Angel Arnaout

p27 Phosphorylation by Src Regulates Inhibition of Cyclin E-Cdk2

The kinase inhibitor p27Kip1 regulates the G1 cell cycle phase. Here, we present data indicating that the oncogenic kinase Src regulates p27 stability through phosphorylation of p27 at tyrosine 74 and tyrosine 88. Src inhibitors increase cellular p27 stability, and Src overexpression accelerates p27 proteolysis. Src-phosphorylated p27 is shown to inhibit cyclin E-Cdk2 poorly in vitro, and Src transfection reduces p27-cyclin E-Cdk2 complexes. Our data indicate that phosphorylation by Src impairs the Cdk2 inhibitory action of p27 and reduces its steady-state binding to cyclin E-Cdk2 to facilitate cyclin E-Cdk2-dependent p27 proteolysis. Furthermore, we find that Src-activated breast cancer lines show reduced p27 and observe a correlation between Src activation and reduced nuclear p27 in 482 primary human breast cancers. Importantly, we report that in tamoxifen-resistant breast cancer cell lines, Src inhibition can increase p27 levels and restore tamoxifen sensitivity. These data provide a new rationale for Src inhibitors in cancer therapy.

Sentinel Node Biopsy After Neoadjuvant Chemotherapy in Biopsy-Proven Node-Positive Breast Cancer: The SN FNAC Study

PURPOSE An increasing proportion of patients (> 30%) with node-positive breast cancer will obtain an axillary pathologic complete response after neoadjuvant chemotherapy (NAC). If sentinel node (SN) biopsy (SNB) is accurate in this setting, completion node dissection (CND) morbidity could be avoided. PATIENTS AND METHODS In the prospective multicentric SN FNAC study, patients with biopsy-proven node-positive breast cancer (T0-3, N1-2) underwent both SNB and CND. Immunohistochemistry (IHC) use was mandatory, and SN metastases of any size, including isolated tumor cells (ypN0[i+], ≤ 0.2 mm), were considered positive. The optimal SNB identification rate (IR) ≥ 90% and false-negative rate (FNR) ≤ 10% were predetermined. RESULTS From March 2009 to December 2012, 153 patients were accrued to the study. The SNB IR was 87.6% (127 of 145; 95% CI, 82.2% to 93.0%), and the FNR was 8.4% (seven of 83; 95% CI, 2.4% to 14.4%). If SN ypN0(i+)s had been considered negative, the FNR would have increased to 13.3% (11 of 83; 95% CI, 6.0% to 20.6%). There was no correlation between size of SN metastases and rate of positive non-SNs. Using this method, 30.3% of patients could potentially avoid CND. CONCLUSION In biopsy-proven node-positive breast cancer after NAC, a low SNB FNR (8.4%) can be achieved with mandatory use of IHC. SN metastases of any size should be considered positive. The SNB IR was 87.6%, and in the presence of a technical failure, axillary node dissection should be performed. We recommend that SN evaluation with IHC be further evaluated before being included in future guidelines on the use of SNB after NAC in this setting.

Lymph node retrieval and assessment in stage II colorectal cancer: a population-based study.

Background: Adjuvant chemotherapy for patients with stage III (node-positive) colorectal cancer (CRC) reduces mortality by one third. Retrieval of an inadequate number of lymph nodes in the surgical specimen may result in incorrectly designating some patients as stage II (node negative), and consequently, such patients may not be offered appropriate chemotherapy. Recent National Cancer Institute guidelines suggest that a minimum of 12 nodes should be examined to ensure accurate staging.Methods: This population-based study identified stage II (T3N0 and T4N0) CRC cases by using CRC pathology reports (1997–2000) from the Ontario Cancer Registry. Patients aged 19 to 75 years were identified, and demographic, surgical, pathologic, and hospital data were extracted. Factors relating to the number of lymph nodes assessed were examined.Results: A total of 8848 CRC cases were reviewed, and 1789 stage II cases were identified. Seventy-three percent of cases were designated as node negative on the basis of assessment of <12 lymph nodes. Multivariate analysis showed that age, tumor size, specimen length, use of a pathology template, and academic status of the hospital were significant predictors of the number of lymph nodes assessed.Conclusions: A subset of patients with CRC in Ontario were assigned stage II disease on the basis of examination of relatively few lymph nodes.

Use of Preoperative Magnetic Resonance Imaging for Breast Cancer: A Canadian Population-Based Study.

