Circulating tumor cell (CTC) measurement in peripheral blood of patients with breast cancer offers prognostic information. In this review, we will try to identify evidence that could be used for prognosis, predictive power to draw this tool to clinical utility. We reviewed 81 manuscripts, and categorized those in discovery datasets, prognostic factors in metastatic breast cancer, identification of clinical utility in early breast cancer and in novel approaches. With each patient responding differently to chemotherapy, more efficient markers would improve clinical outcome. Current CTC diagnostic techniques use epithelial markers predominantly; however, the most appropriate method is the measurement of circulating DNA. It has been hypothesized that micrometastasis occurs early in the development of tumors. That implies the presence of CTCs in nonmetastatic setting. The origin of stimulus for malignant transformation is yet unknown. The role of microenvironment as a stimulus is also being investigated. It has been shown that CTCs vary in numbers with chemotherapy. The markers, which are followed-up in the primary tumors, are also being studied on the CTCs. There is discordance of the human epidermal growth factor receptor-2 status between the primary tumor and CTCs. This review summarizes our current knowledge about the CTCs. With genetic profiling and molecular characterization of CTCs, it is possible to overcome the diagnostic difficulties. Evidence for clinical utility of CTC as prognostic and predictive marker is increasing. Appropriate patient stratification according to CTC determination among other tests, would make personalized cancer therapy more feasible.
Cellsearch; circulating tumor cells; epithelial cell adhesion molecule; metastatic breast cancer; molecular profiling of circulating tumor cells
Eribulin mesylate, a novel non-taxane microtubule dynamics inhibitor, is approved for treatment of metastatic breast cancer (MBC) in patients who have previously received at least 2 chemotherapeutic regimens for MBC that should have included an anthracycline and a taxane in the adjuvant or metastatic setting. This phase 2 study evaluated efficacy and safety of eribulin as first-line therapy for human epidermal growth factor receptor 2-negative (HER2-negative) MBC. Patients with measurable HER2-negative locally recurrent breast cancer or MBC with ≥12 months since prior neoadjuvant or adjuvant (neo/adjuvant) chemotherapy received eribulin mesylate 1.4 mg/m2 IV on days 1 and 8 of each 3-week cycle. Endpoints included objective response rate (ORR) per RECIST v1.1 (primary), safety, progression-free survival (PFS), clinical benefit rate (ORR + stable disease ≥6 months; CBR), and duration of response (DOR). Fifty-six patients were enrolled and received eribulin; 38 (68 %) had prior neo/adjuvant therapy, including 33 who had anthracycline and/or taxane-containing chemotherapy; 41 (73 %) had estrogen receptor-positive disease, and 12 (21 %) had estrogen receptor-negative, progesterone receptor-negative, and HER2-negative (triple-negative) disease. Patients received a median of 7 cycles (range 1–43); 6 (11 %) received treatment for ≥12 months. ORR was 29 % (95 % CI 17.3–42.2), CBR was 52 %, and median DOR was 5.8 months. Median PFS was 6.8 months. Thirty-six patients (64 %) had grade 3/4 treatment-related adverse events; most common were neutropenia (50 %), leukopenia (21 %), and peripheral neuropathy (21 %). These results demonstrate that eribulin has substantial antitumor activity as first-line treatment for HER2-negative MBC with acceptable safety.
Metastatic breast cancer; HER2-negative breast cancer; Triple-negative breast cancer; Eribulin; Progression-free survival
A 21-year-old male presented to the emergency department after a 5-day history of recurrent vomiting and decreased urine output. History revealed ingestion of ibuprofen. During the diagnostic workup, the following was identified: white blood cell count 13.4 (×10(3)/mcL), hemoglobin 11.9 (×10(6)/mcL) with an MCV of 73 fL, hematocrit 34% and platelets were 31,000/mcL, sodium of 130 mmol/L, potassium of 5.1 mmol/L, chloride of 83 mmol/L, bicarbonate of 21 mmol/L, blood urea nitrogen of 184 mg/dL and creatinine of 19.1 mg/dL. He was later diagnosed with thrombotic thrombocytopenic purpura (TTP) based on the fact that he presented with most components of the TTP pentad (except for fever), which included altered mental status, acute kidney injury, thrombocytopenia, and evidence of red cell fragmentation and his ADAMTS13 level was found to be less than 10% prior to therapy. The patient then received plasma exchange, oral corticosteroids, and hemodialysis, which led to a full recovery of platelet count and renal function.
