Adjuvant paclitaxel and trastuzumab for node-negative, HER2-positive breast cancer: final 10-year analysis of the open-label, single-arm, phase 2 APT trial.

BACKGROUND: We aimed to report on long-term outcomes of patients with small, node-negative, HER2-positive breast cancer treated with adjuvant paclitaxel and trastuzumab and to establish potential biomarkers to predict prognosis. METHODS: In this open-label, single-arm, phase 2 study, patients aged 18 years or older, with small (≤3 cm), node-negative, HER2-positive breast cancer, and an Eastern Cooperative Oncology Group performance status of 0-1, were recruited from 16 institutions in 13 cities in the USA. Eligible patients were given intravenous paclitaxel (80 mg/m2) with intravenous trastuzumab (loading dose of 4 mg/kg, subsequent doses 2 mg/kg) weekly for 12 weeks, followed by trastuzumab (weekly at 2 mg/kg or once every 3 weeks at 6 mg/kg) for 40 weeks to complete a full year of trastuzumab. The primary endpoint was 3-year invasive disease-free survival. Here, we report 10-year survival outcomes, assessed in all participants who received protocol-defined treatment, with exploratory analyses using the HER2DX genomic tool. This study is registered on ClinicalTrials.gov, NCT00542451, and is closed to accrual. FINDINGS: Between Oct 29, 2007, and Sept 3, 2010, 410 patients were enrolled and 406 were given adjuvant paclitaxel and trastuzumab and included in the analysis. Mean age at enrolment was 55 years (SD 10·5), 405 (99·8%) of 406 patients were female and one (0·2%) was male, 350 (86·2%) were White, 28 (6·9%) were Black or African American, and 272 (67·0%) had hormone receptor-positive disease. After a median follow-up of 10·8 years (IQR 7·1-11·4), among 406 patients included in the analysis population, we observed 31 invasive disease-free survival events, of which six (19·4%) were locoregional ipsilateral recurrences, nine (29·0%) were new contralateral breast cancers, six (19·4%) were distant recurrences, and ten (32·3%) were all-cause deaths. 10-year invasive disease-free survival was 91·3% (95% CI 88·3-94·4), 10-year recurrence-free interval was 96·3% (95% CI 94·3-98·3), 10-year overall survival was 94·3% (95% CI 91·8-96·8), and 10-year breast cancer-specific survival was 98·8% (95% CI 97·6-100). HER2DX risk score as a continuous variable was significantly associated with invasive disease-free survival (hazard ratio [HR] per 10-unit increment 1·24 [95% CI 1·00-1·52]; p=0·047) and recurrence-free interval (1·45 [1·09-1·93]; p=0·011). INTERPRETATION: Adjuvant paclitaxel and trastuzumab is a reasonable treatment standard for patients with small, node-negative, HER2-positive breast cancer. The HER2DX genomic tool might help to refine the prognosis for this population. FUNDING: Genentech.

Bridging the Gap Among Clinical Practice Guidelines for Pain Management in Cancer and Sickle Cell Disease.

Opioids are a critical component of pain relief strategies for the management of patients with cancer and sickle cell disease. The escalation of opioid addiction and overdose in the United States has led to increased scrutiny of opioid prescribing practices. Multiple reports have revealed that regulatory and coverage policies, intended to curb inappropriate opioid use, have created significant barriers for many patients. The Centers for Disease Control and Prevention, National Comprehensive Cancer Network, and American Society of Clinical Oncology each publish clinical practice guidelines for the management of chronic pain. A recent JAMA Oncology article highlighted perceived variability in recommendations among these guidelines. In response, leadership from guideline organizations, government representatives, and authors of the original article met to discuss challenges and solutions. The meeting featured remarks by the Commissioner of Food and Drugs, presentations on each clinical practice guideline, an overview of the pain management needs of patients with sickle cell disease, an overview of perceived differences among guidelines, and a discussion of differences and commonalities among the guidelines. The meeting revealed that although each guideline varies in the intended patient population, target audience, and methodology, there is no disagreement among recommendations when applied to the appropriate patient and clinical situation. It was determined that clarification and education are needed regarding the intent, patient population, and scope of each clinical practice guideline, rather than harmonization of guideline recommendations. Clinical practice guidelines can serve as a resource for policymakers and payers to inform policy and coverage determinations.

Phase II Study of Weekly Paclitaxel with Trastuzumab and Pertuzumab in Patients with Human Epidermal Growth Receptor 2 Overexpressing Metastatic Breast Cancer: 5-Year Follow-up.

