Evaluation of the international Ki67 working group cut point recommendations for early breast cancer: comparison with 21-gene assay results in a large integrated health care system.

PURPOSE: The International Ki67 Working Group (IKWG) has developed training for immunohistochemistry (IHC) scoring reproducibility and recommends cut points of ≤ 5% and ≥ 30% for prognosis in ER+, HER2-, stage I/II breast cancer. We examined scoring reproducibility following IKWG training and evaluated these cut points for selecting patients for further testing with the 21-gene Recurrence Score (RS) assay. METHODS: We included 307 women aged 50+ years with node-negative, ER+PR+HER2- breast cancer and with available RS results. Slides from the diagnostic biopsy were stained for Ki67 and scored using digital image analysis (IA). Two IHC pathologists underwent IKWG training and visually scored slides, blinded to each other and IA readings. Interobserver reproducibility was examined using intraclass correlation (ICC) and Kappa statistics. RESULTS: Depending on reader, 8.8-16.0% of our cohort had Ki67 ≤ 5% and 11.4-22.5% had scores ≥ 30%. The ICC for Ki67 scores by the two pathologists was 0.82 (95% CI 0.78-0.85); it was 0.79 (95% CI 0.74-0.83) for pathologist 1 and IA and 0.76 (95% CI 0.71-0.80) for pathologist 2 and IA. For Ki67 scores ≤ 5%, the percentages with RS < 26 were 92.6%, 91.8%, and 90.9% for pathologist 1, pathologist 2, and IA, respectively. For Ki67 scores ≥ 30%, the percentages with RS ≥ 26 were 41.5%, 51.4%, and 27.5%, respectively. CONCLUSION: The IKWG's Ki67 training resulted in moderate to strong reproducibility across readers but cut points had only moderate overlap with RS cut points, especially for Ki67 ≥ 30% and RS ≥ 26; thus, their clinical utility for a 21-gene assay testing pathway remains unclear.

Evaluation of approaches to recruitment of racially and ethnically diverse breast cancer patients from an integrated health care setting for collection of observational social network data.

PURPOSE: We compared approaches to recruitment of diverse women with breast cancer in a study designed to collect complex social network data. METHODS: We recruited 440 women from the Kaiser Permanente Northern California population newly diagnosed with breast cancer, either in person at a clinic, by email, or by mailed letter. In clinic and mail recruitment, women completed a brief 3-page paper survey (epidemiologic data only), and women had the option to complete a separate, longer (30-40 min) personal social network survey online. In email recruitment, we administered epidemiologic and personal social network measures together in a single online survey. In email and mail recruitment, we limited the sample of non-Hispanic white (NHW) women to 30% of their total. We used descriptive analysis and multinomial logistic regression to examine odds of recruitment vs. mailed letter. RESULTS: Women responded to the social network surveys on average 3.7 months post-diagnosis. Mean age was 59.3 (median = 61.0). In-person clinic recruitment was superior with a 52.1% success rate of recruitment compared with 35.6% by mail or 17.3% by email (χ2 = 65.9, p < 0.001). Email recruitment produced the highest completion rate (82.1%) of personal network data compared with clinic (36.5%) or mail (28.7%), (χ2 = 114.6, p < 0.001). Despite intentional undersampling of NHW patients, response rates for Asian, Hispanic, and Black women by email were lower. However, we found no significant differences in recruitment rates by race and ethnicity for face-to-face clinic recruitment vs. by letter. Letter recruitment produced the highest overall response. CONCLUSION: Mailed letter was the best approach to representative recruitment of diverse women with breast cancer and collection of social network data, and further yielded the highest absolute response.

Germline Genetic Testing Among Women ≤ 45 Years of Age with Ductal Carcinoma In Situ Versus Invasive Breast Cancer in a Large Integrated Health Care System.

