Simultaneous inference of a misclassified outcome and competing risks failure time data

<div><p>Ipsilateral breast tumor relapse (IBTR) often occurs in breast cancer patients after their breast conservation therapy. The IBTR status' classification (true local recurrence versus new ipsilateral primary tumor) is subject to error and there is no widely accepted gold standard. Time to IBTR is likely informative for IBTR classification because new primary tumor tends to have a longer mean time to IBTR and is associated with improved survival as compared with the true local recurrence tumor. Moreover, some patients may die from breast cancer or other causes in a competing risk scenario during the follow-up period. Because the time to death can be correlated to the unobserved true IBTR status and time to IBTR (if relapse occurs), this terminal mechanism is non-ignorable. In this paper, we propose a unified framework that addresses these issues simultaneously by modeling the misclassified binary outcome without a gold standard and the correlated time to IBTR, subject to dependent competing terminal events. We evaluate the proposed framework by a simulation study and apply it to a real data set consisting of 4477 breast cancer patients. The adaptive Gaussian quadrature tools in SAS procedure NLMIXED can be conveniently used to fit the proposed model. We expect to see broad applications of our model in other studies with a similar data structure.</p></div

Estrogen receptor alpha is cell cycle-regulated and regulates the cell cycle in a ligand-dependent fashion

<p>Estrogen receptor alpha (ERα) has been implicated in several cell cycle regulatory events and is an important predictive marker of disease outcome in breast cancer patients. Here, we aimed to elucidate the mechanism through which ERα influences proliferation in breast cancer cells. Our results show that ERα protein is cell cycle-regulated in human breast cancer cells and that the presence of 17-β-estradiol (E2) in the culture medium shortened the cell cycle significantly (by 4.5 hours, <i>P</i> < 0.05) compared with unliganded conditions. The alterations in cell cycle duration were observed in the S and G₂/M phases, whereas the G₁ phase was indistinguishable under liganded and unliganded conditions. In addition, ERα knockdown in MCF-7 cells accelerated mitotic exit, whereas transfection of ERα-negative MDA-MB-231 cells with exogenous ERα significantly shortened the S and G₂/M phases (by 9.1 hours, <i>P</i> < 0.05) compared with parental cells. Finally, treatment of MCF-7 cells with antiestrogens revealed that tamoxifen yields a slower cell cycle progression through the S and G₂/M phases than fulvestrant does, presumably because of the destabilizing effect of fulvestrant on ERα protein. Together, these results show that ERα modulates breast cancer cell proliferation by regulating events during the S and G₂/M phases of the cell cycle in a ligand-dependent fashion. These results provide the rationale for an effective treatment strategy that includes a cell cycle inhibitor in combination with a drug that lowers estrogen levels, such as an aromatase inhibitor, and an antiestrogen that does not result in the degradation of ERα, such as tamoxifen.</p

Univariate analysis of prognostic factors for disease-specific survival and overall survival in patients with T1-T2 invasive lobular carcinoma and 1-2 positive lymph nodes who underwent breast conserving therapy.

<p>Abbreviations: DSS, disease-specific survival; OS, overall survival; LN, lymph node; ER, estrogen receptor; PR, progesterone receptor; SLND, sentinel lymph node dissection; ALND, axillary lymph node dissection.</p

Algorithm for patient selection.

<p>The Surveillance Epidemiology and End Results 1998–2009 database was used to identify patients diagnosed with invasive lobular carcinoma (ILC). Patients were excluded if their disease stage was unknown, if they had stage III or stage IV disease, if their follow-up time was less than 24 months, if they did not undergo surgery, underwent mastectomy or did not receive radiation as a component of breast conserving therapy. Patients who underwent breast conserving therapy (BCT) who had more than 2 positive lymph nodes were also excluded. This left a final study cohort of 1,269 patients with T1–T2 ILC with 1–2 positive lymph nodes who underwent BCT.</p

Comparison of clinicopathologic characteristics between patients with T1–T2 ILC and 1–2 positive lymph nodes undergoing SLND alone and those undergoing ALND.

<p>Abbreviations: SLND, sentinel lymph node dissection; ALND, axillary lymph node dissection; LN, lymph node; ER, estrogen receptor; PR, progesterone receptor.</p><p>^*Cases with unknown status were excluded from statistical analysis.</p

Survival outcomes based on the number of positive lymph nodes.

<p>Overall survival (A and B) and disease-specific survival (C and D) were not different among patients who underwent SLND alone and those who underwent ALND for patients with one positive lymph node (A and C) or two positive lymph nodes (B and D).</p

Overall and disease-specific survival of patients with T1-T2 invasive lobular carcinoma and 1-2 positive lymph nodes who underwent breast conserving therapy.

<p>Abbreviations: CI, confidence interval; OS, overall survival; DSS, disease-specific survival; LN, lymph node; SLND, sentinel lymph node dissection; ALND, axillary lymph node dissection.</p

Survival outcomes for patients with T1–T2 ILC with 1–2 positive lymph nodes who underwent breast conserving therapy.

<p>No differences were identified in overall survival (A) or disease-specific survival (B) for patients who underwent sentinel lymph node dissection alone compared to those who underwent axillary lymph node dissection.</p

Nomogram for predicting 5- and 10-year probability of death by breast cancer after surgery.

<p>To estimate risk, calculate points for each variable by drawing a straight line from patient's variable value to the axis labeled “Points.” Sum all points and draw a straight line from the total point axis to the 5- and 10-year probability of death by breast cancer axis.</p

LMW-E renders hMECs tumorigenic, and LMW-E expression is selected with increased <i>in vivo</i> passaging.

<p>(A) Schematic of the generation of <i>in vivo</i> passaged clones with 3 successive injections (T1G2, T1G3, and T1G4). (B) Tumors from <i>in vivo</i> passaging were removed from mice, minced, and cultured on monolayer plates. Lysates were extracted and subjected to Western blot analysis with antibodies against cyclin E, elafin, and β-actin. EL (C), LMW-E (D), and elafin (E) protein levels were quantified by densitometry and compared between different generations of <i>in vivo</i> passaged cells (Student <i>t</i> test, *p<0.05). (F) Paraffin-embedded slides of 4 representative tumors were stained with hematoxylin and eosin (top panel) and cyclin E antibody (bottom panel).</p