Refining the indications for neoadjuvant chemotherapy for patients with HER2+ breast cancer: A single institution experience.

BACKGROUND: We aim to compare the clinical outcomes of patients with early-stage HER2+ breast cancer treated with adjuvant chemotherapy (AC) and neoadjuvant chemotherapy (NAC). METHODS: Patients with non-metastatic HER2+ breast cancer treated from 2009 to 2018 at our institution comprised our study cohort (n = 1254). Pathologic complete response (pCR) was defined as the absence of invasive disease in the breast and axilla after NAC. Log-rank, Kaplan-Meier, and inverse probability of treatment weighting were used to assess differences in disease-free and overall survival between groups stratified by AC vs. NAC and pCR vs. non-pCR. RESULTS: The majority received AC (n = 787 or 62.8%) while 467 (37.2%) patients received NAC. Median follow up for AC and NAC groups was 46 and 28 months, respectively. The crude disease-free survival and overall survival of our study cohort were 92.2% and 89.1% for AC, 89.1% and 82.2% for NAC pCR, and 68.1% and 60.0% for NAC non-pCR, respectively. For clinical stage ≥IIB patients, NAC conferred a positive but statistically nonsignificant treatment effect over AC in multivariate analysis. CONCLUSIONS: After adjusting for imbalances in our subgroups, we found that, regardless of the sequence of chemotherapy (AC vs. NAC), patients with early-stage HER2+ breast cancer had excellent outcomes.

Does time to adjuvant chemotherapy (TTC) affect outcomes in patients with triple-negative breast cancer?

PURPOSE: A recent study reported that time to adjuvant chemotherapy (TTC) > 30 days was significantly associated with worse OS and DFS in triple-negative breast cancer (TNBC). Earlier studies, however, found that worse outcomes were associated with TTC > 60 days or > 90 days. As the trend for mastectomy with reconstruction continues to rise, TTC of < 30 days is often not feasible due to wound-healing issues in some of these patients. To elucidate the impact of TTC, we sought to evaluate the clinical outcomes associated with TTC in a contemporary cohort treated for TNBC at a single institution. METHODS: A single-institution database was queried to identify nonmetastatic TNBC patients who received adjuvant chemotherapy from 2009 to 2018. TTC was defined as interval between date of surgery and adjuvant chemotherapy start date. Median TTC was used to divide our cohort into four quartiles; ≤ 31, 32-42, 43-56, and > 56 days. Logrank, Kaplan-Meier, and inverse probability weighting (IPW) tests were used to analyze disease-free (DFS) and overall survival (OS). RESULTS: The mean TTC of our study cohort (n = 724) was 48 days (median TTC = 42 days). Black race, mastectomy without adjuvant radiation, and mastectomy with immediate reconstruction were associated with delayed TTC (all p-values < 0.01). In multivariate IPW analysis, TTC > 56 (n = 173) days did not impact DFS or OS compared to TTC ≤ 31 (n = 198) days (p = 0.27 and p = 0.21, respectively). Similar results were seen during subgroup analysis for groups identified as higher risk for delayed TTC. CONCLUSION: Our results demonstrated that TTC was not significant or significantly associated with DFS or OS in patient receiving chemotherapy for operable TNBC. Our results were reassuring for patients electing mastectomy with immediate reconstruction, who may experience a longer TTC.

Disparities in Breast Cancer Survival by Socioeconomic Status Despite Medicare and Medicaid Insurance.