BACKGROUND: Favorable progression-free survival (PFS) and overall survival (OS) results were previously reported on a phase II trial of patients with human epidermal growth receptor 2 (HER2)-positive metastatic breast cancer (MBC), treated with weekly paclitaxel in combination with trastuzumab and pertuzumab in the first- and second-line setting, with a median follow-up of 33 months. Here, we report updated PFS and OS results with more than 2 years of additional follow-up. MATERIALS AND METHODS: In this phase II study, adult patients with HER2-positive MBC who received no or one prior therapy received intravenous paclitaxel (80 mg/m2 weekly) with trastuzumab (8 mg/kg loading dose followed by 6 mg/kg every 3 weeks) and pertuzumab (840 mg loading dose followed by 420 mg every 3 weeks), administered in 21-day cycles. Primary endpoint was 6-month PFS, and secondary endpoints included median PFS and OS. RESULTS: From January 2011 to December 2013, 69 patients were enrolled: 51 (74%) and 18 (26%) were treated in first- and second-line metastatic settings, respectively. As of August 21, 2017, the median follow-up was 59 months (range, 20-75 months; 67 [97%] patients were evaluable for efficacy). The 6-month PFS was 86% (95% confidence interval [CI] 0.76-0.93). The median PFS was 24.2 months (95% CI 17-35) for the overall population; it was 25.7 months (95% CI 17.0 to not reached) and 20.1 months (95% CI 8.5-33.0) for patients with no and one prior treatment, respectively. The median OS was not reached for the overall group; it was not reached and 39.7 months (95% CI 32.9-66.7) for patients with no and one prior treatment, respectively. Treatment was well tolerated with no additional safety concerns. CONCLUSION: With a longer follow-up of almost 5 years, combination of weekly paclitaxel, trastuzumab, and pertuzumab remains effective with a favorable median PFS and a median OS not reached. IMPLICATIONS FOR PRACTICE: The combination of weekly paclitaxel, trastuzumab, and pertuzumab has been endorsed by the National Comprehensive Cancer Network as one of the first-line treatment options in patients with human epidermal growth receptor 2 (HER2)-positive metastatic breast cancer (MBC). However, the long-term safety and efficacy are still unknown. Findings from this phase II study provide favorable preliminary data on the safety and efficacy of trastuzumab and pertuzumab in combination with weekly paclitaxel at 5-year follow-up, and it remains an effective first-line treatment option for patients with HER2-positive MBC.

Local-regional recurrence in women with small node-negative, HER2-positive breast cancer: results from a prospective multi-institutional study (the APT trial).

PURPOSE: Women with HER2-positive breast cancer treated prior to effective anti-HER2 therapy have higher rates of local-regional recurrence (LRR) than those with HER2-negative disease. Effective systemic therapy, however, has been shown to decrease LRR. This study examines LRR in women with HER2-positive breast cancer treated on a single-arm prospective multicenter trial of adjuvant trastuzumab (H) and paclitaxel (T). METHODS: Patients with HER2-positive tumors ≤ 3.0 cm with negative axillary nodes or micrometastatic disease were eligible. Systemic therapy included weekly T and H for 12 weeks followed by continuation of H to complete 1 year. Radiation therapy (RT) was required following breast-conserving surgery (BCS), but dose and fields were not specified. Disease-free survival (DFS) and LRR-free survival were calculated using the Kaplan-Meier method. RESULTS: Of the 410 patients enrolled from September 2007 to September 2010, 406 initiated protocol therapy and formed the basis of this analysis. A total of 272 (67%) had hormone receptor-positive tumors. Of 162 patients undergoing mastectomy, local therapy records were unavailable for two. None of the 160 for whom records were available received RT. Among 244 BCS patients, detailed RT records were available for 217 (89%). With a median follow-up of 6.5 years, 7-year DFS was 93.3% (95% CI 90.4-96.2), and LRR-free survival was 98.6% (95% CI 97.4-99.8). CONCLUSION: LRR in this select group of early-stage patients with HER2-positive disease receiving effective anti-HER2 therapy is extremely low. If confirmed in additional studies, future investigational efforts should focus on de-escalating local therapy.

Copper-64 trastuzumab PET imaging: a reproducibility study.

