Jacqueline S. Jeruss

Preservation of fertility in patients with cancer

The increasing number of young survivors of cancer who have favorable outcomes necessitates planning for the preservation of fertility, which may mean modifying the strategy for oncologic treatment. In addition to in vitro fertilization in women and sperm banking in men, new methods on the horizon include in vitro follicle maturation and techniques for tissue transplantation.

Axillary Recurrence After Sentinel Node Biopsy

BackgroundSentinel node biopsy (SNB) has evolved as the standard of care in the surgical staging of breast cancer. This technique is accurate for surgical staging of axillary nodal disease. We hypothesized that axillary recurrence after SNB is rare and that SNB may provide regional control in patients with microscopic nodal involvement.MethodsWith institutional review board approval, SNB was performed with peritumoral injection of 99mTc-labeled sulfur colloid. From 1996 to 2003, 1167 patients were entered into a prospective cancer database after surgical therapy; 916 patients consented to long-term follow-up. Fifty-two patients (5.7%) did not map successfully and were excluded, leading to a study population of 864 patients. The median follow-up was 27.4 months (range, 1–98 months).ResultsThe median number of sentinel nodes harvested was 2, and 633 (73%) patients had negative sentinel nodes. Thirty (4.7%) of those sentinel node–negative patients underwent completion axillary dissection, whereas 592 (94%) patients were followed up with observation. A total of 231 (27%) had positive sentinel nodes: 158 (68%) of these patients underwent completion axillary dissection, and 73 (32%) were managed with observation alone. Two (.32%) patients who were sentinel node negative had an axillary recurrence; one of these patients had undergone completion axillary dissection. No patient in the observed sentinel node–positive group had an axillary recurrence (odds ratio, .37; P = .725).ConclusionsOn the basis of a median follow-up of 27.4 months, axillary recurrence after SNB is extraordinarily rare regardless of nodal involvement, thus indicating that this technique provides an accurate measure of axillary disease and may impart regional control for patients with node-positive disease.

Activin A Mediates Growth Inhibition and Cell Cycle Arrest through Smads in Human Breast Cancer Cells

The transforming growth factor-beta (TGF-beta) superfamily of growth factors is responsible for a variety of physiologic actions, including cell cycle regulation. Activin is a member of the TGF-beta superfamily that inhibits the proliferation of breast cancer cells. Activin functions by interacting with its type I and type II receptors to induce phosphorylation of intracellular signaling molecules known as Smads. Smads regulate transcription of many genes in a cell- and tissue-specific manner. In this study, the role of activin A in growth regulation of breast cancer cells was investigated. Activin stimulated the Smad-responsive promoter, p3TP, 2-fold over control in T47D breast cancer cells. Activin inhibited cellular proliferation of T47D breast cancer cells after 72 hours, an effect that could be abrogated by incubation with the activin type I receptor inhibitor, SB431542. Activin arrested T47D cells in the G0-G1 cell cycle phase. Smad2 and Smad3 were phosphorylated in response to activin and accumulated in the nucleus of treated T47D cells. Infection of T47D cells with adenoviral Smad3 resulted in cell cycle arrest and activation of p3TP-luciferase, whereas a adenoviral dominant-negative Smad3 blocked activin-mediated cell cycle arrest and gene transcription. Activin maintained expression of p21 and p27 cyclin-dependent kinase inhibitors involved in cell cycle control, enhanced expression of p15, reduced cyclin A expression, and reduced phosphorylation of the retinoblastoma (Rb) protein. Smad3 overexpression recapitulated activin-induced p15 expression and repression of cyclin A and Rb phosphorylation. These data indicate that activin A inhibits breast cancer cellular proliferation and activates Smads responsible for initiating cell cycle arrest.

Validation of a Novel Staging System for Disease-Specific Survival in Patients With Breast Cancer Treated With Neoadjuvant Chemotherapy