Policy Points Patients with low socioeconomic status (SES) experience poorer survival rates after diagnosis of breast cancer, even when enrolled in Medicare and Medicaid. Most of the difference in survival is due to more advanced cancer on presentation and the general poor health of lower SES patients, while only a very small fraction of the SES disparity is due to differences in cancer treatment. Even when comparing only low- versus not-low-SES whites (without confounding by race) the survival disparity between disparate white SES populations is very large and is associated with lower use of preventive care, despite having insurance. CONTEXT: Disparities in breast cancer survival by socioeconomic status (SES) exist despite the "safety net" programs Medicare and Medicaid. What is less clear is the extent to which SES disparities affect various racial and ethnic groups and whether causes differ across populations. METHODS: We conducted a tapered matching study comparing 1,890 low-SES (LSES) non-Hispanic white, 1,824 black, and 723 Hispanic white women to 60,307 not-low-SES (NLSES) non-Hispanic white women, all in Medicare and diagnosed with invasive breast cancer between 1992 and 2010 in 17 US Surveillance, Epidemiology, and End Results (SEER) regions. LSES Medicare patients were Medicaid dual-eligible and resided in neighborhoods with both high poverty and low education. NLSES Medicare patients had none of these factors. MEASUREMENTS: 5-year and median survival. FINDINGS: LSES non-Hispanic white patients were diagnosed with more stage IV disease (6.6% vs 3.6%; p < 0.0001), larger tumors (24.6 mm vs 20.2 mm; p < 0.0001), and more chronic diseases such as diabetes (37.8% vs 19.0%; p < 0.0001) than NLSES non-Hispanic white patients. Disparity in 5-year survival (NLSES - LSES) was 13.7% (p < 0.0001) when matched for age, year, and SEER site (a 42-month difference in median survival). Additionally, matching 55 presentation factors, including stage, reduced the disparity to 4.9% (p = 0.0012), but further matching on treatments yielded little further change in disparity: 4.6% (p = 0.0014). Survival disparities among LSES blacks and Hispanics, also versus NLSES whites, were significantly associated with presentation factors, though black patients also displayed disparities related to initial treatment. Before being diagnosed, all LSES populations used significantly less preventive care services than matched NLSES controls. CONCLUSIONS: In Medicare, SES disparities in breast cancer survival were large (even among non-Hispanic whites) and predominantly related to differences of presentation characteristics at diagnosis rather than differences in treatment. Preventive care was less frequent in LSES patients, which may help explain disparities at presentation.

Racial disparities in colon cancer survival: a matched cohort study.

BACKGROUND: Differences in colon cancer survival by race are a recognized problem among Medicare beneficiaries. OBJECTIVE: To determine to what extent the racial disparity in survival is due to disparity in presentation characteristics at diagnosis or disparity in subsequent treatment. DESIGN: Black patients with colon cancer were matched with 3 groups of white patients: a "demographic characteristics" match controlling for age, sex, diagnosis year, and Survey, Epidemiology, and End Results (SEER) site; a "presentation" match controlling for demographic characteristics plus comorbid conditions and tumor characteristics, including stage and grade; and a "treatment" match, including presentation variables plus details of surgery, radiation, and chemotherapy. SETTING: 16 U.S. SEER sites. PATIENTS: 7677 black patients aged 65 years or older diagnosed between 1991 and 2005 in the SEER-Medicare database and 3 sets of 7677 matched white patients, followed until 31 December 2009. MEASUREMENTS: 5-year survival. RESULTS: The absolute difference in 5-year survival between black and white patients was 9.9% (95% CI, 8.3% to 11.4%; P<0.001) in the demographic characteristics match. This disparity remained unchanged between 1991 and 2005. After matching for presentation characteristics, the difference decreased to 4.9% (CI, 3.6% to 6.1%; P<0.001). After additional matching for treatment, this difference decreased to 4.3% (CI, 2.9% to 5.5%; P<0.001). The disparity in survival attributed to treatment differences made up only an absolute 0.6% of the overall 9.9% survival disparity. LIMITATION: An observational study limited to elderly Medicare fee-for-service beneficiaries living in selected geographic areas. CONCLUSION: Racial disparities in colon cancer survival did not decrease among patients diagnosed between 1991 and 2005. This persistent disparity seemed to be more related to presentation characteristics at diagnosis than to subsequent treatment differences. PRIMARY FUNDING SOURCE: Agency for Healthcare Research and Quality and National Science Foundation.

Characteristics associated with differences in survival among black and white women with breast cancer.

