Kathleen M. Diehl

Changes in surgical management resulting from case review at a breast cancer multidisciplinary tumor board.

The treatment of breast cancer requires a multidisciplinary approach, and patients are often referred to a multidisciplinary cancer clinic. The purpose of the current study was to evaluate the impact of this approach on the surgical management of breast cancer.

Clinicopathologic features of metastasis in nonsentinel lymph nodes of breast carcinoma patients: A metaanalysis

In breast carcinoma patients with a positive sentinel lymph node (SN), the value of complete axillary lymph node dissection has been questioned. Multiple published reports have attempted to identify clinicopathologic characteristics of the primary tumor and SN that are associated with an increased likelihood of positive nonsentinel lymph nodes (NSN). Because of differences in lymph node evaluation techniques and limited patient numbers in each study, the authors performed a meta‐analysis to assess the regularity and relative strength of association between various characteristics and the risk of NSN metastasis.

Inhibition of NF-κB activation and augmentation of IκBβ by secretory leukocyte protease inhibitor during lung inflammation

In earlier experiments, exogenous administration of secretory leukocyte protease inhibitor (SLPI) suppressed acute lung injury induced by deposition of IgG immune complexes. In the current studies we examined the mechanism of the protective effects of SLPI in this model. The presence of SLPI in the IgG immune complex-model of lung injury reduced the increase in extravascular leakage of 125I-albumin, the intensity of up-regulation of lung vascular intercellular adhesion molecule-1, and the numbers of neutrophils accumulating in the lung. The presence of SLPI caused greatly reduced activation (ie, nuclear translocation) of the transcription nuclear factor-κB (NF-κB) in lung cells but did not suppress activation of lung mitogen-activated protein kinase. SLPI did not alter NF-κB activation in alveolar macrophages harvested 30 minutes after initiation of lung inflammation. In the presence of SLPI, content of tumor necrosis factor-α, CXC chemokines, and C5a in bronchoalveolar fluids was unaffected. In the inflamed lungs, inhibition of NF-κB activation by SLPI was associated with elevated levels of lung IκBβ (but not IκBα) protein in the absence of elevated mRNA for IκBβ. When instilled into normal lung, SLPI also caused similar changes (increases) in lung IκBβ. Finally, in the lung inflammatory model used, the presence of anti-SLPI caused accentuated activation of NF-κB. These data confirm the anti-inflammatory effect of SLPI in lung and point to a mechanism of anti-inflammatory effects of SLPI. SLPI appears to function as an endogenous regulator of lung inflammation.

Sentinel Lymph Node Biopsy Performed After Neoadjuvant Chemotherapy is Accurate in Patients with Documented Node-Positive Breast Cancer at Presentation

BackgroundThe optimal strategy for incorporating lymphatic mapping and sentinel lymph node biopsy into the management of breast cancer patients receiving neoadjuvant chemotherapy remains controversial. Previous studies of sentinel node biopsy performed following neoadjuvant chemotherapy have largely reported on patients whose prechemotherapy, pathologic axillary nodal status was unknown. We report findings using a novel comprehensive approach to axillary management of node-positive-patients receiving neoadjuvant chemotherapy.MethodsWe evaluated 54 consecutive breast cancer patients with biopsy-proven axillary nodal metastases at the time of diagnosis that underwent lymphatic mapping with nodal biopsy as well as concomitant axillary lymph node dissection after receiving neoadjuvant chemotherapy. All cases were treated at a single comprehensive cancer center between 2001 and 2005.ResultsThe sentinel node identification rate after delivery of neoadjuvant chemotherapy was 98%. Thirty-six patients (66%) had residual axillary metastases (including eight patients that had undergone resection of metastatic sentinel nodes at the time of diagnosis), and in 12 cases (31%) the residual metastatic disease was limited to the sentinel lymph node. The final, post-neoadjuvant chemotherapy sentinel node was falsely negative in three cases (8.6%). The negative final sentinel node accurately identified patients with no residual axillary disease in 17 cases (32%).ConclusionsSentinel lymph node biopsy performed after the delivery of neoadjuvant chemotherapy in patients with documented nodal disease at presentation accurately identified cases that may have been downstaged to node-negative status and can spare this subset of patients (32%) from experiencing the morbidity of an axillary dissection.

