Circulating tumor DNA in neoadjuvant-treated breast cancer reflects response and survival.

BACKGROUND: Pathologic complete response (pCR) to neoadjuvant chemotherapy (NAC) is strongly associated with favorable outcome. We examined the utility of serial circulating tumor DNA (ctDNA) testing for predicting pCR and risk of metastatic recurrence. PATIENTS AND METHODS: Cell-free DNA (cfDNA) was isolated from 291 plasma samples of 84 high-risk early breast cancer patients treated in the neoadjuvant I-SPY 2 TRIAL with standard NAC alone or combined with MK-2206 (AKT inhibitor) treatment. Blood was collected at pretreatment (T0), 3 weeks after initiation of paclitaxel (T1), between paclitaxel and anthracycline regimens (T2), or prior to surgery (T3). A personalized ctDNA test was designed to detect up to 16 patient-specific mutations (from whole-exome sequencing of pretreatment tumor) in cfDNA by ultra-deep sequencing. The median follow-up time for survival analysis was 4.8 years. RESULTS: At T0, 61 of 84 (73%) patients were ctDNA positive, which decreased over time (T1: 35%; T2: 14%; and T3: 9%). Patients who remained ctDNA positive at T1 were significantly more likely to have residual disease after NAC (83% non-pCR) compared with those who cleared ctDNA (52% non-pCR; odds ratio 4.33, P = 0.012). After NAC, all patients who achieved pCR were ctDNA negative (n = 17, 100%). For those who did not achieve pCR (n = 43), ctDNA-positive patients (14%) had a significantly increased risk of metastatic recurrence [hazard ratio (HR) 10.4; 95% confidence interval (CI) 2.3-46.6]; interestingly, patients who did not achieve pCR but were ctDNA negative (86%) had excellent outcome, similar to those who achieved pCR (HR 1.4; 95% CI 0.15-13.5). CONCLUSIONS: Lack of ctDNA clearance was a significant predictor of poor response and metastatic recurrence, while clearance was associated with improved survival even in patients who did not achieve pCR. Personalized monitoring of ctDNA during NAC of high-risk early breast cancer may aid in real-time assessment of treatment response and help fine-tune pCR as a surrogate endpoint of survival.

Predicted sensitivity to endocrine therapy for stage II-III hormone receptor-positive and HER2-negative (HR+/HER2-) breast cancer before chemo-endocrine therapy.

BACKGROUND: We proposed that a test for sensitivity to the adjuvant endocrine therapy component of treatment for patients with stage II-III breast cancer (SET2,3) should measure transcription related to estrogen and progesterone receptors (SETER/PR index) adjusted for a baseline prognostic index (BPI) combining clinical tumor and nodal stage with molecular subtype by RNA4 (ESR1, PGR, ERBB2, and AURKA). PATIENTS AND METHODS: Patients with clinically high-risk, hormone receptor-positive (HR+), human epidermal growth factor receptor 2 (HER2)-negative (HR+/HER2-) breast cancer received neoadjuvant taxane-anthracycline chemotherapy, surgery with measurement of residual cancer burden (RCB), and then adjuvant endocrine therapy. SET2,3 was measured from pre-treatment tumor biopsies, evaluated first in an MD Anderson Cancer Center (MDACC) cohort (n = 307, 11 years' follow-up, U133A microarrays), cut point was determined, and then independent, blinded evaluation was carried out in the I-SPY2 trial (n = 268, high-risk MammaPrint result, 3.8 years' follow-up, Agilent-44K microarrays, NCI Clinical Trials ID: NCT01042379). Primary outcome measure was distant relapse-free survival. Multivariate Cox regression models tested prognostic independence of SET2,3 relative to RCB and other molecular prognostic signatures, and whether other prognostic signatures could substitute for SETER/PR or RNA4 components of SET2,3. RESULTS: SET2,3 added independent prognostic information to RCB in the MDACC cohort: SET2,3 [hazard ratio (HR) 0.23, P = 0.004] and RCB (HR 1.77, P < 0.001); and the I-SPY2 trial: SET2,3 (HR 0.27, P = 0.031) and RCB (HR 1.68, P = 0.008). SET2,3 provided similar prognostic information irrespective of whether RCB-II or RCB-III after chemotherapy, and in both luminal subtypes. Conversely, RCB was most strongly prognostic in cancers with low SET2,3 status (MDACC P < 0.001, I-SPY2 P < 0.001). Other molecular signatures were not independently prognostic; they could effectively substitute for RNA4 subtype within the BPI component of SET2,3, but they could not effectively substitute for SETER/PR index. CONCLUSIONS: SET2,3 added independent prognostic information to chemotherapy response (RCB) and baseline prognostic score or subtype. Approximately 40% of patients with clinically high-risk HR+/HER2- disease had high SET2,3 and could be considered for clinical trials of neoadjuvant endocrine-based treatment.