TTP; NSAIDs; Ibuprofen; drug-induced TTP; thrombotic thrombocytopenic purpura
In recent years advances in molecular biology have launched disruptive innovations in breast cancer diagnostics and therapeutics. The advent of genomics has revolutionized our understanding of breast cancer as several different biologically and molecularly distinct diseases. This research has led to commercially available polymerase chain reaction (PCR) and microarray tests that have begun to fundamentally change the way medical oncologists quantify recurrence risk in early stage breast cancer patients. The Genomics era has altered the clinicopathologic paradigm of selecting patients for adjuvant cytotoxic chemotherapy. Sufficiently powered prospective studies are underway that may establish these molecular assays as elements of standard clinical practice in breast cancer treatment. In this article, we review the strengths and limitations of currently available breast cancer-specific molecular tests.
early breast cancer; molecular profiling; prognostic and predictive tests; Oncotype DX; MammaPrint; PAM50
In recent years, molecular research has translated into remarkable changes of breast cancer diagnostics and therapeutics. Molecular tests such as the 21 gene expression test (Oncotype DXTM) and 70 gene microarray test (MammaPrint®) have revolutionized the predictive and prognostic tools in the clinic. By stratifying the risk of recurrence for patients, the tests are able to provide clinicians with more information on the treatment outcomes of using chemotherapy, HER2 targeted therapy or endocrine therapy or the combination of the therapies for patients with particular genetic expressions. However, it is still questionable for clinical applications as some areas remain unclear and that the true benefit still needs prospective evaluation. Such studies are under way and are anxiously awaited. In this paper, the limitation of the molecular tests are discussed. As we are moving towards personalized medicine, molecular profiling will not only result in better outcomes but in a certain proportion of patients, likely will spare unnecessary use of cytotoxic compounds and reduce the cost to the health care systems.
Early breast cancer; gene profiling; predictive and prognostic power
Metastatic breast cancer (MBC) is a major cause of death among women worldwide. Progress has been made in treating MBC with the advent of anti-estrogen therapies, potent cytotoxic agents, and monoclonal antibodies. Bevacizumab is a monoclonal antibody against circulating vascular endothelial growth factor (VEGF), which was approved in 2008 by the US Food and Drug Administration (FDA), for first-line treatment of HER-2 negative MBC in combination with paclitaxel. The FDA then reversed this decision in December 2010 by recommending removal of the MBC indication from bevacizumab, citing primarily safety concerns, and that these risks did not outweigh the ability of bevacizumab to significantly prolong progression-free survival. This decision was unexpected in the oncology community and remains controversial. This review looks at all available phase 3 data with bevacizumab in the MBC setting to determine whether the data support this decision by the FDA, and discusses the future of bevacizumab in breast cancer.
Bevacizumab; metastatic breast cancer; randomized control (phase 3) trials; review; chemotherapy; anti-angiogenesis
Breast cancer is the most frequently diagnosed malignancy in women, with over 200,000 new cases diagnosed each year. Adjuvant systemic endocrine therapy has demonstrated its benefits in reducing the risk of occult micro metastatic infiltration by preventing breast cancer cells from receiving endogenous estrogen stimulation. Initial adjuvant treatment with an aromatase inhibitor (AI) is considered the standard of care for most postmenopausal women with node-positive and high-risk node-negative estrogen receptor (ER)-positive breast cancer. Aromatase inhibitors (AIs) are generally preferred over tamoxifen due to their effectiveness in preventing breast cancer recurrence post surgery and when tamoxifen side effects are to be avoided. When compared with tamoxifen, AIs are associated with significantly improved disease-free survival, however no OS advantage has been noted. Potential toxicities such as bone loss, dyslipidemia, musculoskeletal and cardiovascular health issues should be taken into consideration when AIs are to be used.
