I-SPY 2 - Toward more rapid progress in breast cancer treatment

Clinical trials of systemic therapy for operable breast cancer are evolving. Our understanding of breast cancer as a family of biologically distinct diseases has implications for patient selection and the optimization of drug choices. In addition, there is a growing dissatisfaction with trials of adjuvant therapy that are large, take many years to complete, and often result in very small improvements in outcome. For these reasons, we must be thoughtful and rigorous in focusing the testing of promising agents in patients who could derive a meaningful benefit. These realities are in part responsible for the explosion of “neoadjuvant,” or preoperative, trials of systemic therapy in breast cancer. Neoadjuvant therapy, by virtue of the intermediate end point of complete tumor eradication before surgery (called pathological complete response), allows new regimens to be tested in much smaller trials and for results to be obtained far more rapidly than in adjuvant studies

Another breast cancer entity confirmed: Genomics of invasive lobular breast cancer

Invasive lobular carcinoma (ILC) accounts for up to 15% of all invasive breast cancers. We have long recognized the unique clinical characteristics of ILC, but an increased understanding of its biology in contrast with the more common breast cancer histologic type, infiltrating ductal carcinoma (IDC), has emerged. The article that accompanies this editorial by Desmedt et al reinforces and extends this understanding

Unmet needs in clinical research in breast cancer: Where do we need to go?

This CCR Focus highlights areas in breast cancer research with the greatest potential for clinical and therapeutic application. The articles in this CCR Focus address the state of the science in a broad range of areas with a focus on "hot" although sometimes controversial topics, unanswered questions, and unmet need. From mutational signatures, the cancer genomic revolution, and new inroads in immunotherapy for breast cancer to unique concerns of vulnerable populations as well as national and global health disparities, these works represent much of the promise of breast cancer research as well as the challenges in the coming years. Each review focuses not only on recent discoveries but also on putting the topic in context, including limitations to overcome. This overview is designed to further contextualize the highlighted issues within the broader research landscape. We also present new information from a poll of ALLIANCE for Clinical Trials in Oncology Breast Committee members regarding the most needed and viable potential future National Cancer Institute (NCI)- supported clinical trials in breast cancer. The great challenge is to translate the potential benefits of greater scientific knowledge reflected in this CCR Focus section into improvements in outcomes for individuals and populations with breast cancer. A unifying theme across the six articles contained in this CCR Focus is the increasingly recognized value and necessity of collaboration across disciplines from bench to bedside to populations. Only continued and iteratively amplified scientific, clinical, and governmental commitment to creating, testing, and implementing new knowledge will reduce the global morbidity and mortality of breast cancer

Understanding and treating triple-negative breast cancer

Triple-negative breast cancer is a subtype of breast cancer that is clinically negative for expression of estrogen and progesterone receptors (ER/PR) and HER2 protein. It is characterized by its unique molecular profile, aggressive behavior, distinct patterns of metastasis, and lack of targeted therapies. Although not synonymous, the majority of triple-negative breast cancers carry the "basal-like" molecular profile on gene expression arrays. The majority of BRCA1-associated breast cancers are triple-negative and basal-like; the extent to which the BRCA1 pathway contributes to the behavior of sporadic basal-like breast cancers is an area of active research. Epidemiologic studies illustrate a high prevalence of triple-negative breast cancers among younger women and those of African descent. Increasing evidence suggests that the risk factor profile differs between this subtype and the more common luminal subtypes. Although sensitive to chemotherapy, early relapse is common and a predilection for visceral metastasis, including brain metastasis, is seen. Targeted agents, including epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), and poly (ADP-ribose) polymerase (PARP) inhibitors, are currently in clinical trials and hold promise in the treatment of this aggressive disease

PARP and cancer - If it's broke, don't fix it

With apologies to Nietzsche, who once said “that which does not kill us makes us stronger,” sometimes that which does not kill weakens us so the next blow will be lethal. In this issue of the Journal, O'Shaughnessy and colleagues1 describe a study in which poly(adenosine diphosphate-ribose) polymerase (PARP) inhibition was added to cytotoxic chemotherapy in an effort to set breast cancers up for that “next blow” (ClinicalTrials.gov number, NCT00540358). PARP inhibitors represent an exciting new therapeutic direction in oncology: the rational targeting of tumor-cell vulnerability during DNA repair

Implications of neoadjuvant therapy in human epidermal growth factor receptor 2–positive breast cancer

Breast cancer outcomes have markedly improved in great part because of advances in therapy. These improved outcomes, however, have been accompanied by greater financial costs, toxicities, and overtreatment of a substantial number of patients. We must now focus on studies that leverage our accumulated knowledge and use a more individualized approach for the locoregional and systemic management of this disease. De-escalation trials can be harder to perform as a result of the complexities of noninferiority designs, difficulty in funding them, and human nature. Behavioral economists find that people experience negative feelings about losses more strongly than positive feelings about gains of similar size. This makes it harder to conduct trials that are designed to treat breast cancer precisely rather than comprehensively, including studies that aim to de-escalate standard therapy

Leveraging existing data to contextualize phase II clinical trial findings in oncology