IMPORTANCE: Difference in breast cancer survival by race is a recognized problem among Medicare beneficiaries. OBJECTIVE: To determine if racial disparity in breast cancer survival is primarily attributable to differences in presentation characteristics at diagnosis or subsequent treatment. DESIGN, SETTING, AND PATIENTS: Comparison of 7375 black women 65 years and older diagnosed between 1991 to 2005 and 3 sets of 7375 matched white control patients selected from 99,898 white potential controls, using data for 16 US Surveillance, Epidemiology and End Results (SEER) sites in the SEER-Medicare database. All patients received follow-up through December 31, 2009, and the black case patients were matched to 3 white control populations on demographics (age, year of diagnosis, and SEER site), presentation (demographics variables plus patient comorbid conditions and tumor characteristics such as stage, size, grade, and estrogen receptor status), and treatment (presentation variables plus details of surgery, radiation therapy, and chemotherapy). MAIN OUTCOMES AND MEASURES: 5-Year survival. RESULTS: The absolute difference in 5-year survival (blacks, 55.9%; whites, 68.8%) was 12.9% (95% CI, 11.5%-14.5%; P < .001) in the demographics match. This difference remained unchanged between 1991 and 2005. After matching on presentation characteristics, the absolute difference in 5-year survival was 4.4% (95% CI, 2.8%-5.8%; P < .001) and was 3.6% (95% CI, 2.3%-4.9%; P < .001) lower for blacks than for whites matched also on treatment. In the presentation match, fewer blacks received treatment (87.4% vs 91.8%; P < .001), time from diagnosis to treatment was longer (29.2 vs 22.8 days; P < .001), use of anthracyclines and taxols was lower (3.7% vs 5.0%; P < .001), and breast-conserving surgery without other treatment was more frequent (8.2% vs 7.3%; P = .04). Nevertheless, differences in survival associated with treatment differences accounted for only 0.81% of the 12.9% survival difference. CONCLUSIONS AND RELEVANCE: In the SEER-Medicare database, differences in breast cancer survival between black and white women did not substantially change among women diagnosed between 1991 and 2005. These differences in survival appear primarily related to presentation characteristics at diagnosis rather than treatment differences.

Detection of Medication Taking Using a Wrist-Worn Commercially Available Wearable Device.

PURPOSE: Medication nonadherence is a persistent and costly problem across health care. Measures of medication adherence are ineffective. Methods such as self-report, prescription claims data, or smart pill bottles have been used to monitor medication adherence, but these are subject to recall bias, lack real-time feedback, and are often expensive. METHODS: We proposed a method for monitoring medication adherence using a commercially available wearable device. Passively collected motion data were analyzed on the basis of the Movelet algorithm, a dictionary learning framework that builds person-specific chapters of movements from short frames of elemental activities within the movements. We adapted and extended the Movelet method to construct a within-patient prediction model that identifies medication-taking behaviors. RESULTS: Using 15 activity features recorded from wrist-worn wearable devices of 10 patients with breast cancer on endocrine therapy, we demonstrated that medication-taking behavior can be predicted in a controlled clinical environment with a median accuracy of 85%. CONCLUSION: These results in a patient-specific population are exemplar of the potential to measure real-time medication adherence using a wrist-worn commercially available wearable device.

Ruxolitinib and exemestane for estrogen receptor positive, aromatase inhibitor resistant advanced breast cancer.

Circulating IL-6, an activator of JAK/STAT signaling, is associated with poor prognosis and aromatase inhibitor (AI) resistance in hormone-receptor positive (HR+) breast cancer. Here we report the results of a phase 2 single-arm Simon 2-stage trial combining Ruxolitinib, an oral selective inhibitor of JAK1/2, with exemestane, a steroidal AI, in patients with HR+ metastatic breast cancer (MBC) after progression on non-steroidal AI (NSAI). Safety and efficacy were primary objectives, and analysis of inflammatory markers as predictors of response was a key secondary objective. Twenty-five subjects enrolled. The combination of ruxolitinib and exemestane was safe, though anemia requiring transfusion in 5/15 (33%) at the 25 mg dose in stage 1 led to a reduction to 15 mg twice daily in stage 2 (with no additional transfusions). Clinical benefit rate (CBR) in the overall study population was 24% (95% CI 9.4-45.1); 6/25 patients demonstrated stable disease for ≥6 months. Median progression-free survival was 2.8 months (95% CI 2.6-3.9). Exploratory biomarkers revealed high levels of systemic inflammation and 60% harbored a high-risk IL-6 genotype. Pharmacodynamics demonstrated modest on-target inhibition of phosphorylated-STAT3 by ruxolitinib at a tolerable dose. Thus, ruxolitinib combined with exemestane at a tolerable dose was safe but minimally active in AI-resistant tumors of patients with high levels of systemic inflammation. These findings highlight the need for more potent and specific therapies targeting inflammation in MBC.

