Michaela L. Tsai

Periodontal Disease as a Risk Factor for Bisphosphonate-Related Osteonecrosis of the Jaw

BACKGROUND Previous case reports and animal studies suggest that periodontitis is associated with bisphosphonate-related osteonecrosis of the jaw (BRONJ). This case-control study is conducted to evaluate the association between clinical and radiographic measures of periodontal disease and BRONJ. METHODS Twenty-five patients with BRONJ were matched with 48 controls. Trained examiners measured probing depth, clinical attachment level (CAL), and bleeding on probing on all teeth except third molars and gingival and plaque indices on six index teeth. Alveolar bone height was measured from orthopantomograms. Most patients with BRONJ were using antibiotics (48%) or a chlorhexidine mouthrinse (84%) at enrollment. Adjusted comparisons of patients with BRONJ versus controls used multiple linear regression. RESULTS The average number of bisphosphonate (BP) infusions was significantly higher in patients with BRONJ compared with controls (38.4 versus 18.8, P = 0.0001). In unadjusted analyses, patients with BRONJ had more missing teeth (7.8 versus 3.1, P = 0.002) and higher average CAL (2.18 versus 1.56 mm, P = 0.047) and percentage of sites with CAL ≥3 mm (39.0 versus 23.3, P = 0.039) than controls. Also, patients with BRONJ had lower average bone height (as a fraction of tooth length, 0.59 versus 0.62, P = 0.004) and more teeth with bone height less than half of tooth length (20% versus 6%, P = 0.001). These differences remained significant after adjusting for age, sex, smoking, and number of BP infusions. CONCLUSIONS BRONJ patients have fewer teeth, greater CAL, and less alveolar bone support compared with controls after adjusting for number of BP infusions. Group differences in antibiotics and chlorhexidine rinse usage may have masked differences in the other clinical measures.

Breast and colorectal cancer survivors’ knowledge about their diagnosis and treatment

IntroductionAspects of a personal cancer history can have implications for future decisions regarding screening, diagnosis, and treatment. Clinicians must sometimes rely on patients’ self-report of their medical history. This study assessed knowledge of details of cancer diagnosis and treatment among breast and colorectal cancer survivors.MethodsWritten surveys were completed by 480 breast cancer survivors and 366 colorectal cancer survivors diagnosed between 1999 and 2008 at a large cancer center in the Minneapolis, MN, area (81% response rate). Responses were compared with cancer registry and medical records.ResultsForty percent of breast cancer survivors and 65% of colorectal cancer survivors were unable to identify their stage of disease. Seven percent of breast cancer survivors and 21% of colorectal cancer survivors in whom regional nodes were examined did not know whether they had positive nodes. Accuracy of knowledge of estrogen and progesterone status among breast cancer survivors was 58% and 39%, respectively. Of breast cancer survivors treated with doxorubicin, 43% correctly identified it as a drug they had received. Their accuracy of identification of receipt of tamoxifen or specific aromatase inhibitors was >90%. Of colorectal cancer survivors treated with oxaliplatin, 52% correctly identified it as a drug they had received. Accuracy on many items decreased with patient age.ConclusionsThis study identifies several gaps in adult cancer survivors’ knowledge of details of their diagnosis and treatment that have implications for follow-up care.Implications for cancer survivorsProvision of written treatment summaries to cancer survivors could help them obtain appropriate patient-centered long-term follow-up care.

Surgical Outcomes of Lobular Neoplasia Diagnosed in Core Biopsy: Prospective Study of 316 Cases

BACKGROUND Management recommendations for lobular neoplasia (LN) including lobular carcinoma-in-situ (LCIS) and atypical lobular hyperplasia (ALH) diagnosed in core biopsies (CB) are controversial. Our aim was to prospectively identify a subset of patients who do not require subsequent surgical excision (SE). PATIENTS AND METHODS All patients diagnosed with LN on CB were enrolled and referred for SE. Cases with coexistent ductal carcinoma-in-situ or invasive carcinoma were excluded. Cases with coexistent ductal atypia (LN-DA) and LCIS variants (LN-V) were separated from pure classic LN (LN-C). Dedicated breast pathologists and radiologists reviewed cases with careful imaging/pathology correlation. RESULTS Of 13,772 total percutaneous breast CB procedures, 302 of 370 patients diagnosed with LN underwent SE. Upgrade to carcinoma was present in 3.5% (8/228) LN-C, 26.7% LN-V (4/15), and 28.3% LN-DA (15/53). Calcifications were the imaging target for 180 (79%) of 228 LN-C cases; 7 were associated with upgrade (3.9%). Upgrades were rare for mass lesions (1/32) and magnetic resonance imaging-targeted lesions (0/14). Upgrades were similar for ALH and LCIS (3.4% vs. 4.5%). During postsurgical follow-up (mean, 34.5 months), 6.5% LN-C patients developed carcinoma in either breast. CONCLUSION Although LN with nonclassic morphology or with associated ductal atypia requires SE, this can be avoided in LN-C diagnosed on CB targeting calcifications when careful imaging/pathology correlation is applied. Until larger numbers are studied, excising LN-C diagnosed as masses or magnetic resonance imaging-detected lesions may be prudent. Regardless of their selection for surgical management, LN patients need close surveillance in view of their long-term risk of breast cancer.