The value of embedding: integrated palliative care for patients with metastatic breast cancer.

PURPOSE: The American Society of Clinical Oncology recommends concurrent palliative care (PC) for patients with metastatic cancer. Recent data show benefits of early PC (at least 90 days before death). However, little is known about PC among patients who die from metastatic breast cancer. METHODS: Patients with metastatic breast cancer at a comprehensive cancer center. Analysis of medical records and clinician and patient surveys. Assess referral patterns and value to patients at the end of life (EOL) of a specialty PC service embedded in a breast oncology program; compare to a prior period of stand-alone PC. RESULTS: In the 18-month study period, oncologists referred for palliative care 105 of their 515 (20.4%) patients; 59 (11.5%) patients were seen by the PC physician. Of the 38 referred patients who died, 23 (60.5%) were seen by embedded PC and all 23 received PC within 90 days of death; 0 of 18 decedents with data available for analysis had ICU stays within 30 days of death. In an earlier 24-month period of stand-alone PC, 43 patients died after receiving PC, but only 11 (25.5%) received PC within 90 days of death (p < 0.01) and 7 of 43 had ICU stays within 30 days of death (p = 0.074). CONCLUSIONS: Embedded PC was well-received by patients and oncologists, increased early PC referrals, and improved EOL care. Avoidable, unnecessary health care utilization at the end of life, such as ICU stays in the last month of life, represent an important potential reduction in patient suffering and system costs.

The Novel Application of Genomic Profiling Assays to Shorten Inactive Status for Potential Kidney Transplant Recipients With Breast Cancer.

The concern about cancer recurrence has traditionally resulted in delaying kidney transplantation for 2-5 years after a cancer diagnosis in patients who are otherwise eligible for transplant. This period of inactive status to observe the tumor biology can result in significant morbidity and decreased quality of life for patients with end-stage renal disease (ESRD). We reported the novel application of genomic profiling assays in breast cancer to identify low-risk cancers in two patients with ESRD who were able to have the mandatory inactive status eliminated prior to kidney transplantation.

Recommendations for standardized pathological characterization of residual disease for neoadjuvant clinical trials of breast cancer by the BIG-NABCG collaboration.

Neoadjuvant systemic therapy (NAST) provides the unique opportunity to assess response to treatment after months rather than years of follow-up. However, significant variability exists in methods of pathologic assessment of response to NAST, and thus its interpretation for subsequent clinical decisions. Our international multidisciplinary working group was convened by the Breast International Group-North American Breast Cancer Group (BIG-NABCG) collaboration and tasked to recommend practical methods for standardized evaluation of the post-NAST surgical breast cancer specimen for clinical trials that promote accurate and reliable designation of pathologic complete response (pCR) and meaningful characterization of residual disease. Recommendations include multidisciplinary communication; clinical marking of the tumor site (clips); and radiologic, photographic, or pictorial imaging of the sliced specimen, to map the tissue sections and reconcile macroscopic and microscopic findings. The information required to define pCR (ypT0/is ypN0 or ypT0 yp N0), residual ypT and ypN stage using the current AJCC/UICC system, and the Residual Cancer Burden system were recommended for quantification of residual disease in clinical trials.