BACKGROUND: We compared the results of hereditary cancer multigene panel testing among patients ≤ 45 years of age diagnosed with ductal carcinoma in situ (DCIS) versus invasive breast cancer (IBC) in a large integrated health care system. METHODS: A retrospective cohort study of hereditary cancer gene testing among women ≤ 45 years of age diagnosed with DCIS or IBC at Kaiser Permanente Northern California between September 2019 and August 2020 was performed. During the study period, institutional guidelines recommended the above population be referred to genetic counselors for pretesting counseling and testing. RESULTS: A total of 61 DCIS and 485 IBC patients were identified. Genetic counselors met with 95% of both groups, and 86.4% of DCIS patients and 93.9% of IBC patients (p = 0.0339) underwent gene testing. Testing differed by race/ethnicity (p = 0.0372). Among those tested, 11.76% (n = 6) of DCIS patients and 16.71% (n = 72) of IBC patients had a pathogenic variant (PV) or likely pathogenic variant (LPV) based on the 36-gene panel (p = 0.3650). Similar trends were seen in 13 breast cancer (BC)-related genes (p = 0.0553). Family history of cancer was significantly associated with both BC-related and non-BC-related PVs in IBC, but not DCIS. CONCLUSION: In our study, 95% of patients were seen by a genetic counselor when age was used as an eligibility criterion for referral. While larger studies are needed to further compare the prevalence of PVs/LPVs among DCIS and IBC patients, our data suggest that even in younger patients, the prevalence of PVs/LPVs in BC-related genes is lower in DCIS patients.

Patients Older 65 Years With Early Breast Cancer Prefer Intraoperative Radiation as a Locoregional Treatment Choice.

BACKGROUND: Patients 65 years old or older with early endocrine-responsive breast cancer have many treatment options, including no radiation. This study aimed to evaluate treatment preference when intraoperative radiation therapy (IORT) is offered in this population. METHODS: The study reviewed patients 65 years old or older with a diagnosis of early-stage endocrine-responsive breast cancer in 2016-2019 at a single hospital in a large integrated health care system. Electronic medical records of multidisciplinary breast tumor board discussion, treatment options documented by the treatment team, and final treatment offered were reviewed. Variables including age at biopsy, language, endocrine treatment, and comorbidities were collected. Regression analysis was used to evaluate for variables associated with patients' choice regarding radiation treatment. RESULTS: The institutional IORT guidelines were met by 63 patients in the described age group who had a documented offer of all radiation treatment options. The median age of the patients was 70 years (interquartile range 63-77 years). Overall, 74.6% of the patients chose IORT, and 14.3% opted for whole-breast irradiation. Only 4.8% chose to omit radiation after breast-conserving surgery, and 6.3% chose mastectomy. The patients who chose IORT were more likely to receive endocrine treatment (odds ratio 3.70; p = 0.03). Age, race, language, and comorbidities were not associated with preference for IORT (p < 0.05). CONCLUSIONS: Patients 65 years old or older with early-stage endocrine-responsive breast cancer preferred to have IORT despite counsel about the lack of survival benefit. This study suggests that local cancer control with the convenient radiation delivery method is important to the described patient population.

Implementation of Intraoperative Ultrasound Localization for Breast-Conserving Surgery in a Large, Integrated Health Care System is Feasible and Effective.

BACKGROUND: Intraoperative ultrasound (IUS) localization for breast cancer is a noninvasive localization technique. In 2015, an IUS program for breast-conserving surgery (BCS) was initiated in a large, integrated health care system. This study evaluated the clinical results of IUS implementation. METHODS: The study identified breast cancer patients with BCS from 1 January to 31 October 2015 and from 1 January to 31 October 2019. Clinicopathologic characteristics were collected, and localization types were categorized. Clinical outcomes were analyzed, including localization use, surgeon adoption of IUS, day-of-surgery intervals, and re-excision rates. Multivariate logistic regression analysis was performed to evaluate predictors of re-excision. RESULTS: The number of BCS procedures increased 23%, from 1815 procedures in 2015 to 2226 procedures in 2019. The IUS rate increased from 4% of lumpectomies (n = 79) in 2015 to 28% of lumpectomies (n = 632) in 2019 (p < 0.001). Surgeons using IUS increased from 6% (5 of 88 surgeons) in 2015 to 70% (42 of 60 surgeons) in 2019. In 2019, 76% of IUS surgeons performed at least 25% of lumpectomies with IUS. The mean time from admission to incision was shorter with IUS or seed localization than with wire localization (202 min with IUS, 201 with seed localization, 262 with wire localization in 2019; p < 0.001). The IUS re-excision rates were lower than for other localization techniques (13.6%, vs 19.6% for seed localization and 24.7% for wire localization in 2019; p = 0.006), and IUS predicted lower re-excision rates in a multivariable model (odds ratio [OR], 0.59). CONCLUSIONS: In a high-volume integrated health system, IUS was adopted for BCS by a majority of surgeons. The use of IUS decreased the time from admission to incision compared with wire localization, and decreased re-excision rates compared with other localization techniques.

