered intravenously on days 1 and 8 of each cycle at 1 of 4 dose levels: 0.7, 1.0, 1.3, or 1.5 mg/m2. ICE began day 8 of cycle 1 and day 1 of subsequent cycles. Rituximab was included on day 1 of cycles 2 to 6 for CD20+ lymphomas. Twenty-three patients were enrolled. The maximum tolerated dose of bortezomib was not reached. Grade 4 toxicities attributable to bortezomib were limited to myelosuppression. Responses occurred in 17 (77%) of 22 patients receiving any protocol therapy. The 1-year overall survival was 57%. After bortezomib alone, both patients with Kaposi sarcoma herpesvirus (KSHV)–positive lymphoma had more than a 1-log increase in KSHV viral load. In 12 patients with Epstein-Barr virus (EBV)–positive lymphoma, median values of EBV viral load increased. Undetectable HIV viremia at baseline in the majority of patients limited evaluation of HIV inhibition. APOBEC3G levels increased in 75% of evaluable patients. Bortezomib combined with ICE/R in patients with relapsed/refractory HAL is feasible with response and survival comparing favorably against previously reported second-line therapies. Changes in GHV viral loads and APOBEC3G levels trended as hypothesized. This trial was registered at www.clinicaltrials.gov as #NCT00598169.

IMPORTANCE: Late recurrence 5 or more years after diagnosis accounts for at least one-half of all cases of recurrent hormone receptor–positive breast cancer. OBJECTIVE: To determine whether the presence of circulating tumor cells (CTCs) in a peripheral blood sample obtained approximately 5 years after diagnosis was associated with late clinical recurrence of operable human epidermal growth factor receptor 2–negative breast cancer. DESIGN, SETTING, AND PARTICIPANTS: This per-protocol secondary analysis of the Double-Blind Phase III Trial of Doxorubicin and Cyclophosphamide Followed by Paclitaxel With Bevacizumab or Placebo in Patients With Lymph Node Positive and High Risk Lymph Node Negative Breast Cancer enrolled patients from 2007 to 2011 who were without clinical evidence of recurrence between 4.5 and 7.5 years after primary surgical treatment of human epidermal growth factor receptor 2–negative stage II-III breast cancer followed by adjuvant systemic therapy. Patients were enrolled in a subprotocol for secondary analysis from February 25, 2013, to July 29, 2016, after signing consent for the subprotocol. The analysis was performed in April 2018. INTERVENTIONS: A blood sample was obtained for identification and enumeration of CTCs. MAIN OUTCOME AND MEASURES: The association between a positive CTC assay result (at least 1 CTC per 7.5 mL of blood) and clinical recurrence. RESULTS: Among 547 women included in this analysis, the results of the CTC assay were positive for 18 of 353 with hormone receptor–positive disease (5.1% [95% CI, 3.0%-7.9%]); 23 of 353 patients (6.5% [95% CI, 4.2%-9.6%]) had a clinical recurrence. The recurrence rates per person-year of follow-up in the CTC-positive and CTC-negative groups were 21.4% (7 recurrences per 32.7 person-years) and 2.0% (16 recurrences per 796.3 person-years), respectively. In multivariate models including clinical covariates, a positive CTC assay result was associated with a 13.1-fold higher risk of recurrence (hazard ratio point estimate, 13.1; 95% CI, 4.7-36.3). Seven of 23 patients (30.4% [95% CI, 13.2%-52.9%]) with recurrence had a positive CTC assay result at a median of 2.8 years (range, 0.1-2.8 years) before clinical recurrence. The CTC assay result was also positive for 8 of 193 patients (4.1% [95% CI, 1.8%-8.0%]) with hormone receptor–negative disease, although only 1 patient (0.5% [95% CI, 0%-2.9%]) experienced disease recurrence (this patient was CTC negative). CONCLUSIONS AND RELEVANCE: A single positive CTC assay result 5 years after diagnosis of hormone receptor–positive breast cancer provided independent prognostic information for late clinical recurrence, which provides proof of concept that liquid-based biomarkers may be used to risk stratify for late recurrence and guide therapy. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00433511