Application of a decision analytic framework for adoption of clinical trial results: are the data regarding TARGIT-A IORT ready for prime time?

The results from randomized clinical trials are often adopted slowly. This practice potentially prevents many people from benefiting from more effective care. Provide a framework for analyzing clinical trial results to determine whether and when early adoption of novel interventions is appropriate. The framework includes the evaluation of three components: confidence in trial results, impact of early, and late adoption if trial results are reversed or sustained. The adverse impact of early adoption, and the opportunity cost of late adoption are determined using Markov modeling to simulate the impact of early and late adoption in terms of quality of life years and resources gained or lost. We applied the framework to the TARGIT-A randomized clinical trial comparing intraoperative radiation (IORT) to standard external beam radiation (EBRT) and considered these results in the context of trials comparing endocrine therapy with and without radiation therapy in postmenopausal women. Confidence in the TARGIT-A trial 4 year results is high because the peak hazard for local recurrence in the trial is between 2 and 3 years. This is consistent with most trials, and no second peak has been observed in similar patient populations, suggesting that the TARGIT-A trial results are stable. The interventions offer approximately equivalent life expectancy. If IORT local recurrences rate were as high as 10 % at 10 years (which is higher than expected), we would project only 0.002 fewer expected life years (less than 1 day) compared to EBRT if IORT is adopted early. However, there is a $1.7 billion opportunity cost of waiting an additional 5 years to adopt IORT in low risk, hormone-receptor-positive, postmenopausal women. EBRT costs an additional $1467 in indirect costs per patient. Applying an evaluative framework for the adoption of clinical trial results to the TARGIT-A IORT therapy trial results in the assessment that the trial results are stable, early adoption would lead to minimal adverse impact, and substantially less resource use. Both IORT and no radiation are reasonable strategies to adopt.

Mammographic screening detects low-risk tumor biology breast cancers.

Overdiagnosis of breast cancer, i.e. the detection of slow-growing tumors that would never have caused symptoms or death, became more prevalent with the implementation of population-based screening. Only rough estimates have been made of the proportion of patients that are overdiagnosed and identification of those patients is difficult. Therefore, the aim of this study is to evaluate whether tumor biology can help identify patients with screen-detected tumors at such a low risk of recurrence that they are likely to be overdiagnosed. Furthermore, we wish to evaluate the impact of the transition from film-screen mammography (FSM) to the more sensitive full-field digital mammography (FFDM) on the biology of the tumors detected by each screening-modality. All Dutch breast cancer patients enrolled in the MINDACT trial (EORTC-10041) accrued 2007-2011, who participated in the national screening program (biennial screening ages 50-75) were included (n = 1,165). We calculated the proportions of high-, low- and among those the ultralow-risk tumors according to the 70-gene signature for patients with screen-detected (n = 775) and interval (n = 390) cancers for FSM and FFDM. Screen-detected cancers had significantly more often a low-risk tumor biology (68 %) of which 54 % even an ultralow-risk compared to interval cancers (53 % low-, of which 45 % ultralow-risk (p = 0.001) with an OR of 2.33 (p < 0.0001; 95 % CI 1.73-3.15). FFDM detected significantly more high-risk tumors (35 %) compared to FSM (27 %) (p = 0.011). Aside from favorable clinico-pathological factors, screen-detected cancers were also more likely to have a biologically low-risk or even ultralow-risk tumor. Especially for patients with screen-detected cancers the use of tools, such as the 70-gene signature, to differentiate breast cancers by risk of recurrence may minimize overtreatment. The recent transition in screening-modalities led to an increase in the detection of biologically high-risk cancers using FFDM.