Identification of tools to measure changes in musculoskeletal symptoms and physical functioning in women with breast cancer receiving aromatase inhibitors.

PURPOSE/OBJECTIVES To estimate and compare responsiveness of standardized self-reported measures of musculoskeletal symptoms (MSSs) and physical functioning (PF) during treatment with aromatase inhibitors (AIs). DESIGN Prospective, longitudinal study. SETTING Park Nicollet Institute and North Memorial Cancer Center, both in Minneapolis, MN. SAMPLE 122 postmenopausal women with hormone receptor-positive breast cancer. METHODS MSSs and PF were assessed before starting AIs and at one, three, and six months using six self-reported MSSs measures and two PF tests. MAIN RESEARCH VARIABLES MSSs and PF changes from baseline to six months. FINDINGS Using the Breast Cancer Prevention Trial-Musculoskeletal Symptom (BCPT-MS) subscale, 54% of participants reported MSSs by six months. Scores from the BCPT-MS subscale and the physical function subscales of the Australian/Canadian Osteoarthritis Hand Index (AUSCAN) and Western Ontario and McMaster Osteoarthritis Index (WOMAC) were most responsive to changes over six months. CONCLUSIONS BCPT-MS, AUSCAN, and WOMAC were the most responsive instruments for measuring AI-associated MSSs. IMPLICATIONS FOR NURSING Assessment and management of MSSs are important aspects of oncology care because MSSs can affect functional ability and AI adherence. KNOWLEDGE TRANSLATION The three measures with the greatest sensitivity were the BCPT-MS, AUSCAN, and WOMAC questionnaires. These measures will be useful when conducting research on change in MSSs associated with AI treatment in women with breast cancer.

Cancer rehabilitation: outcome evaluation of a strengthening and conditioning program.

Background: Cancer treatments can lead to detriments in patients’ health and declines in quality of life (QOL). Cancer rehabilitation programs may improve functional status, symptom control, and QOL. Objective: The objective of this study was to determine if an outpatient, physical therapy–supervised Cancer Rehabilitation Strengthening and Conditioning (CRSC) program improved patients’ conditioning level, functional status, QOL, and symptoms. Methods: This was a prospective study of oncology patients participating in CRSC program. Measurements included conditioning level (6-minute walk test [SMWT], metabolic equivalent level, grip strength), functional status (Physical Component Summary of Short Form 36), QOL (Mental Component Summary of Short Form 36), and symptoms (M. D. Anderson Symptom Inventory). Paired t tests were conducted to determine significant changes between pre- and post-CRSC program measures, and regression methods identified predictors of change from baseline. Results: One hundred fifteen patients with cancer were enrolled in the study; 75 patients completed pre- and post-CRSC program measures. Significant improvements were noted in SMWT by 186.4 ft, SMWT speed by 0.35 mph, treadmill time (3.5 minutes longer), metabolic equivalent level (by 0.87 units), QOL, symptom severity, symptom interference with daily life, fatigue, shortness of breath, and sadness. Conclusions: In a pretest-posttest design, significant improvements were noted in conditioning level, functional status, QOL, and symptoms. Greater improvements were noted in participants who were most deconditioned at baseline. Implications for Practice: Further research should be conducted to provide additional support for CRSC programs. Cancer rehabilitation strengthening and condition programs may benefit patients across the continuum of care, including deconditioned patients.