BACKGROUND: The current study aims to assess the safety, pharmacokinetics, feasibility, and reproducibility of immunoPET imaging with copper-64 (64Cu) trastuzumab. METHODS: An IV injection of 296-370 MBq/5 mg 64Cu-trastuzumab was administered between 1 to 4 hours after routine trastuzumab treatment. Whole-body PET scans were performed immediately post-injection and at 24 hours post-injection. Serial pharmacokinetics were performed. Of 11 patients (median age of 52; range of 31-61), 8 underwent a repeat study with 64Cu-trastuzumab to assess image and pharmacokinetic reproducibility. Patients were monitored for toxicity. RESULTS: Patients experienced no allergic reactions or significant adverse effects from 64Cu-trastuzumab. Eight patients successfully completed a repeat 64Cu-trastuzumab study, with acceptable reproducibility of both the biodistribution and pharmacokinetic clearance. Study 1 versus study 2 showed similar serum concentration post-injection (mean 42.4±7.8 %ID/L vs. 44.7±12.6 %ID/L) and similar T1/2 (single exponential 46.1 vs. 44.2 hours), P>0.5. The volume of distribution (median 2.50 L) was in the range reported for trastuzumab and close to the estimated plasma volume of 2.60 L. Of 11 patients, two had 64Cu-trastuzumab localization corresponding to known tumor sites - one in liver and one in breast. CONCLUSIONS: Preliminary results suggest that scanning with 64Cu-trastuzumab is feasible, safe, and reproducible. Tumor uptake of 64Cu-trastuzumab was observed, but tumor detection exhibited low sensitivity in this study in which imaging was performed in the presence of trastuzumab therapy.

MicroRNA-335 inhibits tumor reinitiation and is silenced through genetic and epigenetic mechanisms in human breast cancer.

Post-transcriptional regulators have emerged as robust effectors of metastasis and display deregulated expression through unknown mechanisms. Here, we reveal that the human microRNA-335 locus undergoes genetic deletion and epigenetic promoter hypermethylation in every metastatic derivative obtained from independent patients' malignant cell populations. Genetic deletion of miR-335 is a common event in human breast cancer, is enriched for in breast cancer metastases, and also correlates with ovarian cancer recurrence. We furthermore identify miR-335 as a robust inhibitor of tumor reinitiation. We thus implicate the miR-335 locus on 7q32.2 as the first selective metastasis suppressor and tumor initiation suppressor locus in human breast cancer.

Correlative imaging reveals physiochemical heterogeneity of microcalcifications in human breast carcinomas.

Microcalcifications (MCs) are routinely used to detect breast cancer in mammography. Little is known, however, about their materials properties and associated organic matrix, or their correlation to breast cancer prognosis. We combine histopathology, Raman microscopy, and electron microscopy to image MCs within snap-frozen human breast tissue and generate micron-scale resolution correlative maps of crystalline phase, trace metals, particle morphology, and organic matrix chemical signatures within high grade ductal carcinoma in situ (DCIS) and invasive cancer. We reveal the heterogeneity of mineral-matrix pairings, including punctate apatitic particles (<2 µm) with associated trace elements (e.g., F, Na, and unexpectedly Al) distributed within the necrotic cores of DCIS, and both apatite and spheroidal whitlockite particles in invasive cancer within a matrix containing spectroscopic signatures of collagen, non-collagen proteins, cholesterol, carotenoids, and DNA. Among the three DCIS samples, we identify key similarities in MC morphology and distribution, supporting a dystrophic mineralization pathway. This multimodal methodology lays the groundwork for establishing MC heterogeneity in the context of breast cancer biology, and could dramatically improve current prognostic models.

Adjuvant paclitaxel and trastuzumab for node-negative, HER2-positive breast cancer.

BACKGROUND: No single standard treatment exists for patients with small, node-negative, human epidermal growth factor receptor type 2 (HER2)-positive breast cancers, because most of these patients have been ineligible for the pivotal trials of adjuvant trastuzumab. METHODS: We performed an uncontrolled, single-group, multicenter, investigator-initiated study of adjuvant paclitaxel and trastuzumab in 406 patients with tumors measuring up to 3 cm in greatest dimension. Patients received weekly treatment with paclitaxel and trastuzumab for 12 weeks, followed by 9 months of trastuzumab monotherapy. The primary end point was survival free from invasive disease. RESULTS: The median follow-up period was 4.0 years. The 3-year rate of survival free from invasive disease was 98.7% (95% confidence interval [CI], 97.6 to 99.8). Among the 12 relapses seen, 2 were due to distant metastatic breast cancer. Excluding contralateral HER2-negative breast cancers and nonbreast cancers, 7 disease-specific events were noted. A total of 13 patients (3.2%; 95% CI, 1.7 to 5.4) reported at least one episode of grade 3 neuropathy, and 2 had symptomatic congestive heart failure (0.5%; 95% CI, 0.1 to 1.8), both of whom had normalization of the left ventricular ejection fraction after discontinuation of trastuzumab. A total of 13 patients had significant asymptomatic declines in ejection fraction (3.2%; 95% CI, 1.7 to 5.4), as defined by the study, but 11 of these patients were able to resume trastuzumab therapy after a brief interruption. CONCLUSIONS: Among women with predominantly stage I HER2-positive breast cancer, treatment with adjuvant paclitaxel plus trastuzumab was associated with a risk of early recurrence of about 2%; 6% of patients withdrew from the study because of protocol-specified adverse events. (Funded by Genentech; ClinicalTrials.gov number, NCT00542451.).