Sentinel node biopsy prior to neoadjuvant chemotherapy

BACKGROUND Several studies have explored sentinel lymph node biopsy (SLNB) after neoadjuvant chemotherapy, but false negative rates and the loss of pretreatment nodal staging are limitations. Sentinel lymph node biopsy prior to induction chemotherapy may address both. METHODS Sentinel lymph node biopsy was performed in clinically node negative patients prior to initiating chemotherapy. Standard level I/II axillary lymph node dissection (ALND) was performed at the time of surgery in those patients who had metastases in the sentinel lymph node (SLN). RESULTS Twenty-five patients had 26 SLNB prior to the initiation of chemotherapy. The SLN was identified in all cases (100%). Twelve patients (48%) were found to be node negative and did not require axillary node dissection after chemotherapy. Of the patients who were SLN positive and underwent completion ALND, residual nodal disease was identified in 60%. There were no surgical complications or delay of chemotherapy. CONCLUSIONS Sentinel lymph node biopsy prior to neoadjuvant chemotherapy can avoid the morbidity of ALND without compromising the accuracy of axillary staging. It allows for identification of node positive patients subsequently rendered disease free in the regional nodes, which can assist in planning additional chemotherapy or radiation.

Reversal of the Estrogen Receptor–Negative Phenotype in Breast Cancer and Restoration of Antiestrogen Response

Purpose: In breast cancer, the presence of estrogen receptor α (ER) denotes a better prognosis and response to antiestrogen therapy. Lack of ERα correlates with overexpression of epidermal growth factor receptor or c-erbB-2. We have shown that hyperactivation of mitogen-activated protein kinase (MAPK) directly represses ERα expression in a reversible manner. In this study, we determine if inhibition of MAPK in established ERα− breast cancer cell lines and tumors results in reexpression of ERα, and further, if reexpression of ERα in these ERα− tumors and cell lines could restore antiestrogen responses. Experimental Design: Established ERα− breast cancer cell lines, ERα− breast tumors, and tumor cell cultures obtained from ERα− tumors were used in this study. Inhibition of hyperactive MAPK was accomplished via the MAPK/ERK kinase 1/2 inhibitor U0126 or via upstream inhibition with Iressa or Herceptin. Western blotting or reverse transcription-PCR for ERα was used to assess the reexpression of ERα in cells treated with U0126. Growth assays with WST-1 were done to assess restoration of antiestrogen sensitivity in these cells. Results: Inhibition of MAPK activity in ERα− breast cancer cell lines results in reexpression of ERα; upstream inhibition via targeting epidermal growth factor receptor or c-erbB-2 is equally effective. Importantly, this reexpressed ERα can now mediate an antiestrogen response in a subset of these ERα− breast cancer cell lines. Treatment of ERα− tumor specimens with MAPK inhibitors results in restoration of ERα mRNA, and similarly in epithelial cultures from ERα− tumors, MAPK inhibition restores both ERα protein and antiestrogen response. Conclusions: These data show both the possibility of restoring ERα expression and antiestrogen responses in ERα− breast cancer and suggest that there exist ERα− breast cancer patients who would benefit from a combined MAPK inhibition/hormonal therapy.

Assessing Dynamic Breast Cancer Screening Policies

Questions regarding the relative value and frequency of mammography screening for premenopausal women versus postmenopausal women remain open due to the conflicting age-based dynamics of both the disease (increasing incidence, decreasing aggression) and the accuracy of the test results (increasing sensitivity and specificity). To investigate these questions, we formulate a partially observed Markov chain model that captures several of these age-based dynamics not previously considered simultaneously. Using sample-path enumeration, we evaluate a broad range of policies to generate the set of “efficient” policies, as measured by a lifetime breast cancer mortality risk metric and an expected mammogram count, from which a patient may select a policy based on individual circumstance. We demonstrate robustness with respect to small changes in the input data and conclude that, in general, to efficiently achieve a lifetime risk comparable to the current risk among U.S. women, screening should start relatively early in life and continue relatively late in life regardless of the screening interval(s) adopted. The frontier also exhibits interesting patterns with respect to policy type, where policy type is defined by the relationship between the screening interval prescribed in younger years and that prescribed later in life.