adjuvant; aromatase inhibitors; breast cancer; hormonal therapy; postmenopausal
For many years, the medical treatment of breast cancer was reliant solely on cytotoxic chemotherapy. However, over the past twenty years, treatment has evolved to a more target-directed approach. We now employ tailored therapy based on the presence or absence of receptors for estrogen, progesterone, and human epidermal growth factor 2 (HER2). We expect this trend to continue, as agents that use novel approaches to target HER2, as well as targeting different portions of the HER signaling pathway, are in various stages of development. Notably, pertuzumab, a humanized monoclonal antibody that binds to a different domain of the extracellular portion of the HER2 receptor than trastuzumab, was recently approved for use, as was lapatinib, a small-molecule tyrosine kinase inhibitor. Patients with triple negative breast cancer, particularly those with the BRCA mutation, have more limited treatment options and carry a worse prognosis than those who are hormone receptor positive. However, recent data has shown that PARP inhibitors may have significant anti-tumor effect in those with this subtype of breast cancer. Novel agents that inhibit mTOR, PI3K, the insulin-like growth factor, heat shock protein 90, and histone deacetylase have shown promise in phase I-III trials and offer exciting new possibilities for the treatment of this often fatal disease. As we are presented with an ever increasing number of treatment options, the timing and combinations of therapeutic agents used becomes ever more complex in the age of personalized care, but we are hopeful that ultimately this will lead to improved patient outcomes.
breast cancer; chemotherapy; novel therapeutics; biologics; HER2; PARP inhibitors.
This is a case study of a 52-year-old female patient diagnosed in June 2007 with primary metastatic invasive ductal carcinoma of the left breast and synchronous metastases in the bone, lymph nodes, and lung. Biopsy results of the tumor tissue were negative for the estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 (HER2). In November 2007, she participated in a phase II study of metastatic HER2-negative breast cancer. Treatment consisted of systemic chemotherapy with gemcitabine 1,500 mg/m2, nab-paclitaxel 150 mg/m2, and bevacizumab 10 mg/kg once every other week. The patient experienced pain relief in her sternum after 5 weeks of chemotherapy, and her analgesic therapy was discontinued. After 7 months, the patient achieved a complete radiographic response, which was maintained for nearly 2 additional years. She continued receiving treatment throughout this period, requiring 1 dose reduction due to fatigue. The patient experienced no other adverse events, including neuropathy, and continued working uninterrupted throughout her treatment. The patient was discontinued from the study in May 2010 after disease progression, almost a full 3 years after diagnosis. The patient showed minimal response to subsequent therapies but had disease stabilization and died from her disease in April 2012. Median overall survival for patients with metastatic triple-negative breast cancer is between 12 and 13.3 months. This patient survived nearly 5 years following diagnosis. This case exemplifies how therapy with nab-paclitaxel, bevacizumab, and gemcitabine may prolong survival, with minimal toxicity, in select patients with triple-negative metastatic breast cancer.
Triple-negative breast cancer; Metastatic breast cancer; HER2 negative; nab-paclitaxel; Long-term response
Pulmonary toxicities associated with chemotherapeutic agents utilized as adjuvant therapy in patients with breast cancer are distinctly uncommon. The chemotherapy regimen of docetaxel/cyclophosphamide has a more favorable therapeutic index compared to anthracycline-based regimens due to a significantly lower incidence of heart failure and leukemia. Consequently, docetaxel/cyclophosphamide is the preferred adjuvant chemotherapy of choice in older women or in women where anthracyclines may be contraindicated. Pulmonary complications in patients with breast cancer receiving taxane-based adjuvant chemotherapy in the absence of radiation are distinctly uncommon. Here, we report the case of a patient receiving adjuvant docetaxel/cyclophosphamide who developed rapid-onset, biopsy-proven interstitial pneumonitis.