Serum Markers of Bone Turnover and Angiogenesis in Patients With Bisphosphonate-Related Osteonecrosis of the Jaw After Discontinuation of Long-Term Intravenous Bisphosphonate Therapy

PURPOSE To analyze serum markers of bone turnover, angiogenesis, endocrine function, and inflammation in patients with bisphosphonate-related osteonecrosis of the jaw (BRONJ) who discontinued long-term intravenous bisphosphonate (BP) therapy. PATIENTS AND METHODS Serum samples were obtained from 25 BRONJ patients who had discontinued long-term intravenous BP therapy for an average of 11.4 ± 8.7 months and 48 non-BRONJ controls who continued receiving intravenous BP therapy. Samples were analyzed for total alkaline phosphatase, bone-specific alkaline phosphatase, osteocalcin, C-telopeptide, vascular endothelial growth factor, triiodothyronine, thyroxine, thyroid-stimulating hormone, 25-hydroxyvitamin D, and C-reactive protein. RESULTS The mean number of BP infusions was significantly higher in BRONJ patients compared with controls (38.4 ± 26.3 infusions vs 18.8 ± 7.2 infusions, P < .0001); however, the duration of BP therapy was not significantly different between the groups (P = .23). Overall, there were no significant differences in any of the markers between BRONJ patients and controls (all P values ≥ .16). In a subgroup analysis that matched BRONJ patients and controls according to mean age and number of BP infusions (10 BRONJ patients and 48 controls), log10 vascular endothelial growth factor (2.9 ± 0.4 pg/mL vs 2.4 ± 0.4 pg/mL, P < .001) and C-reactive protein (34 ± 26 mg/L vs 13 ± 8 mg/L, P < .01) levels were significantly higher in BRONJ patients compared with controls. Within BRONJ patients, none of the serum markers were correlated with duration of BP discontinuation. CONCLUSIONS Levels of bone turnover and endocrine markers in BRONJ patients who discontinue long-term intravenous BP therapy are similar to those in non-BRONJ controls receiving intravenous BP therapy. However, levels of angiogenesis and inflammation markers are higher in BRONJ patients who discontinue long-term intravenous BP therapy. The prolonged skeletal half-life of BPs may suppress bone turnover markers in BRONJ patients for several years after discontinuation of intravenous BP therapy, suggesting an extended effect on bone homeostasis.

Salivary proteomics in bisphosphonate-related osteonecrosis of the jaw

OBJECTIVE The objective of this study was to identify differentially expressed salivary proteins in bisphosphonate-related osteonecrosis of the jaw (BRONJ) patients that could serve as biomarkers for BRONJ diagnosis. SUBJECTS AND METHODS Whole saliva obtained from 20 BRONJ patients and 20 controls were pooled within groups. The samples were analyzed using iTRAQ-labeled two-dimensional liquid chromatography-tandem mass spectrometry. RESULTS Overall, 1340 proteins were identified. Of these, biomarker candidates were selected based on P-value (<0.001), changes in protein expression (≥1.5-fold increase or decrease), and unique peptides identified (≥2). Three comparisons made between BRONJ and control patients identified 200 proteins to be differentially expressed in BRONJ patients. A majority of these proteins were predicted to have a role in drug metabolism and immunological and dermatological diseases. Of all the differentially expressed proteins, we selected metalloproteinase-9 and desmoplakin for further validation. Immunoassays confirmed increased expression of metalloproteinase-9 in individual saliva (P = 0.048) and serum samples (P = 0.05) of BRONJ patients. Desmoplakin was undetectable in saliva. However, desmoplakin levels tended to be lower in BRONJ serum than controls (P = 0.157). CONCLUSIONS Multiple pathological reactions are involved in BRONJ development. One or more proteins identified by this study may prove to be useful biomarkers for BRONJ diagnosis. The role of metalloproteinase-9 and desmoplakin in BRONJ requires further investigation.

Utility of Oncotype DX risk assessment in patients with invasive lobular carcinoma (ILC).

28 Background: Oncotype DX (Genomic Health, Redwood City, CA) is a breast cancer assay that uses reverse transcriptase polymerase chain reaction (RT-PCR) to measure gene expression in paraffin-embedded tumor tissue, which correlates with recurrence risk. This test is used to guide chemotherapy decisions in patients with estrogen receptor-positive breast cancer. Invasive lobular carcinoma (ILC) is a distinct histologic subtype, inherently estrogen receptor rich, that has not been the unique focus of prior studies validating Oncotype DX. The study purpose was to determine if there are certain features of ILC that predict uniformly low Oncotype DX Recurrence Scores (RS) such that Oncotype DX testing may be unnecessary, saving patients time and financial resources. METHODS A search was conducted of all ILC cases having Oncotype DX testing in our hospital pathology database. The Oncotype DX RS, histologic tumor characteristics (including subtype and grade), immunohistochemical (IHC) analyses of estrogen receptor (ER)/progesterone receptor (PR) percent (by image analysis), E-cadherin expression, and Ki-67 levels were obtained for each case. Discriminant analysis was used to test the hypothesis that tumors classified as low or high risk based on the Oncotype DX RS would differ significantly on a linear combination of selected variables. RESULTS From 2006 to 2013, 158 cases of ILC having Oncotype DX testing were identified; 90 low risk (RS <18), 66 intermediate risk (RS 18 - 30) and 2 high risk (RS > 30). Discriminant analysis showed that PR% followed by Ki-67 provided the greatest contribution to discriminating between low versus high RS. A subset of 57 cases (~ 36%) with predicted probabilities > 86% for either low or high RS yielded 96.5% correct classification, 92.3% sensitivity, and 97.7% specificity. CONCLUSIONS Our analytical model may be useful in predicting high versus low recurrence risk in some patients with ILC. If validated, this provides a faster and less expensive alternative to Oncotype DX testing in certain patients with ILC.