IMPORTANCE Contrary to practice guidelines, breast magnetic resonance imaging (MRI) is commonly used in the preoperative evaluation of women with breast cancer. While existing literature has found little benefit to MRI in most patients, potential downstream consequences associated with breast MRI are not well described. OBJECTIVE To describe patterns of preoperative breast MRI utilization in a health care system with universal insurance and its association with downstream investigations and clinical outcomes. DESIGN, SETTING, AND PARTICIPANTS This was a population-based retrospective cohort study using administrative heath care databases in Ontario, Canada (2012 population, 13.5 million) over 14 geographic regions were evaluated within the data set. Participants comprised 53 015 patients with primary operable breast cancer treated from 2003 to 2012. MAIN OUTCOMES AND MEASURES Use of preoperative breast MRI by year, geographic region, and breast cancer stage. Postdiagnosis imaging, biopsy, and short-term surgical outcomes were also evaluated between those who did and did not receive MRI. RESULTS Overall, 14.8% of patients (7824 of 53 015) had a preoperative MRI. During the 10-year study period, MRI use increased across all stages by 8-fold (from 3% to 24%; P < .001 for trend). Factors associated with MRI use were younger age, higher socioeconomic status, higher Charlson comorbidity score, surgery performed in a teaching hospital, and fewer years of surgeon experience. Multivariate analyses showed that preoperative breast MRI was associated with higher likelihood of the following: postdiagnosis breast imaging (odds ratio [OR], 2.09; 95% CI, 1.92-2.28), postdiagnosis breast biopsies (OR, 1.74; 95% CI, 1.57-1.93), postdiagnosis imaging to assess for distant metastatic disease (OR, 1.51; 95% CI, 1.42-1.61), mastectomy (OR, 1.73; 95% CI, 1.62-1.85), contralateral prophylactic mastectomy (OR, 1.48; 95% CI, 1.23-1.77), and a greater than 30-day wait to surgery (OR, 2.52; 95% CI, 2.36-2.70) (all ORs are adjusted). CONCLUSIONS AND RELEVANCE Preoperative breast MRI use has increased substantially in routine clinical practice and is associated with a significant increase in ancillary investigations, wait time to surgery, mastectomies, and contralateral prophylactic mastectomies.

Imaging for distant metastases in women with early-stage breast cancer: a population-based cohort study

Background: Practice guidelines recommend that imaging to detect metastatic disease not be performed in the majority of patients with early-stage breast cancer who are asymptomatic. We aimed to determine whether practice patterns in Ontario conform with these recommendations. Methods: We used provincial registry data to identify a population-based cohort of Ontario women in whom early-stage, operable breast cancer was diagnosed between 2007 and 2012. We then determined whether imaging of the skeleton, thorax, and abdomen or pelvis had been performed within 3 months of tissue diagnosis. We calculated rates of confirmatory imaging of the same body site. Results: Of 26 547 patients with early-stage disease, 22 811 (85.9%) had at least one imaging test, and a total of 83 249 imaging tests were performed (mean of 3.7 imaging tests per patient imaged). Among patients with pathologic stage I and II disease, imaging was performed in 79.6% (10 921/13 724) and 92.7% (11 882/12 823) of cases, respectively. Of all imaging tests, 19 784 (23.8%) were classified as confirmatory investigations. Imaging was more likely for patients who were younger, had greater comorbidity, had tumours of higher grade or stage or had undergone preoperative breast ultrasonography, mastectomy or surgery in the community setting. Interpretation: Despite recommendations from multiple international guidelines, most Ontario women with early-stage breast cancer underwent imaging to detect distant metastases. Inappropriate imaging in asymptomatic patients with early-stage disease is costly and may lead to harm. The use of population datasets will allow investigators to evaluate whether or not strategies to implement practice guidelines lead to meaningful and sustained change in physician practice.

Invasive Pleomorphic Lobular Carcinoma of the Breast: Pathologic, Clinical, and Therapeutic Considerations

Pleomorphic lobular carcinoma is an uncommon form of breast cancer and a subtype of invasive lobular carcinoma. It has unique histopathologic features that translate to a more aggressive phenotype with an associated poor prognosis. Unlike classical invasive lobular carcinoma, it can lose estrogen and progesterone receptor expression and demonstrate HER-2/neu amplification. It remains to be determined, however, whether the pleomorphic histology independently predicts a worse outcome or whether other known associated negative prognostic factors such as larger tumor size, increased metastatic disease, and associated worse molecular subtypes commonly present in pleomorphic carcinoma account for the poor prognosis. Here we present an updated review of the unique pathologic and clinical features of pleomorphic lobular carcinoma needed to guide management for women with this subtype of cancer.