A 72-year-old Hispanic woman was diagnosed as having stage 3 hormone-receptor positive, human epidermal growth factor receptor 2/neu negative, invasive breast cancer. Due to the estimated 10-year risk of recurrence of approximately 80 percent, a decision was made to treat our patient with adjuvant chemotherapy. Due to her age and increased risk of cardiac toxicity with anthracycline-based chemotherapy regimens, our patient was treated with docetaxel/cyclophosphamide chemotherapy for a total of four planned cycles. However, approximately two weeks after receiving the third cycle of chemotherapy, our patient developed rapidly progressive dyspnea, and a non-productive cough and went to the emergency room at an outside medical facility. She was found to have mild hypoxemia, and new onset of peripheral, subpleural fibrotic changes not present on pre-treatment scans. A thorascopic-guided wedge biopsy of the lung tissue revealed subacute interstitial pneumonitis. Our patient made a rapid clinical recovery after treatment with corticosteroids.
Interstitial pneumonitis is a rare complication of docetaxel/cyclophosphamide chemotherapy that carries a high mortality rate. The only way to make a definitive diagnosis is with a wedge biopsy of the lung, which should be performed when feasible. Our patient’s case illustrates that no therapeutic intervention is without its intrinsic and unanticipated risks, and interstitial pneumonitis should be discussed as a potential side effect with all patients prior to administering docetaxel/cyclophosphamide chemotherapy.
Following FDA approval of trastuzumab in 1998 and lapatinib in 2007, several clinical studies have addressed the question of whether trastuzumab and lapatinib combination therapy is better than trastuzumab alone in the metastatic breast cancer and neoadjuvant setting. In this review, updated to September 2012, we focus on the relevant clinical trials that address this question and, based on the available data, reach conclusions regarding a rational and reasonably individualized approach to the management of HER2+ breast cancer. With the FDA approval of pertuzumab in June 2012 and the likely approval of T-DM1 approaching, several ethical issues overshadow the excitement oncologists have for these new treatment options. We discuss the potential evolution of highly active anti-HER2 therapy (HAAHT) as an optimal treatment paradigm for HER2+ breast cancer. Additionally, we review lessons learned from the evolution of HAART for HIV treatment.
HER2; breast cancer; lapatinib; trastuzumab; dual; T-DM1; pertuzumab
Exemestane is an irreversible inhibitor of the aromatase enzyme, which is a key component in the production of estrogen. The majority of breast cancers are sensitive to the proliferative effects of estrogen. Exemestane is approved for the adjuvant treatment of postmenopausal women with breast cancer after 2 to 3 years of tamoxifen therapy, based on a 32% improvement in disease-free survival compared with 5 years of tamoxifen alone (P < 0.001). Exemestane has also shown clinical benefits as an upfront therapy. The safety profile of exemestane shares some side effects with tamoxifen (hot flashes and arthralgia), but is not associated with an increased risk of endometrial cancer or thromboembolic events. This review will discuss in detail the efficacy and safety of exemestane in early breast cancer.
aromatase inhibitor; breast cancer; exemestane; disease-free survival; tamoxifen
Incremental advances over the last two decades in the treatment of stage IV metastatic breast cancer (MBC) have resulted in significantly prolonging the average life expectancy. In 2008, the estimated 5-year relative survival rate for MBC is 27% which compares favorably to rates in stage IV lung (3%) and pancreatic cancers (1%). Despite these advances, MBC remains an incurable disease, often associated with many symptoms and a decreased quality of life (QoL). Therefore, therapy goals in the treatment of MBC include prolonging both progression-free survival and overall survival rates, while at the same time improving QoL by palliation of symptoms. Therefore, systemic chemotherapy ideally should not induce unnecessary toxicities. Once chemotherapy is indicated, a number of drugs and regimens are available but only a few offer both palliation of symptoms (responses to therapy) and overall survival benefit. The addition of novel biologic compounds to chemotherapy has been shown in phase III trials to improve all the above mentioned clinical outcomes in MBC. This review will discuss data supporting the use of gemcitabine/taxane combinations in the treatment of MBC.