PURPOSE We previously described a novel breast cancer staging system for assessing prognosis after neoadjuvant chemotherapy on the basis of pretreatment clinical stage (CS), estrogen receptor status (E), grade (G), and post-treatment pathologic stage (PS). This clinical-pathologic stage (CPS) + EG staging system assigned and summed points for each factor, allowing for better determination of breast cancer-specific survival than CS or PS alone. The current study was undertaken to validate this staging system using internal and external cohorts. METHODS We identified an internal cohort of 804 patients treated with neoadjuvant chemotherapy at our institution from 2003 to 2005 and an external cohort of 165 patients treated at another institution. Clinicopathologic characteristics, treatment regimens, and patient outcomes were assessed. Outcomes were stratified by CPS + EG score. RESULTS Five-year disease-specific survival (DSS) for the internal cohort was 77% (95% CI, 72 to 82) at a median follow-up of 3.4 years (range, 0.3 to 5.9 years). Five-year DSS for the external cohort was 86% (95% CI, 79 to 91) at a median follow-up of 4.7 years (range, 0.5 to 10.5 years). The ability of the CPS + EG score to stratify outcomes was confirmed in both the internal and external cohorts. Application of the CPS + EG staging system facilitated more refined categorization of patients into prognostic subgroups by outcome than presenting CS or final PS as defined by the American Joint Committee on Cancer (AJCC) staging system. CONCLUSION The current study validates the CPS + EG staging system in two independent cohorts. We recommend that biologic markers and response to treatment be incorporated into revised versions of the AJCC staging system for patients receiving neoadjuvant chemotherapy.

In vivo capture and label-free detection of early metastatic cells

Breast cancer is a leading cause of death for women, with mortality resulting from metastasis. Metastases are often detected once tumor cells affect the function of solid organs, with a high disease burden limiting effective treatment. Here we report a method for the early detection of metastasis using an implanted scaffold to recruit and capture metastatic cells in vivo, which achieves high cell densities and reduces the tumor burden within solid organs 10-fold. Recruitment is associated with infiltration of immune cells, which include Gr1hiCD11b+ cells. We identify metastatic cells in the scaffold through a label-free detection system using inverse-spectroscopic optical coherence tomography, which identifies changes to nanoscale tissue architecture associated with the presence of tumor cells. For patients at risk of recurrence, scaffold implantation following completion of primary therapy has the potential to identify metastatic disease at the earliest stage, enabling initiation of therapy while the disease burden is low.

Maintaining Fertility in Young Women with Breast Cancer

Opinion statementBreast cancer effects nearly 200,000 American women each year, with 9% of these women still in their childbearing years. For this subset of future survivors, the issue of fertility may be a significant quality-of-life concern. Both the causes and treatments for infertility in young breast cancer patients must be thoroughly understood by the multidisciplinary team caring for these women in order for the caregivers to be effective advocates for their patients. Radiation, cytotoxic chemotherapy, and hormonal therapy all effect ovarian function to greater or lesser degrees, with the incidence of permanent post-treatment amenorrhea following systemic treatment for breast cancer in women age 50 or younger estimated as between 33% and 76%. The science of fertility preservation continues to experience significant advances in terms of the success of oocyte, embryo, and ovarian tissue preservation, and it is crucial that physicians and patients are aware of the available fertility preservation options. The optimal time to address the possibility of treatment-related infertility and strategies to combat this with younger patients is prior to treatment, rather than after cancer therapy has begun, and a full knowledge of the available technologies is a prerequisite for an informed discussion. Causes of ovarian suppression and options for treatment, including consideration of preimplantation genetic diagnosis and alternative parenting approaches are also discussed to assist the clinician caring for young patients with cancer.

Phospho-specific Smad3 signaling: Impact on breast oncogenesis

Members of the TGFβ superfamily are known to exert a myriad of physiologic and pathologic growth controlling influences on mammary development and oncogenesis. In epithelial cells, TGFβ signaling inhibits cell growth through cytostatic and pro-apoptotic activities but can also induce cancer cell EMT and, thus, has a dichotomous role in breast cancer biology. Mechanisms governing this switch are the subject of active investigation. Smad3 is a critical intracellular mediator of TGFβ signaling regulated through phosphorylation by the TGFβ receptor complex at the C terminus. Smad3 is also a substrate for several other kinases that phosphorylate additional sites within the Smad protein. This discovery has expanded the understanding of the significance and complexity of TGFβ signaling through Smads. This review highlights recent advances revealing the critical role of phospho-specific Smad3 in malignancy and illustrates the potential prognostic and therapeutic impact of Smad3 phospho-isoforms in breast cancer.