Adoption of Opioid-Sparing and Non-Opioid Regimens After Breast Surgery in a Large, Integrated Health Care Delivery System.

BACKGROUND: Postoperative prescriptions have contributed to the opioid epidemic. In response, a large, integrated health care delivery system implemented initiatives to reduce outpatient opioid prescriptions. We evaluated the impact of these interventions on opioid-prescribing practices after breast surgery. METHODS: We examined postoperative prescribing practices before and after the 2016-2018 intervention period. Primary endpoints were the use of non-opioid regimens (NORs) and morphine milligram equivalents (MMEs) prescribed for postoperative pain management, while secondary endpoints were emergency department (ED) visits and readmissions within 7 days of surgery. RESULTS: In a survey of breast surgeons, 23% reported using NORs in 2017 versus 79% in 2019 (p < 0.001). Comparing 1917 breast operations from 2016 with 2166 operations from 2019, NORs increased from 9% in 2016 to 39% in 2019 (p < 0.001). Average discharge MMEs per operation decreased from 190 in 2016 to 106 in 2019 (p < 0.001). NOR failure (defined as an additional opioid prescription within 2 weeks of surgery) was < 1%. Significantly fewer postoperative ED visits occurred in the NOR group (1.9% NOR vs. 3.4% opioid regimen [OR]; p < 0.001). The 7-day readmission rates for NOR and OR patients were similar (0.49% NOR vs. 0.32% OR; p = 0.45). CONCLUSION: Between 2016 and 2019, breast surgeons in a large, integrated health care delivery system adopted NORs for nearly 40% of breast operations, and prescribed significantly fewer MMEs, with no increases in ED visits or readmissions for NOR patients. This suggests that initiatives to decrease opioid prescribing were successful and that a NOR for pain management after breast surgery is feasible.

Implementation of a Post-mastectomy Home Recovery Program in a Large, Integrated Health Care Delivery System.

BACKGROUND: The number of outpatient mastectomies, with and without reconstruction, has increased nationwide. In well-selected patient populations, same-day surgery for mastectomy is a safe option. A pilot project was initiated within the Kaiser Permanente Northern California healthcare system to facilitate surgical home recovery (SHR) for mastectomy patients, including patients undergoing implant-based reconstruction and bilateral mastectomies. METHODS: Surgical home recovery for mastectomy patients was implemented in October 2017. Specific measures in this initiative included management of patient expectations at initial consultation, education about postoperative home care, multimodality pain management, and timely post-discharge follow-up. All patients undergoing mastectomy were included, except those undergoing autologous tissue reconstructions. After a 6-month implementation period, rate of same day discharge over 6 months was compared before and after the SHR initiative. We also compared emergency department (ED) visits, reoperations, and readmissions within 7 days. RESULTS: Twenty-one medical centers participated in this initiative. Before implementing SHR, 164 of the 717 (23%) mastectomies were outpatient procedures, compared with 403 of the 663 (61%) after the implementation period. Although the rate of outpatient mastectomy increased significantly, there were no statistically significant differences in ED visits (5.2% vs. 5.1%, p = 0.98), reoperation (3.5% vs. 3.5%, p = 0.99), or readmission rates (1.4% vs. 2.7%, p = 0.08). CONCLUSIONS: By implementing standard expectations and sharing best practices, there was a significant increase in the rate of home recovery for mastectomy without compromising quality of patient care. The success of this pilot program supports SHR for mastectomy.

Intraoperative Radiation Therapy: A Large Integrated Health Care System's Approach and Outcomes.