The quality of life index: a pilot study integrating treatment efficacy and quality of life in oncology.

The majority of women diagnosed with breast cancer will experience some form of drug-related toxicity and subsequent impairments in Health-related Quality of Life (HRQoL). Despite this, HRQoL is assessed inconsistently and there is no validated method to integrate HRQoL data into the assessment of therapeutic agents. This proof of concept study utilizes data from the neoadjuvant I-SPY 2 clinical trial to describe the development of the Quality of Life Index (QoLI) measure. The QoLI represents a single composite score that incorporates validated longitudinal measures of clinical efficacy and QoL and one that permits a more comprehensive, direct comparison of individual therapeutic agents. Preliminary data suggest the QoLI is able to distinguish between agents based on their efficacy and toxicity; with further validation, the QoLI has the potential to provide more patient-centered evaluations in clinical trials and help guide treatment decision making in breast cancer and other oncologic diseases.

Precision surgery and avoiding over-treatment.

Over-diagnosis and over-treatment are consequences of greater awareness about breast cancer, more intensive screening, and the resultant identification of more cases of breast cancer that are low or ultralow risk. This area represents an important opportunity to optimize the delivery of appropriate targeted therapy for breast cancer patients. Despite the evolution of breast cancer care over the last few decades and our ability to tailor treatment to biology, a one-size fits all approach is still prevalent in the local and regional management of and screening for breast cancer, failing to reflect the unique biology and tumor characteristics of each patient. In this review, we explore how we can use new tools to better define tumor biology and also how we can change current clinical practices based on already available data. Every surgeon should be knowledgeable about how to craft personalized breast cancer care in the areas of systemic therapy, adjuvant radiation therapy, management of ductal carcinoma in situ (DCIS), precision surgery, and breast cancer screening.

Challenge with mammary tumor cells expressing MHC class II and CD80 prevents the development of spontaneously arising tumors in MMTV-neu transgenic mice.

The HER-2/Neu oncogene has been implicated in human and mouse breast cancer. Indeed, transgenic MMTV-neu mice expressing this oncogene from the mammary tumor virus long terminal repeat develop spontaneous mammary tumors and die within 1 year of life. We have expressed the class II transactivator (CIITA) and/or the costimulatory molecule CD80 (B7.1) in a mammary carcinoma cell line (MCNeuA) derived from these mice. Class II transactivator directs the expression of MHC class II and the machinery for antigen processing and presentation by this pathway. When injected into MMTV-neu mice, tumor cells expressing CD80 or CD80 and CIITA, were rejected completely. In addition, following the rejection of dual expressing cells, 75% of the mice were protected against the development of subsequent spontaneous tumors. Cells expressing only CD80 or CIITA were not as effective as antitumor vaccines in preventing the development of spontaneous tumors. Thus, converting cancer cells into antigen presenting cells could represent an effective immunotherapy for breast cancer.

Ductal lavage for detection of cellular atypia in women at high risk for breast cancer.

BACKGROUND: Breast cancer originates in breast epithelium and is associated with progressive molecular and morphologic changes. Women with atypical breast ductal epithelial cells have an increased relative risk of breast cancer. In this study, ductal lavage, a new procedure for collecting ductal cells with a microcatheter, was compared with nipple aspiration with regard to safety, tolerability, and the ability to detect abnormal breast epithelial cells. METHODS: Women at high risk for breast cancer who had nonsuspicious mammograms and clinical breast examinations underwent nipple aspiration followed by lavage of fluid-yielding ducts. All statistical tests were two-sided. RESULTS: The 507 women enrolled included 291 (57%) with a history of breast cancer and 199 (39%) with a 5-year Gail risk for breast cancer of 1.7% or more. Nipple aspirate fluid (NAF) samples were evaluated cytologically for 417 women, and ductal lavage samples were evaluated for 383 women. Adequate samples for diagnosis were collected from 111 (27%) and 299 (78%) women, respectively. A median of 13,500 epithelial cells per duct (range, 43-492,000 cells) was collected by ductal lavage compared with a median of 120 epithelial cells per breast (range, 10-74,300) collected by nipple aspiration. For ductal lavage, 92 (24%) subjects had abnormal cells that were mildly (17%) or markedly (6%) atypical or malignant (<1%). For NAF, corresponding percentages were 6%, 3%, and fewer than 1%. Ductal lavage detected abnormal intraductal breast cells 3.2 times more often than nipple aspiration (79 versus 25 breasts; McNemar's test, P<.001). No serious procedure-related adverse events were reported. CONCLUSIONS: Large numbers of ductal cells can be collected by ductal lavage to detect atypical cellular changes within the breast. Ductal lavage is a safe and well-tolerated procedure and is a more sensitive method of detecting cellular atypia than nipple aspiration.