More than 250 000 women are diagnosed with early-stage breast cancer (EBC) in the USA each year. Of these, up to 30% have amplification of the human epidermal growth factor 2 (HER2). The current standard of care for HER2-positive (HER2þ) EBC is chemotherapy plus HER2-directed therapy to complete 1 year of treatment. There is growing interest in determining which patients with HER2þ tumors could achieve favorable outcomes with less chemotherapy through better HER2-targeting. The phase II Adjuvant Paclitaxel and Trastuzumab (APT) trial by Tolaney and colleagues provided compelling evidence that patients with small HER2þ tumors without nodal macrometastases can achieve highly favorable outcomes with paclitaxel and trastuzumab alone (TH), avoiding the toxicity associated with multi-agent chemotherapy regimens. Use of TH in this context has been widely adopted in the clinical setting despite the lack of a confirmatory phase III trial

Social support needs among patients with advanced breast cancer: Sensitivity trumps substance

Background The importance of social support for cancer patients has been established in previous studies. However, much of the existing research has identified associations between general measures of social support and various health indicators. Nevertheless, some research has begun to suggest the utility of more nuanced understandings of how patients receive and use social support. Objective To examine the roles of nondirective (ie, support that accepts recipients' feelings and is cooperative with their plans) and directive support (ie, support that prescribes "correct" choices and feelings) as well as social support needs and desires among patients with advanced breast cancer. Methods We conducted semi-structured interviews (qualitative method) with 8 patients with stage IV breast cancer to collect qualitative information about the disease-related challenges they faced, the support they received from their families and medical teams, and the appropriateness of directive and nondirective support. In addition, we used the 14-item Hospital Anxiety and Depression Scale (HADS) to assess clinically relevant cut-offs for anxiety and depression and the 16-item Social Support Inventory to assess the provision of nondirective and directive social support to the patients (quantitative method). Results Qualitative findings suggested that there was considerable variability among patients' reports of social support provided by family, friends, and the medical team. From the qualitative data, patients reported directive support as more useful in times of acute need and emphasized the importance of supportive systems rather than supportive persons in providing emotional support. From the quantitative data, patients reported nondirective support as more typical of support received from both family and medical teams than directive support. On the HADS, 1 patient had a score of 9 on the anxiety subscale, above the score of 7 that is for mild anxiety. No patients scored above the criterion for mild depression, also a score of 7. Limitations Very small sample limits the ability to generalize findings. Conclusions The right type of support for patients with advanced breast cancer is contingent on a range of variables, which suggests that the key characteristic of support may not be any particular feature, but the nuanced adjustment of its content and style of delivery to the patient's circumstances. Funding Peers for Progress

Risk factors for Luminal A ductal carcinoma in situ (DCIS) and invasive breast cancer in the Carolina Breast Cancer Study

Purpose Invasive breast cancers are thought to arise from in situ lesions, but some ductal carcinoma in situ (DCIS) are indolent with low likelihood of progressing to invasive carcinoma. Comparison of risk factor associations between DCIS and invasive disease may elucidate which factors influence early versus late stages of carcinogenesis. Therefore, we determined whether there were differences in risk factor profiles for screen-detected DCIS and invasive breast cancer among Luminal A lesions. Methods We conducted a case-control analysis using data from the Carolina Breast Cancer Study (1993-2001). Analyses were restricted to Luminal A tumors and screen-detected tumors among mammography-eligible women, to limit confounding by mode of detection (N = 108 DCIS; N = 203 invasive). Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) for associations between risk factors and lesion type. Results In stratified analyses, we observed qualitative differences in the direction of association for ever smoking, obese BMI, high waist-To-hip-ratio (WHR), and ?10 years of oral contraceptive use between DCIS and invasive disease. Breastfeeding was inversely associated with invasive disease and was not associated with DCIS. Interaction tests for risk factor associations between Luminal A DCIS and invasive breast cancer were not statistically significant (p>0.05). Conclusions Among Luminal A tumors, established breast cancer risk factors may exert stronger effects on progression of early lesions to invasive disease, with lesser effects on risk of DCIS

What Is the Real Impact of Estrogen Receptor Status on the Prognosis and Treatment of HER2-Positive Early Breast Cancer?

HER2+ early breast cancer is a heterogeneous disease, comprising all the intrinsic breast cancer subtypes. The only biomarker available nowadays for anti-HER2 treatment selection is HER2 status itself, but estrogen receptor (ER) status is emerging as a robust predictive marker within HER2+ disease. In this Perspective, we discuss the biological and clinical differences between patients with HER2+/ER-positive (ER+) disease versus those with HER2+/ ER-negative (ER-neg) tumors, namely, short-term and long-term (>5 years after diagnosis) prognosis, response to neoadjuvant treatment and benefit from adjuvant anti-HER2–targeted therapies. We also address other possible biomarkers to be used for patient selection in future clinical trials, such as gene signatures, PAM50 subtypes, tumor-infiltrating lymphocytes, PIK3CA mutations, and changes in Ki67 score during treatment and discuss their limitations. Finally, we suggest new clinical trial designs that can have an impact on clinical practice, aiming to test treatment deescalation separately for patients with HER2+/ER+ and HER2+/ER-neg tumors. We also propose an integrated classification of HER2+ disease, comprising DNA, RNA, protein expression, and microenvironment characteristics, in order to identify those tumors that are truly “HER2-addicted” and may benefit the most from anti-HER2 treatment