Introduction Intraoperative radiation therapy (IORT) may not be as effective in the community compared with clinical trials. Methods The authors reviewed data from the electronic health records of patients who received IORT between February 2014 and February 2020 at a single center within a large integrated health care system. The primary outcome was ipsilateral breast tumor recurrence. Results Of 5731 potentially eligible patients, 245 (4.3%) underwent IORT (mean age: 65.4 ± 0.4 years; median follow-up time: 3.5 years ± 2.2 months). According to the American Society for Radiation Oncology's accelerated partial breast irradiation guidelines based on final pathology, 51% of patients were suitable candidates for IORT, 38.4% were cautionary, and 10.6% were unsuitable. For adjuvant therapy, 6.5% had consolidative whole breast irradiation, and 66.4% received endocrine treatment. At the median follow-up time of 3.5 years, overall ipsilateral breast tumor recurrence was 3.7%. Recurrences tended to be more frequent in patients who refused or did not complete endocrine treatment than in those who received it (7.4% vs 1.9%, p = 0.07). The complication rate was 14.7%, with seroma being the most common (8.2%). Discussion The IORT ipsilateral breast tumor recurrence rate of 3.7% confirms a higher-than-expected rate compared to randomized clinical trials, possibly due to less compliance with endocrine therapy. Conclusion The authors subsequently revised their IORT protocol to require endocrine treatment as a part of the IORT treatment plan and to strongly recommend adjuvant whole breast irradiation for all patients deemed cautionary or unsuitable for IORT according to the American Society for Radiation Oncology's accelerated partial breast irradiation guidelines.

Outpatient Mastectomy: Factors Influencing Patient Selection and Predictors of Return to Care.

BACKGROUND: After implementation of the Surgical Home Recovery (SHR) initiative for mastectomy within a large, integrated health delivery system, most patients are discharged on the day of the procedure. We sought to identify predictors of SHR and unplanned return to care (RTC). STUDY DESIGN: Mastectomy cases with and without reconstruction from October 2017 to August 2019 were analyzed. Patient characteristics, operative variables, and multimodal pain management were compared between admitted patients and SHR patients using logistic regression. We identified predictors of RTC in SHR patients, defined as 7-day readmission, reoperation, or emergency department visit. RESULTS: Of 2,648 mastectomies, 1,689 (64%) were outpatient procedures and the mean age of patients was 58.5 years. Predictors of SHR included perioperative IV acetaminophen (odds ratio [OR] 1.59; 95% CI, 1.28 to 1.97), perioperative opiates (OR 1.47; 95% CI, 1.06 to 2.02), and operation performed by a high-volume breast surgeon (OR 2.12; 95% CI, 1.42 to 3.18). Bilateral mastectomies (OR 0.70; 95% CI, 0.54 to 0.91), immediate reconstruction (OR 0.52; 95% CI, 0.39 to 0.70), and American Society of Anesthesiologists class 3 to 4 (OR 0.69; 95% CI, 0.54 to 0.87) decreased the odds of SHR. Of SHR patients, 111 of 1,689 patients (7%) experienced RTC. Patients with American Society of Anesthesiologists class 3 to 4 (OR 2.01; 95% CI, 1.29 to 3.14) and African American race (OR 2.30; 95% CI, 1.38 to 4.91) were more likely to RTC; receiving IV acetaminophen (OR 0.56; 95% CI, 0.35 to 0.88) and filling an opiate prescription (OR 0.51; 95% CI, 0.34 to 0.77) decreased the odds of RTC. CONCLUSIONS: Surgeon volume and multimodal pain medication increased the odds of SHR. Within the SHR group, American Society of Anesthesiologists Class 3 to 4 and African American patients increased the likelihood of RTC. This study helps optimize patient selection and perioperative practice for successful SHR.

Pathologic and biologic response to preoperative endocrine therapy in patients with ER-positive ductal carcinoma in situ.