Compared to non-Hispanic whites, African-American women tend to be diagnosed with breast cancer at an earlier age, to have less favorable tumor characteristics, and to have poorer outcomes from breast cancer. The extent to which differences in clinical characteristics account for the black/white disparity in breast cancer mortality is unclear. The purpose of this investigation was to examine the association of clinical, demographic, and treatment variables with total mortality and breast cancer recurrence by race/ethnicity in a cohort of women diagnosed with invasive breast cancer. To this end, we used data on 3890 invasive breast cancer cases diagnosed at a single medical center. Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (95% CI) for the association of tumor characteristics and treatment variables with mortality and recurrence. Compared to white women, black women with breast cancer presented with tumors that had worse prognostic factors, particularly higher stage, lower frequency of hormone-receptor positive tumors, and higher frequency of comorbidities. Hispanics also generally had less favorable prognostic factors compared to non-Hispanic whites. Among estrogen receptor-positive cases, blacks had roughly a two-fold increased risk of recurrence compared to non-Hispanic whites. However, ethnicity/race was not associated with total mortality. Tumor stage, tumor size, and Charlson comorbidity index were positively associated with mortality, and mammography and chemotherapy and hormone therapy were inversely associated with mortality. In spite of poorer prognostic factors among blacks compared whites, race/ethnicity was not associated with total mortality in our study.

ABSTRACTIntroduction: Metastatic breast cancer (MBC) is an incurable disease and treatment is directed towards symptom palliation and survival prolongation. Treatment selection in patients is based on tumor biology, age, comorbidities, performance status, tumor burden, and prior treatment history.Areas covered: This present review summarizes the recent treatment strategies in the management of MBC, highlighting regimens after first-line therapy. Topics discussed include new strategies for endocrine therapy, anti-HER2 therapy, and promising strategies for the management of triple negative breast cancer.Expert opinion: MBC is a heterogeneous entity and despite recent advances, there is significant room for improvement of treatment beyond first-line therapies. Combination regimens that can maximize clinical efficacy while minimizing toxicities are required. Current investigation approaches in advanced stages of clinical development include immunoconjugates, immune checkpoint blockade, novel cyclin-dependent-kinase inhibitors, and PARP inhibitors for MBC associated with germline BRCA mutations. We recommend that every patient with MBC should be evaluated for clinical trial options.

Supplemental Digital Content is available in the text.Assessment of the immune response to tumors is growing in importance as the prognostic implications of this response are increasingly recognized, and as immunotherapies are evaluated and implemented in different tumor types. However, many different approaches can be used to assess and describe the immune response, which limits efforts at implementation as a routine clinical biomarker. In part 1 of this review, we have proposed a standardized methodology to assess tumor-infiltrating lymphocytes (TILs) in solid tumors, based on the International Immuno-Oncology Biomarkers Working Group guidelines for invasive breast carcinoma. In part 2 of this review, we discuss the available evidence for the prognostic and predictive value of TILs in common solid tumors, including carcinomas of the lung, gastrointestinal tract, genitourinary system, gynecologic system, and head and neck, as well as primary brain tumors, mesothelioma and melanoma. The particularities and different emphases in TIL assessment in different tumor types are discussed. The standardized methodology we propose can be adapted to different tumor types and may be used as a standard against which other approaches can be compared. Standardization of TIL assessment will help clinicians, researchers and pathologists to conclusively evaluate the utility of this simple biomarker in the current era of immunotherapy.

Supplemental Digital Content is available in the text.Assessment of tumor-infiltrating lymphocytes (TILs) in histopathologic specimens can provide important prognostic information in diverse solid tumor types, and may also be of value in predicting response to treatments. However, implementation as a routine clinical biomarker has not yet been achieved. As successful use of immune checkpoint inhibitors and other forms of immunotherapy become a clinical reality, the need for widely applicable, accessible, and reliable immunooncology biomarkers is clear. In part 1 of this review we briefly discuss the host immune response to tumors and different approaches to TIL assessment. We propose a standardized methodology to assess TILs in solid tumors on hematoxylin and eosin sections, in both primary and metastatic settings, based on the International Immuno-Oncology Biomarker Working Group guidelines for TIL assessment in invasive breast carcinoma. A review of the literature regarding the value of TIL assessment in different solid tumor types follows in part 2. The method we propose is reproducible, affordable, easily applied, and has demonstrated prognostic and predictive significance in invasive breast carcinoma. This standardized methodology may be used as a reference against which other methods are compared, and should be evaluated for clinical validity and utility. Standardization of TIL assessment will help to improve consistency and reproducibility in this field, enrich both the quality and quantity of comparable evidence, and help to thoroughly evaluate the utility of TILs assessment in this era of immunotherapy.