HER-2/neu overexpression as a predictor for the transition from in situ to invasive breast cancer.

The clinical implications of HER-2/neu (HER2) expression in ductal carcinoma in situ (DCIS) lesions have yet to be clearly elucidated; this despite the more frequent expression of HER2 in high-grade DCIS lesions compared with invasive cancers. We hypothesized that HER2 overexpression in DCIS is associated with more rapid progression to invasive disease. Immunohistochemical staining for estrogen receptor, progesterone receptor, and HER2 was done on DCIS specimens. Univariate analysis and a multivariate logistic regression were done to determine whether estrogen receptor, progesterone receptor, or HER2 status, comedo necrosis, nuclear grade, lesion size, or patient age predicted the presence of associated invasive disease in patients with DCIS. Invasive foci were found in association with HER2 overexpressing DCIS at a higher frequency than with DCIS that did not overexpress HER2. Although high nuclear grade, large lesion size, and HER2 overexpression were all associated with the presence of invasive disease on univariate analysis, HER2 was the only significant predictor for the presence of invasive disease after multivariate adjustment (odds ratio, 6.4; P = 0.01). These data indicate that HER2 overexpression in DCIS lesions predicts the presence of invasive foci in patients with DCIS and suggest that targeting of HER2 in an early disease setting may forestall or prevent disease progression.

Techniques for fertility preservation in patients with breast cancer.

PURPOSE OF REVIEW: To outline the risks of infertility from breast cancer treatment, and to illustrate current techniques in preserving fertility in breast-cancer patients who wish to become pregnant after treatment is concluded. RECENT FINDINGS: Breast cancer often affects women of reproductive age. Although treatment is effective, cytotoxic chemotherapy causes ovarian reserve depletion, whereas hormonal therapy necessitates a delay in pregnancy, resulting in infertility. Patients of reproductive age should be referred to fertility specialists to explore methods of fertility preservation upon diagnosis. The best established method of fertility preservation is embryo cryopreservation, although investigational techniques such as, oocyte and ovarian tissue cryopreservation, may hold potential. Embryo cryopreservation involves ovarian stimulation to retrieve oocytes in-vitro fertilization prior to freezing. Techniques for the cryopreservation of unfertilized oocytes are under investigation. Successful pregnancies have resulted in breast cancer patients after treatment, without obvious compromise in their risk of recurrence or death from breast cancer. SUMMARY: Ovarian stimulation with retrieval of ooctyes for in-vitro fertilization remains the best known option for fertility preservation in women with early stage breast cancer whose risk of fertility may be compromised by adjuvant chemotherapy.

Targeting HER-2/neu in early breast cancer development using dendritic cells with staged interleukin-12 burst secretion.