BACKGROUND: Endocrine therapy is commonly recommended in the adjuvant setting for patients as treatment for ductal carcinoma in situ (DCIS). However, it is unknown whether a neoadjuvant (preoperative) anti-estrogen approach to DCIS results in any biological change. This study was undertaken to investigate the pathologic and biomarker changes in DCIS following neoadjuvant endocrine therapy compared to a group of patients who did not undergo preoperative anti-estrogenic treatment to determine whether such treatment results in detectable histologic alterations. METHODS: Patients (n = 23) diagnosed with ER-positive pure DCIS by stereotactic core biopsy were enrolled in a trial of neoadjuvant anti-estrogen therapy followed by definitive excision. Patients on hormone replacement therapy, with palpable masses, or with histologic or clinical suspicion of invasion were excluded. Premenopausal women were treated with tamoxifen and postmenopausal women were treated with letrozole. Pathologic markers of proliferation, inflammation, and apoptosis were evaluated at baseline and at three months.Biomarker changes were compared to a cohort of patients who had not received preoperative treatment. RESULTS: Median age of the cohort was 53 years (range 38-78); 14 were premenopausal. Following treatment, predominant morphologic changes included increased multinucleated histiocytes and degenerated cells, decreased duct extension, and prominent periductal fibrosis. Two postmenopausal patients had ADH only with no residual DCIS at excision. Postmenopausal women on letrozole had significant reduction of PR, and Ki67 as well as increase in CD68-positive cells. For premenopausal women on tamoxifen treatment, the only significant change was increase in CD68. No change in cleaved caspase 3 was found. Two patients had invasive cancer at surgery. CONCLUSION: Preoperative therapy for DCIS is associated with significant pathologic alterations. These changes may be clinically significant. Further work is needed to identify which women may be the best candidates for such treatment for DCIS, and whether best responders may safely avoid surgical intervention. TRIAL REGISTRATION: ClinicalTrials.gov NCT00290745.

Utility of Human Epidermal Growth Factor Receptor 2 (HER2) Retesting of Histologic Grade 3 Invasive Breast Carcinomas.

BACKGROUND: American Society of Clinical Oncology and College of American Pathologists guidelines recommend repeated evaluation of human epidermal growth factor receptor 2 (HER2) status on surgical specimens from patients with a diagnosis by core-needle biopsy of Grade 3, HER2-negative invasive tumors of the breast. However, there are limited data to support reflexive testing. OBJECTIVE: To evaluate the utility of HER2 retesting of histologic Grade 3, HER2-negative invasive breast carcinomas. METHODS: We evaluated 78 patients from Kaiser Permanente East Bay in whom Grade 3, HER2-negative invasive breast carcinoma was diagnosed between 2015 and 2017 by core biopsy, to compare HER2 status on core biopsy vs excisional biopsy specimen. The HER2 status was determined by immunohistochemistry, fluorescent in situ hybridization, or both. All patients were retested for HER2 status on surgical specimen according to the aforementioned guidelines. Recipients of neoadjuvant chemotherapy were excluded. RESULTS: One of the 78 patients demonstrated negative-to-positive status discordance between core biopsy and surgical specimens and was treated with trastuzumab. One patient was HER2 negative by core biopsy and was HER2 equivocal by immunohistochemical and fluorescent in situ hybridization evaluation of the surgical specimen. Seventy-six patients demonstrated concordant HER2 status between core biopsy and surgical specimens. CONCLUSION: The rate of clinically significant HER2 status discordance between core biopsy and surgical specimens in patients with Grade 3 breast carcinoma is low. However, given the dramatically improved survival conferred by trastuzumab therapy, our findings support reflex HER2 testing of surgical specimens for patients with core biopsy-diagnosed HER2-negative breast carcinoma.

Rapid Implementation of Intraoperative Ultrasonography to Reduce Wire Localization in The Permanente Medical Group.