PIPELINEs: Creating Comparable Clinical Knowledge Efficiently by Linking Trial Platforms.

Adaptive, seamless, multisponsor, multitherapy clinical trial designs executed as large scale platforms, could create superior evidence more efficiently than single-sponsor, single-drug trials. These trial PIPELINEs also could diminish barriers to trial participation, increase the representation of real-world populations, and create systematic evidence development for learning throughout a therapeutic life cycle, to continually refine its use. Comparable evidence could arise from multiarm design, shared comparator arms, and standardized endpoints-aiding sponsors in demonstrating the distinct value of their innovative medicines; facilitating providers and patients in selecting the most appropriate treatments; assisting regulators in efficacy and safety determinations; helping payers make coverage and reimbursement decisions; and spurring scientists with translational insights. Reduced trial times and costs could enable more indications, reduced development cycle times, and improved system financial sustainability. Challenges to overcome range from statistical to operational to collaborative governance and data exchange.

Building bridges between physicians and patients: results of a pilot study examining new tools for collaborative decision making in breast cancer.

PURPOSE: To present the results of a pilot study testing an intervention designed to improve the quality of medical consultations between breast cancer patients and physicians and, in particular, to report the effects of the intervention on the quality of treatment decisions, the quality of communication, and the satisfaction of patients and physicians. PATIENTS AND METHODS: We enrolled 24 predominantly white, well-educated, early-stage breast cancer patients who were facing local or systemic treatment decisions in a sequential, controlled trial. All patients received a visit preparation session before the consultation in which a trained researcher helped patients organize their questions and concerns. In the control, a researcher observed the consultation. In the intervention, a researcher helped create an agenda, facilitated the discussion, and created a record of the consultation in real time. Valid and reliable surveys measured the quality of treatment decisions and satisfaction with the consultation. RESULTS: Patients in the intervention achieved significantly higher final decision quality scores compared with control patients (median score, 14 v 10, respectively; P =.008) and a significantly higher level of intersubjective agreement with their physicians about decision quality (Cohen's kappa, 0.49 v 0.285, respectively; P <.0001). Consultation recording methods did not affect the length of time required for the consultation. CONCLUSION: Consultation recording methods provide a promising innovation for medical consultations. Further studies are warranted to broaden the findings, assess impacts on the quality of decisions, cost, and health, and develop practical ways to integrate consultation recording methods into clinics.

Management of ductal carcinoma in situ.

The dramatic increase in the incidence of ductal carcinoma in situ (DCIS) of the breast has made it imperative for all clinicians to develop a better understanding of this disease. Although this preinvasive form of breast cancer is not life-threatening, treatment options may include mastectomy, breast-conserving surgery, radiotherapy, or tamoxifen. Current treatment modalities may be overly aggressive because many cases of DCIS may not recur or progress to invasive cancer. Until we are better able to identify those patients at low risk for progression, it is unlikely that current treatment will change. The adequate understanding of risk assessment is fundamental to the treatment planning for DCIS, and physicians are encouraged to include patients in the decision-making process.

Biology of breast cancer in Nigerian women: a pilot study.