Excision of the primary tumour in patients with metastatic breast cancer: a clinical dilemma

BACKGROUND Approximately 10% of new breast cancer patients will present with overt synchronous metastatic disease. The optimal local management of those patients is controversial. Several series suggest that removal of the primary tumour is associated with a survival benefit, but the retrospective nature of those studies raises considerable methodologic challenges. We evaluated our clinical experience with the management of such patients and, more specifically, the impact of surgery in patients with synchronous metastasis. METHODS We reviewed patients with primary breast cancer and concurrent distant metastases seen at our centre between 2005 and 2007. Demographic and treatment data were collected. Study endpoints included overall survival and symptomatic local progression rates. RESULTS The 111 patients identified had a median follow-up of 40 months (range: 0.6-71 months). We allocated the patients to one ot two groups: a nonsurgical group (those who did not have breast surgery, n = 63) and a surgical group (those who did have surgery, n = 48, 29 of whom had surgery before the metastatic diagnosis). When compared with patients in the nonsurgical group, patients in the surgical group were less likely to present with T4 tumours (23% vs. 35%), N3 nodal disease (8% vs. 19%), and visceral metastasis (67% vs. 73%). Patients in the surgical group experienced longer overall survival (49 months vs. 33 months, p = 0.01) and lower rates of symptomatic local progression (14% vs. 44%, p < 0.001). CONCLUSIONS In our study, improved overall survival and symptomatic local control were demonstrated in the surgically treated patients; however, this group had less aggressive disease at presentation. The optimal local management of patients with metastatic breast cancer remains unknown. An ongoing phase iii trial, E2108, has been designed to assess the effect of breast surgery in metastatic patients responding to first-line systemic therapy. If excision of the primary tumour is associated with a survival benefit, then the preselected subgroup of patients who have responded to initial systemic therapy is the desired population in which to put this hypothesis to the test.

Both bulk and cancer stem cell subpopulations in triple-negative breast cancer are susceptible to Wnt, HDAC, and ERα coinhibition

Development of targeted therapies for triple‐negative breast cancer (TNBC, a more aggressive subtype) is an unmet medical need. We analyzed data from 887 patients with invasive breast cancer and observed that increased Wnt and histone deacetylase (HDAC) activities are associated with estrogen receptor 1 (ESR1) and progesterone receptor (PGR) repression, poor survival, and increased relapse. The inverse correlation between Wnt signaling and repression of ESR1 and PGR expression was found to be magnified in cancer stem cell (CSC) subpopulations in TNBC cell lines. Cosuppression of Wnt, HDAC, and ESR1 using clinically relevant low‐dose inhibitors effectively repressed both bulk and CSC subpopulations and converted CSCs to non‐CSCs in TNBC cells without affecting MCF‐10A mammary epithelial cells.

Issues Affecting the Loco-regional and Systemic Management of Patients with Invasive Lobular Carcinoma of the Breast.

Invasive lobular carcinoma (ILC) of the breast is the second most common type of invasive breast carcinoma accounting for 8–14% of all breast cancers. Traditional management of ILC has followed similar paradigms as that for invasive ductal carcinoma (IDC). However, ILC represents a pathologically, clinically and biologically unique variant of breast cancer with particular management challenges. These challenges are seen in both the loco‐regional management of ILC; where ILC tumors tend to avoid detection and hence present as more clinically advanced and surgically challenging carcinomas, and the systemic management with a unique response pattern to standard systemic therapies. Because of these challenges, the outcome for patients with ILC has likely lagged behind the continued improvements seen in outcome for patients with IDC. Here, we discuss some of the unique challenges ILC presents and discuss possible management strategies to best overcome the difficulties in the loco‐regional and systemic management of patients with ILC.

Neoadjuvant endocrine treatment for breast cancer: from bedside to bench and back again?

In recent years, considerable attention has been paid to the role of neoadjuvant chemotherapy as a pluripotential test bed for the treatment of breast cancer. Although traditionally reserved to render inoperable disease operable, neoadjuvant chemotherapy is increasingly being used to improve the chance for breast-conserving surgery, to gain information on pathologic response rates for a more rapid assessment of new chemotherapy-biologic regimens, and also to study in vivo tumour sensitivity or resistance to the agent being used. Similarly, use of neoadjuvant endocrine treatment was also traditionally restricted to elderly or frail patients who were felt to be unsuitable for chemotherapy. It is therefore not surprising that, given the increasing realization of the pivotal role of endocrine therapy in patient care, there is enhanced interest in neoadjuvant endocrine therapy not only as a less-toxic alternative to chemotherapy, but also to assess tumour sensitivity or resistance to endocrine agents. The availability of newer endocrine manipulations and increasing evidence that the benefits of chemotherapy are frequently marginal in many hormone-positive patients is making endocrine therapy increasingly important in the clinical setting. The hope is that, one day, instead of preoperative endocrine therapy being restricted to the infirm and the elderly, it will be used in the time between biopsy diagnosis and surgery to predict which patients will or will not benefit from chemotherapy in the adjuvant setting.