Comprehensive Axillary Evaluation in Neoadjuvant Chemotherapy Patients With Ultrasonography and Sentinel Lymph Node Biopsy

BackgroundThere is ongoing debate regarding the optimal sequence of sentinel lymph node (SLN) biopsy and neoadjuvant chemotherapy (CTX) for breast cancer. We report the accuracy of comprehensive pre–neoadjuvant CTX and post–neoadjuvant CTX axillary staging via ultrasound imaging, fine-needle aspiration (FNA) biopsy, and SLN biopsy.MethodsFrom 2001 to 2004, 91 neoadjuvant CTX patients at the University of Michigan Comprehensive Cancer Center underwent axillary staging by ultrasonography, ultrasound-guided FNA biopsy, SLN biopsy, or a combination of these.ResultsAxillary staging was pathologically negative by pre–neoadjuvant CTX SLN biopsy in 53 cases (58%); these patients had no further axillary surgery. In 38 cases (42%), axillary metastases were confirmed at presentation by either ultrasound-guided FNA or SLN biopsy. These 38 patients underwent completion axillary lymph node dissection (ALND) after delivery of neoadjuvant CTX. Follow-up lymphatic mapping was attempted in 33 of these cases, and the SLN was identified in 32 (identification rate, 97%). One third of these cases were completely node negative on ALND. Residual metastatic disease was identified in 22 cases, and the SLN was falsely negative in 1 (4.5%).ConclusionsPatients receiving neoadjuvant CTX can have accurate axillary nodal staging by ultrasound-guided FNA or SLN biopsy. In cases of documented axillary metastasis at presentation, repeat axillary staging with SLN biopsy can document the post–neoadjuvant CTX nodal status. This strategy optimizes pre–neoadjuvant CTX and post–neoadjuvant CTX staging information by distinguishing the patients who are node negative at presentation from those who have been downstaged to node negativity and offers the potential for avoiding unnecessary ALNDs in both of these patient subsets.

Lymphatic mapping and sentinel lymph node biopsy for patients with local recurrence after breast-conservation therapy.

BackgroundLocal recurrence (LR) after breast-conservation therapy for breast cancer occurs in 10% to 15% of cases. A subset of these represents biologically aggressive disease, yet prognostic features for identifying this high-risk category are lacking. We hypothesized that lymphatic mapping and sentinel lymph node biopsy would provide useful information regarding dominant lymphatic drainage patterns of patients with LR.MethodsBreast cancer case records involving surgery for LR at the University of Michigan from 2002 to 2004 were reviewed. The lymphatic drainage patterns were compared with those of 117 patients who underwent mapping for primary breast cancer.ResultsFourteen LR cases were identified (10 with initial axillary lymph node dissection, 2 with initial sentinel lymph nodes, and 2 with no axillary surgery at the time of primary cancer treatment); lymphatic mapping was performed in 10. The sentinel lymph node identification rate was 90%, the median number of lymph nodes retrieved was 3, and no metastases were detected. Significantly more cases of nonipsilateral axillary sentinel node drainage were observed in mapping procedures performed for LR compared with those for primary breast cancer (67% vs. 15%; P = .001).ConclusionsLymphatic mapping is feasible in patients undergoing mastectomy for LR and is likely to identify aberrantly located sentinel lymph nodes that would otherwise be overlooked with a conventional completion mastectomy.

Clinicopathologic features associated with having four or more metastatic axillary nodes in breast cancer patients with a positive sentinel lymph node

BackgroundThe survival benefit of a completion axillary lymph node dissection (ALND) in patients after removal of a metastatic sentinel lymph node (SLN) is uncertain and is under study in ongoing clinical trials. The completion ALND remains necessary, however, for the identification of cases with at least four metastatic lymph nodes, in which extended-field locoregional and/or postmastectomy radiation will be recommended. Our goal was evaluate clinicopathologic features that might serve as surrogates for determining which patients with a positive SLN are likely or unlikely to belong to this high-risk subset.MethodsRecords were reviewed for 285 patients from 2 comprehensive cancer centers who underwent completion ALND after resection of a metastatic SLN from 1995 to 2002. Clinicopathologic features were analyzed by univariate and multivariate logistic regression. Forty-one cases (14%) were found to have at least four positive nodes after ALND.ResultsFisher’s exact test revealed the following features to be significantly (P < .05) associated with having four or more nodal metastases: tumor size >2 cm, lymphovascular invasion, an increasing ratio of positive SLNs to the total number of resected SLNs, extranodal extension, and the size of the SLN metastasis. Patients whose largest SLN metastasis was <2 mm had only a 1.4% risk of having four or more metastatic nodes (P < .0001).ConclusionsWe conclude that patients with SLN micrometastases face an extremely low likelihood of having extensive nodal disease on completion ALND. Patients with larger primary tumors, lymphovascular invasion, and extranodal extension are more likely to have ALND findings that will affect their cancer management.