Impact of Fertility Concerns on Tamoxifen Initiation and Persistence

BACKGROUND Adjuvant tamoxifen reduces breast cancer recurrence risk and mortality; however, initiation and treatment persistence are poor for younger patients. We hypothesized that a unique set of factors, including fertility concerns, would contribute to the poor tamoxifen use among premenopausal patients. METHODS From 2007 to 2012, 515 premenopausal patients younger than age 45 years, with stage 0 to III hormone receptor-positive breast cancer, for whom tamoxifen was recommended, were identified. Clinical and pathologic tumor characteristics, treatment regimens, and fertility concerns were recorded. Clinical factors associated with tamoxifen noninitiation and discontinuation were identified using univariate and multivariable analysis. After the recommendation for tamoxifen, patient reasons for tamoxifen noninitiation or discontinuation were also documented. All statistical tests were two-sided. RESULTS Based on multivariable analysis, fertility concerns were statistically associated with both noninitiation (odds ratio = 5.04, 95% confidence interval (CI) = 2.29 to 11.07) and early discontinuation (hazard ratio = 1.78, 95% CI = 1.09 to 3.38) of tamoxifen. Other independent predictors of noninitiation included a diagnosis of ductal carcinoma in situ, declining radiation, and not receiving chemotherapy (stage I-III). Additionally, smoking and not receiving radiation therapy were statistically significant predictors of early withdrawal from therapy. Primary patient reasons for noninitiation and early discontinuation included concerns about side effects and fertility. CONCLUSION This study provided insight into factors associated with tamoxifen use for reproductive-aged breast cancer survivors, with a new focus on fertility. Fertility concerns negatively impacted tamoxifen initiation and continuation among premenopausal patients. Interventions to optimize treatment initiation and persistence for young cancer patients should include access to fertility preservation options.

Using decision trees to enhance interdisciplinary team work: The case of oncofertility

PurposeOncofertility, an emerging discipline at the intersection of cancer and fertility, strives to give cancer patients options when they are confronting potential infertility as a consequence of cancer treatment. Fertility preservation decisions must be made before treatment begins, adding stress to the decision-making process.MethodsHealthcare providers need to be aware of the intricacies involved in oncofertility decision making, and the often tight time line that patients face when making these decisions. Cancer patient’s perspectives may also change, as the dual burden of a cancer diagnosis and potential infertility can cause great flux in emotions.ResultsA provider-facing decision tree was created to enhance patient decision-making capacities and outline the multiple potential intervention points.ConclusionsDecision trees, which highlight the important decision points during which providers can approach patients, can be a useful tool to help providers in counseling patients on fertility preservation.

Cyclin-Dependent Kinase 4–Mediated Phosphorylation Inhibits Smad3 Activity in Cyclin D–Overexpressing Breast Cancer Cells

Smad3, a component of the transforming growth factor β signaling cascade, contributes to G1 arrest in breast cancer cells. Cyclin D1/cyclin-dependent kinase 4 (CDK4) promotes G1-S–phase transition, and CDK phosphorylation of Smad3 has been associated with inhibition of Smad3 activity. We hypothesized that overexpression of cyclin D1 exerts tumorigenic effects in breast cancer cells through CDK4-mediated phosphorylation and inhibition of Smad3 and release of G1 arrest. Real-time quantitative reverse transcription-PCR and immunoblotting were used to evaluate expression of study proteins in cyclin D1–overexpressing breast cancer cells. Smad3 transcriptional activity and cell cycle control were examined in cells transfected with wild-type (WT) Smad3 or Smad3 with single or multiple CDK phosphorylation site mutations (M) in the presence or absence of the CDK4 inhibitor or cotransfection with cdk4 small interfering RNA (siRNA). Transfection of the Smad3 5M construct resulted in decreased c-myc and higher p15INK4B expression. Compared with WT Smad3, overexpression of the Smad3 T8, T178, 4M, or 5M mutant constructs resulted in higher Smad3 transcriptional activity. Compared with cells transfected with WT Smad3, Smad3 transcriptional activity was higher in cells overexpressing Smad3 mutant constructs and treated with the CDK4 inhibitor or transfected with cdk4 siRNA. Cells transfected with Smad3 T8 or T178 and treated with the CDK4 inhibitor showed an increase in the G1 cell population. Inhibition of CDK-mediated Smad3 phosphorylation released cyclin D1–regulated blockade of Smad3 transcriptional activity and recovered cell cycle arrest in breast cancer cells. Targeted inhibition of CDK4 activity may have a role in the treatment of cyclin D–overexpressing breast cancers. Mol Cancer Res; 8(10); 1375–87. ©2010 AACR.