CONTEXT: Preoperative wire localization (WL), the most common localization technique for nonpalpable breast lesions, has drawbacks including scheduling constraints, cost, and patient discomfort. OBJECTIVE: To reduce WL use in our health care system, we investigated using hydrogel clips to facilitate intraoperative ultrasonography-guided lumpectomies. DESIGN: We retrospectively reviewed electronic medical records of patients with nonpalpable, ultrasound-visible breast lesions who underwent lumpectomy by 7 surgeons at 4 pilot sites in Kaiser Permanente Northern California between January 2015 and October 2015. Hydrogel clips, used for several years before the study period, were placed routinely during core-needle biopsy in all patients with nonpalpable, ultrasound-visible breast lesions. MAIN OUTCOME MEASURES: Localization method, lesion size, margin positivity, and receipt of neoadjuvant therapy. RESULTS: One hundred forty-three patients underwent hydrogel clip placement and lumpectomy by pilot-site surgeons. Localization consisted of intraoperative ultrasonography alone, preoperative skin marking, or WL. Of the 143 patients, 71.3% did not need WL (60.8% ultrasonography alone and 10.5% skin marking). The non-WL and WL groups had similarly sized lesions, and the positive margin rate was 7.2% overall, with no significant difference between the non-WL and WL groups (5.9% vs 11.5%, p = 0.33). Of the 12 patients who underwent neoadjuvant chemotherapy, 8 (67%) did not require WL. CONCLUSION: A multifacility protocol using intraoperative ultrasonography to visualize hydrogel clips was implemented, which decreased WL procedures and produced no significant difference in margin positivity between the WL and non-WL groups. This technique can be a cost-effective alternative to WL in patients who are candidates for hydrogel clip placement.

Experience with a Nonopioid Protocol in Ambulatory Breast Surgery: Opioids are Rarely Necessary and Use is Surgeon-Dependent.

CONTEXT: Surgeons write 1.8% of all prescriptions and 9.8% of all opioid prescriptions. Even small doses prescribed for short-term use can lead to abuse; thus, surgeons are uniquely able to combat the opioid epidemic by changing prescribing practices. As part of a department wide quality improvement project, we initiated a nonopioid protocol for all patients undergoing ambulatory breast surgery. OBJECTIVE: To determine the feasibility of a nonopioid protocol for patients undergoing ambulatory breast surgery and to determine if patient-related factors contribute to surgeon adherence to a nonopioid protocol in ambulatory breast surgery. DESIGN: Retrospective chart review of a prospectively collected database, with χ2 analysis and a multiple logistic regression model with the surgeon as the random effect. MAIN OUTCOME MEASURE: Protocol adherence. RESULTS: A total of 180 patients, with a median age of 63 years (range = 18-95 years), were included. Of these, 127 (70.6%) did not receive opioids; in this group there were 2 hematomas (1.6%), and 3 patients required an opioid prescription (2.4%). Fifty-three (29.4%) were prescribed opioids against protocol; in this group, there was 1 hematoma (1.9%). The operating surgeon was the only variable independently correlated with protocol adherence (p < 0.0001). Age, race/ethnicity, surgery type, and history of long-term opioid use were not. CONCLUSION: Ambulatory breast surgery patients tolerated a nonopioid pain regimen well. Surgeons' decisions, rather than patient characteristics, primarily drove the choice of pain management in our study. We believe our protocol can be improved with stricter implementation and education, which must be balanced with practitioner independence.

Estrogen receptor-negative breast cancer is less likely to arise among lipophilic statin users.

BACKGROUND: Preclinical studies have shown the anticancer potential of HMG-CoA reductase enzyme inhibitors (statins), whereas epidemiologic studies remain controversial. Because lipophilic statins show preclinical anticancer activity against hormone receptor [estrogen receptor (ER)/progesterone receptor (PR)]-negative breast cancer models, we explored the hormone receptor phenotype of breast cancers that arise in statin users. METHODS: We did a retrospective cohort analysis via electronic pharmacy records from the Kaiser Permanente Northern California Cancer Registry on 2,141 female patients listed in 2003 as incident cases of breast malignancy. Measures included tumor grade, stage, and receptor phenotype in statin users versus nonusers and controlled for hormone replacement therapy and race. RESULTS: 387 of the 2,141 breast cancer patients used lipophilic statins [lovastatin (85%), simvastatin, and atorvastatin]. Fifty-one women developed ER/PR-negative tumors. The age-adjusted odds ratio (OR) of developing an ER/PR negative tumor was 0.63 (95% confidence interval, 0.43-0.92; P = 0.02) for statin use >or=1 year before breast cancer diagnosis compared with statin use <1 year (including nonuse). Breast cancers in patients with >or=1 year of statin use were more likely to be low grade (OR, 1.44) and less invasive stage (OR, 1.42). CONCLUSIONS: Breast cancer patients with exposure to statins have proportionately fewer ER/PR-negative tumors that are of lower grade and stage. Although our data set cannot address whether statins affect the incidence of breast cancer, we show that statin use may influence the phenotype of tumors. This suggests a new potential strategy for breast cancer prevention, that of combining statins with agents that prevent ER-positive cancer (tamoxifen, aromatase inhibitors).