Identification of risk factors for toxicity in patients with hormone receptor-positive advanced breast cancer treated with bevacizumab plus letrozole: a CALGB 40503 (alliance) correlative study.

BACKGROUND: In hormone receptor-positive advanced breast cancer, a progression-free survival benefit was reported with addition of bevacizumab to first-line letrozole. However, increased toxicity was observed. We hypothesized that functional age measures could be used to identify patients at risk for toxicity while receiving letrozole plus bevacizumab for hormone receptor-positive advanced breast cancer. METHODS: CALGB 40503 was a phase III trial that enrolled patients with hormone receptor-positive advanced breast cancer randomized to letrozole with or without bevacizumab. Patients randomized to bevacizumab were approached to complete a validated assessment tool evaluating physical function, comorbidity, cognition, psychological state, social support, and nutritional status. The relationship between pretreatment assessment measures and the incidence of grade ≥ 3 (National Cancer Institute Common Terminology Criteria for Adverse Events Version 3.0) adverse events was determined. RESULTS: One hundred thirteen (58%) of 195 patients treated with letrozole plus bevacizumab completed the pretreatment assessment questionnaire. One patient was excluded due to missing adverse event data. The median age of patients was 56. Frequently reported grade ≥ 3 adverse events were hypertension (26%), pain (20%), and proteinuria (7%). Two hemorrhagic events (one grade 5) and 1 thrombosis event occurred. Age ≥ 65 years (p < 0.01), decreased vision (p = 0.04), and poorer pretreatment physical function measures (p < 0.05) were found on univariate analysis to be significantly associated with increased incidence of grade ≥ 3 adverse events. Upon multivariate analysis, age ≥ 65 years (p = 0.01) and decreased vision (p = 0.04) remained significant. Univariable and multivariable logistic regression models demonstrated associations between age, vision, the ability to walk up flights of stairs, and grade ≥ 3 adverse events. CONCLUSIONS: Age (≥ 65 years), decreased vision, and impairments in physical function correlated with increased incidence of toxicity in patients receiving first-line letrozole plus bevacizumab. When evaluating therapy likely to increase toxicity, functional assessment measures can identify patients at increased risk for side effects who may benefit from closer monitoring.

The Impact of Obesity on Breast Cancer.

The rates of obesity are increasing worldwide and this condition is now recognized as a leading preventable cause of cancer. Several diseases are directly related to obesity, including diabetes, hypertension, atherosclerosis, stroke, musculoskeletal disorders, and a diverse range of malignances-such as breast cancer. Obesity is associated with an increased risk of postmenopausal estrogen receptor-positive breast cancer and worse cancer-related outcomes for all breast tumor subtypes. Several mechanisms have been proposed to contribute to the obesity-cancer link, including high levels of circulating and local estrogens, altered amounts of adipokines (leptin and adiponectin), disrupted insulin/IGF signaling, modifications within the microbiome, and local and systemic effects of inflammation. Here we will review recent advances in our understanding of the complex signaling pathways underlying the obesity-cancer link. An improved understanding of these processes is anticipated to propel novel and effective intervention strategies to reduce the global obesity-cancer burden.

Breast carcinoma with an Oncotype Dx recurrence score <18: Rate of distant metastases in a large series with clinical follow-up.