BACKGROUND: Compared to the developed world, there are relatively few studies that describe the tumor biology of breast cancer in African women. While little is known about the tumor biology, clinical and epidemiologic studies suggest that breast cancer in African women are characterized by presentation at late stage and poor clinical outcomes. Analysis of the biological features of breast cancers in Nigerian women was designed to bring additional insight to better understand the spectrum of disease, the phenotypes that present, and the types of interventions that might improve outcomes. MATERIALS AND METHODS: We performed histological analyses for hormone receptors (estrogen and progesterone receptors), HER2, and tumor infiltrating macrophages (TAM) on 17 breast cancers, obtained from Abia State University Teaching Hospital (Aba, Nigeria), between November 2008 and October 2009. On a subset of these cases, we investigated the potential role of a virus in the etiology of these aggressive cancers. RESULTS: The majority of cases in this cohort were characterized as high grade (100% were grade III), triple-negative (65%), and occur in young women (mean age 47 years). We observed high infiltration of TAMs in these tumors, but no evidence of a viral etiology. CONCLUSION: Our findings indicate that breast cancers in Nigerian women have a highly aggressive phenotype (high grade, hormone receptor negative), which is similar to other studies from Africa and other developing nations, as well as from African American women, but is significantly different from Caucasian women in the developed world. The presence of high numbers of TAMs in these tumors raises the possibility of targeting the immune microenvironment for therapeutic interventions.

I-SPY 2: an adaptive breast cancer trial design in the setting of neoadjuvant chemotherapy.

I-SPY 2 (investigation of serial studies to predict your therapeutic response with imaging and molecular analysis 2) is a process targeting the rapid, focused clinical development of paired oncologic therapies and biomarkers. The framework is an adaptive phase II clinical trial design in the neoadjuvant setting for women with locally advanced breast cancer. I-SPY 2 is a collaborative effort among academic investigators, the National Cancer Institute, the US Food and Drug Administration, and the pharmaceutical and biotechnology industries under the auspices of the Foundation for the National Institutes of Health Biomarkers Consortium.

Integration of breast imaging into cancer management.

This article reviews the use of breast imaging for screening, diagnosis, and staging. Its focus is on the ways in which imaging techniques can most effectively be integrated into clinical management.

Myocardial performance and extracellular ionized calcium in a severely failing human heart.

A 16-year old patient had severe end-stage congestive heart failure that was refractory to large doses of beta-agonists. Low serum ionized calcium (Ca2+) levels were corrected by CaCl2 infusions. Myocardial performance correlated directly with serum Ca2+ levels. At the time of transplantation the patient's heart was removed and studied in vitro by both classic and biochemical pharmacologic techniques. Isolated papillary muscles and adenylate cyclase preparations were markedly subsensitive to isoproterenol stimulation, and myocardial membranes were nearly devoid of beta-adrenergic receptors. In contrast, papillary muscles responded normally to calcium, and adenylate cyclase responses to fluoride and histamine were normal. Beta-adrenergic receptor down-regulation may render beta-agonists ineffective, and in such situations the myocardial contractile state may become dependent on extracellular Ca2+.

Does timely assessment affect the anxiety associated with an abnormal mammogram result?

Anxiety following an abnormal mammogram result can be substantial. We examined whether the time to the first diagnostic test was associated with anxiety. We surveyed 449 women at 2 and 8 months after an abnormal mammogram result, and we reviewed their medical records. Twenty-six percent of women reported being very anxious about their abnormal mammogram result at the time of the two-month interview, and 22% reported persistent anxiety after 8 months. After adjustment, the number of days until the first diagnostic test was not associated with anxiety at the 2-month interview. By the second interview, women who received their first diagnostic test within the first week were significantly more anxious, as were women who did not receive their first test for at least 60 days after their results. Further work is needed to ascertain how to minimize the anxiety associated with the evaluation of an abnormal mammogram.