Clinicopathologic analysis of a large series of microinvasive breast cancers

Clinical management of microinvasive breast cancer (Tmic) remains controversial. Although metastases are infrequent in Tmic carcinoma patients, surgical treatment typically includes lymph node sampling. The objective of this study was to determine the rate and predictors of lymph node metastases, recurrence, and survival in a large series of Tmic breast carcinomas. Consecutive cases of Tmic were identified within our health care system from 2001 to 2015. We reviewed results of lymph node sampling and other pathologic factors including hormone receptor/HER2 status, associated in situ tumor size/grade, margin status, number of invasive foci, surgical/adjuvant therapies, and recurrence/survival outcomes. In this cohort, 294 Tmic cases were identified with mean follow‐up of 4.6 years. Of 260 patients who underwent axillary staging, lymph node metastases were identified in 1.5% (all of which were ductal type). All Tmic cases with positive lymph node metastases had associated DCIS with size > 5 cm (5.3‐8.5 cm) compared to a median DCIS tumor size of 2.5 cm (0.2‐19.0 cm) for the entire cohort. No lymph node metastases were seen with microinvasive lobular carcinoma. During the follow‐up period, there were no regional/distant recurrences or breast cancer‐associated deaths in a mean follow‐up period of 4.6 years. Two patients developed subsequent ipsilateral breast cancer (DCIS) in a different quadrant than the original Tmic. Clinical behavior of microinvasive breast cancer in this series is similar to DCIS. Lymph node metastases are uncommon and were only seen with ductal type microinvasive carcinoma. Our data suggest limited benefit for routine node sampling and support management of Tmic similar to DCIS, particularly for patients with DCIS < 5 cm in size.

Abstract A57: Evaluation of the pathologic predictors of treatment response to neoadjuvant chemotherapy for invasive lobular breast cancer

Introduction: Neoadjuvant chemotherapy (NAC) is becoming the standard of care for locally advanced breast cancer as a tool to objectively measure treatment response prior to surgery, and to downstage tumors to permit breast conserving surgery. Invasive lobular carcinoma (ILC) comprises approximately 10% of all invasive breast cancers, but is less likely than invasive ductal carcinoma to respond to NAC. The purpose of this study was to explore pathological and molecular predictors of response to NAC in patients with ILC. Study Methods: Retrospective pathology review was conducted of all consecutive cases of non-metastatic ILC patients who had received NAC and subsequent surgery for ILC (n=32) within the Allina Health system. Pre-treatment tumor size, grade, stage, HER2 status, hormone receptor status, sub-type, Ki-67 index, and post-treatment Residual Cancer Burden (RCB) were determined by breast pathologists. Mann-Whitney U and Chi-square tests with exact methods were used to test for between group difference of responders (RCB 0-1) versus non-responders (RCB 2-3) to NAC on continuous and dichotomous variables. Multivariate logistic regression was conducted to determine significant predictors of response to NAC. Findings: On univariate analysis, pleomorphic subtype (p=.004), Ki-67 (p=0.013), and HER2 status (p=.054) were significant predictors of response to NAC. On multivariate analysis, HER2 and Ki-67 provided the most efficient model for predicting response to NAC. This model correctly classified 81.3% of patients, 81.8% of RCB 0/1 and 80% of RCB 2/3. Pleomorphic subtype was highly correlated to KI-67. Conclusions: Despite a limited sample size, this study shows that pathologic predictors (pleomorphic subtype, Ki-67, and HER2 status) are significant predictors of response to NAC, and may be useful in determining which ILC patients will benefit from NAC. This is an important finding because NAC for non-responders may delay the initiation of surgery and hormonal treatments for ILC. Citation Format: Michaela L. Tsai, Marsha J. Finkelstein, Tamera J. Lillemoe, Barbara Susnik, Erin Grimm, Sung-Hae Kang, Caitlin Kelly, Karen K. Swenson. Evaluation of the pathologic predictors of treatment response to neoadjuvant chemotherapy for invasive lobular breast cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research; Oct 17-20, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(2_Suppl):Abstract nr A57.