BACKGROUND: A 21-gene expression assay (Oncotype DX recurrence score [RS]) that uses reverse transcriptase-polymerase chain reaction is used clinically in patients with early-stage, estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast carcinoma (ER+/HER2- BC) to determine both prognosis with tamoxifen therapy and the usefulness of adding adjuvant chemotherapy. Use of the assay is associated with reductions in overall chemotherapy use. The current study examined the treatments and outcomes in patients with low RS. METHODS: The authors reviewed the institutional database to identify patients with lymph node-negative, ER+/HER2- BC who were treated at the study institution between September 2008 and August 2013 and their 21-gene RS results. RESULTS: A total of 1406 consecutive patients with lymph node-negative ER+/HER2- BC and a low RS were identified (510 patients had an RS of 0-10 and 896 patients had an RS of 11-17). The median age at the time of diagnosis of BC was 56 years; 63 patients (4%) were aged <40 years. Overall, 1361 patients (97%) received endocrine therapy and 170 patients (12%) received chemotherapy. The median follow-up was 46 months. Six patients (0.4%) developed distant metastases (1 patient with an RS of 5 and 5 patients with an RS of 11-17). In the cohorts of patients with an RS of 11 to 17, the absolute rate of distant metastasis among patients aged <40 years was 7.1% (3 of 42 patients) versus 0.2% among patients aged ≥40 years (2 of 854 patients). CONCLUSIONS: The data from the current study document a 0.4% rate of distant metastasis within 5 years of BC diagnosis among patients with lymph node-negative ER+/HER2- BC with an RS <18. Patients aged <40 years at the time of BC diagnosis were observed to have a higher rate of distant metastases. Analysis of data from other studies is necessary to validate this observation further. Cancer 2017;131-137. © 2016 American Cancer Society.

Obesity and cancer: local and systemic mechanisms.

Obesity is a leading modifiable risk factor for the development of several epithelial malignancies. In addition to increasing risk, obesity also confers worse prognosis for many cancers. Obesity represents an overall state of energy imbalance frequently associated with systemic effects including insulin resistance, altered hormone signaling, and high circulating levels of proinflammatory mediators. In addition to its systemic effects, obesity causes subclinical white adipose inflammation including increased tissue levels of proinflammatory mediators. Both local and systemic effects are likely to contribute to the development and progression of cancer. An understanding of the interplay between local and systemic alterations involved in the obesity-cancer link provides the basis for developing interventions aimed at mitigating the protumorigenic effects.

Cardiac Safety of Dual Anti-HER2 Therapy in the Neoadjuvant Setting for Treatment of HER2-Positive Breast Cancer.

BACKGROUND: Trastuzumab and pertuzumab are approved for the neoadjuvant treatment of human epidermal growth receptor 2 (HER2)-positive breast cancer, but cardiac safety data is limited. We report the cardiac safety of dose-dense doxorubicin and cyclophosphamide (AC) followed by paclitaxel, trastuzumab, and pertuzumab (THP) in the neoadjuvant setting followed by adjuvant trastuzumab-based therapy. METHODS: Fifty-seven patients treated with neoadjuvant dose-dense AC-THP followed by adjuvant trastuzumab-based therapy between September 1, 2013, and March 1, 2015, were identified. The primary outcome was cardiac event rate, defined by heart failure (New York Heart Association [NYHA] class III/IV) or cardiac death. Patients underwent left ventricular ejection fraction (LVEF) monitoring at baseline, after AC, and serially during 1 year of anti-HER2 therapy. RESULTS: The median age was 46 years (range 26-68). Two (3.5%) patients developed NYHA class III/IV heart failure 5 and 9 months after initiation of trastuzumab-based therapy, leading to permanent discontinuation of anti-HER2 treatment. Seven (12.3%) patients developed a significant LVEF decline (without NYHA class III/IV symptoms). The median LVEF was 65% (range 55%-75%) at baseline and 64% (range 53%-72%) after AC, and decreased to 60% (range 35%-70%), 60% (range 23%-73%), 61% (range 25%-73%), and 58% (range 28%-66%) after 3, 6, 9, and 12 months (± 6 weeks) of trastuzumab-based therapy. CONCLUSION: The incidence of NYHA class III/IV heart failure after neoadjuvant AC-THP (followed by adjuvant trastuzumab-based therapy) is comparable to rates reported in trials of sequential doxorubicin and trastuzumab. Our findings do not suggest an increased risk of cardiotoxicity from trastuzumab plus pertuzumab following a doxorubicin-based regimen. IMPLICATIONS FOR PRACTICE: Dual anti-human epidermal growth receptor 2 (HER2) therapy with trastuzumab and pertuzumab combined with standard chemotherapy has received accelerated approval for the neoadjuvant treatment of stage II-III HER2-positive breast cancer. Cardiac safety data for trastuzumab and pertuzumab in this setting are limited to clinical trials that utilized epirubicin-based chemotherapy. Formalized investigations into the cardiac safety of trastuzumab and pertuzumab with doxorubicin- (rather than epirubicin) based regimens are important because these regimens are widely used for the adjuvant and neoadjuvant treatment of breast cancer. The known role of HER2 signaling in the physiological adaptive responses of the heart provides further rationale for study on the potential cardiotoxicity of dual anti-HER2 blockade. Findings from this retrospective study provide favorable preliminary data on the cardiac safety of trastuzumab and pertuzumab in combination with a regimen of neoadjuvant doxorubicin and cyclophosphamide followed by paclitaxel, one of the preferred breast cancer treatment regimens, according to the National Comprehensive Cancer Network.