Overexpression of HER-2/neu (c-erbB2) is associated with increased risk of recurrent disease in ductal carcinoma in situ (DCIS) and a poorer prognosis in node-positive breast cancer. We therefore examined the early immunotherapeutic targeting of HER-2/neu in DCIS. Before surgical resection, HER-2/neu(pos) DCIS patients (n = 13) received 4 weekly vaccinations of dendritic cells pulsed with HER-2/neu HLA class I and II peptides. The vaccine dendritic cells were activated in vitro with IFN-gamma and bacterial lipopolysaccharide to become highly polarized DC1-type dendritic cells that secrete high levels of interleukin-12p70 (IL-12p70). Intranodal delivery of dendritic cells supplied both antigenic stimulation and a synchronized preconditioned burst of IL-12p70 production directly to the anatomic site of T-cell sensitization. Before vaccination, many subjects possessed HER-2/neu-HLA-A2 tetramer-staining CD8(pos) T cells that expressed low levels of CD28 and high levels of the inhibitory B7 ligand CTLA-4, but this ratio inverted after vaccination. The vaccinated subjects also showed high rates of peptide-specific sensitization for both IFN-gamma-secreting CD4(pos) (85%) and CD8(pos) (80%) T cells, with recognition of antigenically relevant breast cancer lines, accumulation of T and B lymphocytes in the breast, and induction of complement-dependent, tumor-lytic antibodies. Seven of 11 evaluable patients also showed markedly decreased HER-2/neu expression in surgical tumor specimens, often with measurable decreases in residual DCIS, suggesting an active process of "immunoediting" for HER-2/neu-expressing tumor cells following vaccination. DC1 vaccination strategies may therefore have potential for both the prevention and the treatment of early breast cancer.

Combination Paclitaxel and Palbociclib: Results of a Phase I Trial in Advanced Breast Cancer.

PURPOSE: The CDK 4/6 inhibitor palbociclib rapidly and reversibly inhibits the cell cycle. The goal of this study was to exploit the cell cycle through intermittent, alternating dosing with palbociclib/paclitaxel to enhance efficacy. We determined the combination dose-limiting toxicity (DLT) in patients with Rb protein-expressing, advanced breast cancer. PATIENTS AND METHODS: This open-label, phase I trial (NCT01320592) enrolled patients to sequential cohorts of palbociclib orally dosed intermittently between days 1 and 19 of a 28-day cycle alternating with weekly paclitaxel. Dose escalation proceeded in a standard 3 + 3 design. Ten additional patients received the combination at the recommended phase II dose (RP2D). Those who reached response plateau ≥6 cycles could continue on palbociclib alone on a 3 week on/1 week off schedule at one dose level above their combination dose. RESULTS: Twenty-seven patients enrolled. Although there was only 1 DLT (grade 3 alanine aminotransferase/aspartate aminotransferase at 125 mg), neutropenia (NTP) requiring dose modification in cycle 1 (C1) resulted in an RP2D of 75 mg palbociclib/80 mg/m2 paclitaxel. During C1, the most common adverse event was NTP, occurring in 15 patients (55.6%); grade 1 or 2 nausea and peripheral neuropathy were also observed in 8 patients each (29.6%). The clinical benefit rate was 55% at the RP2D; benefit was observed across all receptor subtypes. CONCLUSIONS: Alternating sequential palbociclib/paclitaxel in patients with Rb+ advanced breast cancer is feasible and safe, without evidence of additive toxicity. This represents a new application for CDK 4/6 inhibitors in Rb+ breast cancer regardless of subtype; efficacy trials are warranted.

Integrating Oncology Massage Into Chemoinfusion Suites: A Program Evaluation.

OBJECTIVE: This article reports on the development, implementation, and evaluation of an integrative clinical oncology massage program for patients undergoing chemotherapy for breast cancer in a large academic medical center. MATERIALS AND METHODS: We describe the development and implementation of an oncology massage program embedded into chemoinfusion suites. We used deidentified program evaluation data to identify specific reasons individuals refuse massage and to evaluate the immediate impact of massage treatments on patient-reported outcomes using a modified version of the Distress Thermometer delivered via iPad. We analyzed premassage and postmassage data from the Distress Thermometer using paired t test and derived qualitative data from participants who provided written feedback on their massage experiences. RESULTS: Of the 1,090 massages offered, 692 (63%) were accepted. We observed a significant decrease in self-reported anxiety (from 3.9 to 1.7), nausea (from 2.5 to 1.2), pain (from 3.3 to 1.9), and fatigue (from 4.8 to 3.0) premassage and postmassage, respectively (all P < .001). We found that 642 survey participants (93%) were satisfied with their massage, and 649 (94%) would recommend it to another patient undergoing treatment. Spontaneous patient responses overwhelmingly endorsed the massage as relaxing. No adverse events were reported. Among the 398 patients (36%) who declined a massage, top reasons were time concerns and lack of interest. CONCLUSION: A clinical oncology massage program can be safely and effectively integrated into chemoinfusion units to provide symptom control for patients with breast cancer. This integrative approach overcomes patient-level barriers of cost, time, and travel, and addresses the institutional-level barrier of space.