metastatic breast cancer; gemcitabine; taxanes
Combinations of capecitabine and a taxane are highly active in metastatic breast cancer, and synergy between capecitabine and docetaxel has also been demonstrated. Such combinations potentially would provide a promising non–anthracycline-based alternative for patients with early breast cancer. Non-anthracycline preoperative regimens are a particularly interesting proposition in human epidermal growth factor receptor 2 (HER2)-positive breast cancer, as they offer less cardiotoxicity and thus can be used concomitantly with preoperative trastuzumab therapy. Capecitabine plus docetaxel (XT) and trastuzumab with XT (HXT) are promising non-anthracycline regimens for the preoperative treatment of women with HER2-negative and HER2-positive breast cancer, respectively. The Xeloda in Neoadjuvant (XeNA) trial, an open-label, multicenter, phase II study, independently assesses the efficacy of preoperative XT in HER2-negative and HXT in HER2-positive breast cancer. A particularly important feature of the XeNA study is the use of pathologic complete response (pCR) plus near pCR (npCR) as the primary endpoint. pCR is associated with long-term survival, and although it is valuable as a surrogate marker, pCR has some limitations. Measurement of residual breast cancer burden (RCB) has been proposed as a more practical alternative to predict survival after preoperative chemotherapy. The combination of RCB-0 and RCB-I (npCR) expands the subset of patients shown to benefit from preoperative chemotherapy, and achievement of pCR or npCR is associated with long disease-free survival. In XeNA, the sum of pCR and npCR will facilitate correlative studies designed to identify patients most likely to benefit from XT and HXT and may expedite the clinical evaluation of these novel preoperative regimens.
Pathologic complete response; Breast-conserving surgery; Taxane; Anthracycline-induced cardiotoxicity
The cytoplasmic regions of the receptors for epidermal growth factor (EGF) and platelet-derived growth factor (PDGF) bind and activate phospholipase C-γ1 (PLC-γ1) and other signaling proteins in response to ligand binding outside the cell. Receptor binding by PLC-γ1 is a function of its SH2 domains and is required for growth factor-induced cell cycle progression into the S phase. Microinjection into MDCK epithelial cells and NIH 3T3 fibroblasts of a polypeptide corresponding to the noncatalytic SH2-SH2-SH3 domains of PLC-γ1 (PLC-γ1 SH2-SH2-SH3) blocked growth factor-induced S-phase entry. Treatment of cells with diacylglycerol (DAG) or DAG and microinjected inositol-1,4,5-triphosphate (IP3), the products of activated PLC-γ1, did not stimulate cellular DNA synthesis by themselves but did suppress the inhibitory effects of the PLC-γ1 SH2-SH2-SH3 polypeptide but not the cell cycle block imposed by inhibition of the adapter protein Grb2 or p21 Ras. Two c-fos serum response element (SRE)-chloramphenicol acetyltransferase (CAT) reporter plasmids, a wild-type version, wtSRE-CAT, and a mutant, pm18, were used to investigate the function of PLC-γ1 in EGF- and PDGF-induced mitogenesis. wtSRE-CAT responds to both protein kinase C (PKC)-dependent and -independent signals, while the mutant, pm18, responds only to PKC-independent signals. Microinjection of the dominant-negative PLC-γ1 SH2-SH2-SH3 polypeptide greatly reduced the responses of wtSRE-CAT to EGF stimulation in MDCK cells and to PDGF stimulation in NIH 3T3 cells but had no effect on the responses of mutant pm18. These results indicate that in addition to Grb2-mediated activation of Ras, PLC-γ1-mediated DAG production is required for EGF- and PDGF-induced S-phase entry and gene expression, possibly through activation of PKC.