Pathologic Complete Response with Neoadjuvant Doxorubicin and Cyclophosphamide Followed by Paclitaxel with Trastuzumab and Pertuzumab in Patients with HER2-Positive Early Stage Breast Cancer: A Single Center Experience.

OBJECTIVES: Trastuzumab (H) and pertuzumab (P) with standard chemotherapy is approved for use in the neoadjuvant setting for human epidermal growth receptor 2 -positive patients. A retrospective analysis was performed of patients treated with dose-dense (dd) doxorubicin and cyclophosphamide (AC) followed by paclitaxel (T), trastuzumab, and pertuzumab (THP) in the neoadjuvant setting. Here, the pathologic complete response (pCR) rates are reported. METHODS: An electronic medical record review was conducted of patients treated with HP-based therapy in the neoadjuvant setting from September 1, 2013, to March 1, 2015. Data on patient demographics, stage of breast cancer, pathology reports, surgical data, and information on systemic therapy were collected. The pCR was defined as total (tpCR, ypT0/is ypN0), German Breast Group (GBG) pCR (ypT0 ypN0), breast pCR (bpCR) with in situ disease (ypT0/is) and without in situ disease (ypT0), and explored axillary pCR (ypN0). RESULTS: Charts from 66 patients were reviewed, and 57 patients were evaluable for pCR. Median age was 46 years (range 26-68 years). Median tumor size was 4 cm. Of 57 patients, 53 (93%) had operable breast cancer (T1-3, N0-1, M0). Three patients (5.3%) had locally advanced disease (T2-3, N2-3, M0 or T4a-c, any N, M0), and 1 (1.7%) had inflammatory breast cancer (T4d, any N, M0). Overall, 44 (77%) and 13 (23%) had hormone receptor (HR)-positive and negative diseases, respectively. Median numbers of cycles of neoadjuvant treatment were as follows: AC (4, range 1-4), T (4, range 1-4), trastuzumab (6, range 3-8), and pertuzumab (6, range 2-8). In these 57 patients, the rates of tpCR and bpCR with in situ disease were demonstrated in 41/57 (72%) patients, and the rates of GBG pCR and bpCR without in situ disease were found in 30/57 (53%) patients. Of 26 patients with biopsy-proven lymph nodal involvement, axillary pCR occurred in 22 (85%) patients. CONCLUSION: At a single center, the tpCR and GBG pCR rates of dd AC followed by THP are high at 72% and 53%, respectively. The Oncologist 2017;22:139-143Implications for Practice: This is the first study describing the role of doxorubicin and cyclophosphamide followed by paclitaxel and dual anti-HER2 therapy with trastuzumab and pertuzumab (ACTHP) in patients with early stage HER2-positive breast cancer. Total (breast + lymph node) pathological complete remission (pCR) remission (ypT0/is ypN0) and German Breast Group pCR rates (ypT0/ ypN0) were high at 72% and 53%, respectively, with the ACTHP regimen. Rate of axillary clearance in patients with known axillary involvement was high at 85%, which may translate into less extensive axillary surgeries in this subset in the future.

Cardiac safety of non-anthracycline trastuzumab-based therapy for HER2-positive breast cancer.

PURPOSE: Trastuzumab improves overall survival for women with HER2-positive breast cancer but is associated with cardiotoxicity, especially when administered after anthracyclines. Use of non-anthracycline trastuzumab-based regimens is rising, particularly for patients with low-risk disease or with multiple cardiovascular risk factors. We performed a single-center retrospective cohort study to assess the cardiac safety of trastuzumab without anthracyclines outside of a clinical trial setting. METHODS: A retrospective chart review was conducted of patients with HER2-positive early-stage breast cancer receiving non-anthracycline trastuzumab-based therapy between January 2010 and June 2014. Cardiovascular risk factors, left ventricular ejection fraction (LVEF), and treatment interruption data were collected. The primary outcome was a cardiac event (CE), defined by New York Heart Association class III or IV heart failure or cardiac death. The secondary outcome was a significant asymptomatic decline of LVEF (>10% to <55% or >16% from baseline). RESULTS: A total of 165 patients were identified with a median age of 59 years (range 32-85 years). Seventy (42%) had hypertension, 52 (32%) had hyperlipidemia, 29 (18%) had diabetes, and 5 (3%) had coronary artery disease. All patients had a LVEF >50% (median 67%; range 50-80%) at baseline. Two (1.2%) patients with multiple cardiovascular risk factors developed a CE. After discontinuation of trastuzumab, both patients had recovery of LVEF to >50% and resolution of heart failure symptoms. Ten (6.1%) patients developed significant asymptomatic LVEF decline during trastuzumab therapy. CONCLUSIONS: The overall incidence of symptomatic heart failure and asymptomatic LVEF decline among patients receiving trastuzumab without anthracyclines remains low. These findings suggest that less intensive cardiac monitoring may be appropriate during trastuzumab therapy without anthracyclines.