Dendritic Cell Vaccination Enhances Immune Responses and Induces Regression of HER2pos DCIS Independent of Route: Results of Randomized Selection Design Trial.

Purpose: Vaccination with HER2 peptide-pulsed DC1s stimulates a HER2-specific T-cell response. This randomized trial aimed to establish safety and evaluate immune and clinical responses to vaccination via intralesional (IL), intranodal (IN), or both intralesional and intranodal (ILN) injection.Experimental Design: Fifty-four HER2pos patients [42 pure ductal carcinoma in situ (DCIS), 12 early invasive breast cancer (IBC)] were enrolled in a neoadjuvant HER2 peptide-pulsed DC1 vaccine trial. Patients were randomized to IL (n = 19), IN (n = 19), or ILN (n = 16) injection. Immune responses were measured in peripheral blood and sentinel lymph nodes by ELISPOT or in vitro sensitization assay. Pathologic response was assessed in resected surgical specimens.Results: Vaccination by all injection routes was well tolerated. There was no significant difference in immune response rates by vaccination route (IL 84.2% vs. IN 89.5% vs. ILN 66.7%; P = 0.30). The pathologic complete response (pCR) rate was higher in DCIS patients compared with IBC patients (28.6% vs. 8.3%). DCIS patients who achieved pCR (n = 12) and who did not achieve pCR (n = 30) had similar peripheral blood anti-HER2 immune responses. All patients who achieved pCR had an anti-HER2 CD4 immune response in the sentinel lymph node, and the quantified response was higher by response repertoire (P = 0.03) and cumulative response (P = 0.04).Conclusions: Anti-HER2 DC1 vaccination is a safe and immunogenic treatment to induce tumor-specific T-cell responses in HER2pos patients; immune and clinical responses were similar independent of vaccination route. The immune response in the sentinel lymph nodes, rather than in the peripheral blood, may serve as an endpoint more reflective of antitumor activity. Clin Cancer Res; 23(12); 2961-71. ©2016 AACR.

A retrospective study of the impact of 21-gene recurrence score assay on treatment choice in node positive micrometastatic breast cancer.

To assess clinical utility of the 21-gene assay (Oncotype DX® Recurrence Score®), we determined whether women with HER2(-)/ER+ pN1mi breast cancer with low (<18) Recurrence Scores results are given adjuvant chemotherapy in a lower proportion than those with high scores (≥31). This was a multicenter chart review of ≥18 year old women with pN1mi breast cancer, HER2(-)/ER+ tumors, ductal/lobular/mixed histology, with the assay ordered on or after 1 January 2007. One hundred and eighty one patients had a mean age of 60.7 years; 82.9% had ECOG performance status 0; 33.7% had hypertension, 22.7% had osteoporosis, 18.8% had osteoarthritis, and 8.8% had type-2 diabetes. Mean Recurrence Score was 17.8 (range: 0-50). 48.6% had a mastectomy; 55.8% had a lumpectomy. 19.8% of low-risk group patients were recommended chemotherapy vs. 57.9% in the intermediate-risk group and 100% in the high-risk group (p < 0.001). A total of 80.2% of the low-risk group were recommended endocrine therapy alone, while 77.8% of the high-risk group were recommended both endocrine and chemotherapy (p < 0.001). The Oncotype DX Recurrence Score result provides actionable information that can be incorporated into treatment planning for women with HER2(-)/ER+ pN1mi breast cancer. The Recurrence Score result has clinical utility in treatment planning for HER2(-)/ER+ pN1mi breast cancer patients.