Estimating the OncotypeDX score: validation of an inexpensive estimation tool.

BACKGROUND: OncotypeDX, a multi-gene expression assay, has been incorporated into clinical practice as a prognostic and predictive tool. However, its use in resource-constrained international healthcare systems is limited. Here we develop and validate a simplified model using clinicopathologic criteria to predict OncotypeDX score. METHODS: Patients with estrogen receptor (ER) and/or progesterone receptor (PR)-positive and HER2-negative invasive ductal carcinoma for whom the OncotypeDX test was successfully performed between 09/2008 and 12/2011 were retrospectively identified. Tumor size, nuclear and histologic grade, lymphovascular invasion, and ER and PR status were extracted from pathology reports. Data were split into a training dataset comprising women tested 09/2008-04/2011, and a validation dataset comprising women tested 04/2011-12/2011. Using the training dataset, linear regression analysis was used to identify factors associated with OncotypeDX score, and to create a simplified risk score and identify risk cutoffs. RESULTS: Estrogen and progesterone receptors, tumor size, nuclear and histologic grades, and lymphovascular involvement were independently associated with OncotypeDX. The full model explained 39% of the variation in the test data, and the simplified risk score and cutoffs assigned 57% of patients in the test data to the correct risk category (OncotypeDX score <18, 18-30, >30). 41% of patients were predicted to have OncotypeDX score <18, of these 83, 16, and 2% had true scores of <18, 18-30, and >30, respectively. CONCLUSIONS: Awaiting an inexpensive test that is prognostic and predictive, our simplified tool allows clinicians to identify a fairly large group of patients (41%) with very low chance of having high-risk disease (2%).

Postmastectomy Radiotherapy: An American Society of Clinical Oncology, American Society for Radiation Oncology, and Society of Surgical Oncology Focused Guideline Update.

PURPOSE: A joint American Society of Clinical Oncology, American Society for Radiation Oncology, and Society of Surgical Oncology panel convened to develop a focused update of the American Society of Clinical Oncology guideline concerning use of postmastectomy radiotherapy (PMRT). METHODS: A recent systematic literature review by Cancer Care Ontario provided the primary evidentiary basis. The joint panel also reviewed targeted literature searches to identify new, potentially practice-changing data. RECOMMENDATIONS: The panel unanimously agreed that available evidence shows that PMRT reduces the risks of locoregional failure (LRF), any recurrence, and breast cancer mortality for patients with T1-2 breast cancer with one to three positive axillary nodes. However, some subsets of these patients are likely to have such a low risk of LRF that the absolute benefit of PMRT is outweighed by its potential toxicities. In addition, the acceptable ratio of benefit to toxicity varies among patients and physicians. Thus, the decision to recommend PMRT requires a great deal of clinical judgment. The panel agreed clinicians making such recommendations for individual patients should consider factors that may decrease the risk of LRF, attenuate the benefit of reduced breast cancer-specific mortality, and/or increase risk of complications resulting from PMRT. When clinicians and patients elect to omit axillary dissection after a positive sentinel node biopsy, the panel recommends that these patients receive PMRT only if there is already sufficient information to justify its use without needing to know additional axillary nodes are involved. Patients with axillary nodal involvement after neoadjuvant systemic therapy should receive PMRT. The panel recommends treatment generally be administered to both the internal mammary nodes and the supraclavicular-axillary apical nodes in addition to the chest wall or reconstructed breast.

Exocytosis of macrophage lysosomes leads to digestion of apoptotic adipocytes and foam cell formation.

Many types of apoptotic cells are phagocytosed and digested by macrophages. Adipocytes can be hundreds of times larger than macrophages, so they are too large to be digested by conventional phagocytic processes. The nature of the interaction between macrophages and apoptotic adipocytes has not been studied in detail. We describe a cellular process, termed exophagy, that is important for macrophage clearance of dead adipocytes and adipose tissue homeostasis. Using mouse models of obesity, human tissue, and a cell culture model, we show that macrophages form hydrolytic extracellular compartments at points of contact with dead adipocytes using local actin polymerization. These compartments are acidic and contain lysosomal enzymes delivered by exocytosis. Uptake and complete degradation of adipocyte fragments, which are released by extracellular hydrolysis, leads to macrophage foam cell formation. Exophagy-mediated foam cell formation is a highly efficient means by which macrophages internalize large amounts of lipid, which may ultimately overwhelm the metabolic capacity of the macrophage. This process provides a mechanism for degradation of objects, such as dead adipocytes, that are too large to be phagocytosed by macrophages.

Twenty-one-gene recurrence score assay in BRCA-associated versus sporadic breast cancers: Differences based on germline mutation status.

BACKGROUND: Biological differences between BRCA-associated breast cancer and sporadic breast cancer may warrant different adjuvant chemotherapy (ACRx) recommendations despite similar phenotypic features. A 21-gene expression profile (Oncotype DX) generates a prognostic recurrence score (RS) that predicts the ACRx benefit in patients with hormone receptor-positive breast cancer. No reports describe assay results for BRCA-associated breast cancer. METHODS: A review of Memorial Sloan Kettering Cancer Center databases identified 4908 patients with hormone receptor-positive, node-negative breast cancer who underwent Oncotype DX testing between July 2006 and March 2014. BRCA1/BRCA2 carriers (cases) were identified and matched (1:2) by age at diagnosis and tumor size to noncarrier controls. Two-sample nonparametric tests were used to compare the baseline characteristics, RSs, and risk stratification between BRCA1 and BRCA2 patients. Conditional logistic regression was used to assess these differences by mutational status. RESULTS: Fifty mutation-associated cases (19 BRCA1 cases and 31 BRCA2 cases) and 100 controls who were well matched for age (P = .9) and tumor size (P = .6) were included. BRCA1 and BRCA2 carriers had similar median RSs (P = .6) and risk category stratification (P = .3). The median RS was higher for cases versus controls (24 vs 16; P < .0001). Risk stratification also differed by mutational status (P = .0002). Cases had more high-risk disease (28% vs 7%) and intermediate-risk disease (56% vs 36%) and less low-risk disease (16% vs 57%). Cases were more likely than controls to receive ACRx (74% vs 46%; P = .002). CONCLUSIONS: Germline BRCA-associated hormone receptor-positive breast cancer may be associated with intrinsically less favorable biology. Few affected carriers have RS indicating a clear absence of benefit from ACRx. The increased use of ACRx and benefit from ACRx in BRCA carriers may mitigate otherwise inferior outcomes.

White adipose tissue inflammation and cancer-specific survival in patients with squamous cell carcinoma of the oral tongue.

BACKGROUND: Obesity is associated with increased adipose tissue in the tongue. Chronic white adipose tissue (WAT) inflammation commonly occurs in the obese. We investigated whether WAT inflammation in the tongue impacts survival in patients with squamous cell carcinoma (SCC) of the oral tongue. METHODS: In a retrospective cohort study, patients with T1 and T2 SCC of the oral tongue who underwent curative-intent resection were included. Tongue WAT inflammation was defined by the presence of dead or dying adipocytes surrounded by macrophages forming crown-like structures. The primary and secondary endpoints were disease-specific survival (DSS) and overall survival (OS), respectively. Subgroup analyses were carried out in patients without lymph node involvement for whom adjuvant therapies were not indicated. RESULTS: Archived tissue was available from 125 patients. The median follow-up was 55 months (range, 3-156 months). Overall, 49 of 125 patients (39%) had tongue WAT inflammation, which was associated with higher body mass index, increased tumor thickness, and vascular invasion (P < .05). The 3-year DSS rate for patients with tongue WAT inflammation was 59% (95% confidence interval [CI], 46%-76%) versus 82% (95% CI, 73%-92%) for those without inflammation. For patients without lymph node involvement for whom adjuvant therapy was not indicated (N = 70), tongue WAT inflammation was associated with shortened DSS and OS (P < .05). When adjusted for body mass index and potential prognostic covariates, the hazard ratio for DSS and OS was 5.40 (95% CI, 1.20-24.26) and 2.97 (95% CI, 1.02-8.65), respectively. CONCLUSIONS: Tongue WAT inflammation is associated with worse DSS and OS in patients who have early stage SCC of the oral tongue. Cancer 2016;122:3794-3802. © 2016 American Cancer Society.