Menopausal hormone therapy and breast cancer phenotype: does dose matter?

BACKGROUND: Duration and type of menopausal hormone therapy (HT) has been associated with increased breast cancer risk and the development of estrogen receptor (ER)-positive tumors. The effect of HT dose on breast cancer tumor characteristics remains undefined. We sought to determine if HT dosing regimens influence breast cancer phenotype. METHODS: We conducted a retrospective review of incident female breast cancers occurring in the year 2003 listed in the Kaiser Permanente Northern California Cancer Registry. Type of HT, dose, number of tablets dispensed, tumor phenotype, stage, grade, and histology were obtained from electronic records for women aged >/=50 years who had more than 1 year of uninterrupted pharmacy data (n = 1701). A dose index of HT exposure was created and odds ratios were used to determine if tumor phenotype varied between exposure groups. These results were compared with a previously published analysis of HT duration on tumor phenotype conducted with the same dataset. RESULTS: The cumulative effect of estrogen and progesterone hormone therapy as calculated by factoring both dose and duration of HT use prior to breast cancer diagnosis did not reveal any new associations that were not previously identified by analysis of HT duration of exposure alone. Low-dose-index combination-HT users were less likely to have tumors with an ER-positive phenotype. An overall trend developed in which low- and high-dose-index exposed women had the lowest rates of ER- and progesterone receptor (PR) -positive tumors. CONCLUSION: Duration of use is an adequate surrogate for determining overall exposure to HT when considering the effect of HT on breast cancer phenotype.

Cyclooxygenase-2 expression is related to nuclear grade in ductal carcinoma in situ and is increased in its normal adjacent epithelium.

Cyclooxygenase-2 (COX-2) is emerging as an important cancer biomarker and is now an experimental target for solid tumor treatment.However, no study has exclusively focused on COX-2 expression in early lesions such as ductal carcinoma in situ (DCIS). We examined COX-2 expression by immunohistochemistry in 46 cases of women undergoing surgical resection for DCIS. We found that COX-2 expression was detected in 85% of all DCIS specimens, with increased COX-2 staining correlating with higher nuclear grade. Strikingly, COX-2 staining intensity in the normal adjacent epithelium was stronger than in the DCIS lesion itself. Our observations demonstrate that COX-2 is up-regulated in the normal adjacent epithelium and supports the hypothesis that the surrounding epithelial tissue is part of the disease process in DCIS.

Wine, liquor, beer and risk of breast cancer in a large population.

Population studies show a relation of alcohol drinking to an increased risk of breast cancer (BrCa). Aiming to investigate uncertainties about a risk threshold, the role of beverage type and interactions with other BrCa predictors, we performed a cohort study among 70,033 women, 2,829 of whom developed BrCa. Using Cox proportional hazards models with 8 covariates, the following relative risks (95% confidence intervals) for BrCa versus lifelong abstainers were found: 1.08 (0.95-1.22) at <1 drink per day, 1.21 (1.05-1.40, p=0.01) at 1-2 drinks daily and 1.38 (1.13-1.68, p=0.002) at > or = 3 drinks daily. Increased BrCa risk was concentrated in women with oestrogen receptor positive tumours with no major disparity related to choice of wine, liquor, beer or type of wine (red, white, etc). We conclude that with a threshold below 1-2 drinks daily, a hormone-related mechanism mediates a relation of alcohol drinking to an increased BrCa risk.

Type and duration of exogenous hormone use affects breast cancer histology.

BACKGROUND: It is unclear whether hormone replacement therapy (HRT), in addition to increasing risk for breast cancer, affects the type of breast cancer diagnosed. We conducted this investigation to assess whether the type of hormone used (none, estrogen, progesterone, or combined) and duration of use influences subsequent breast cancer histology. METHODS: We performed a retrospective cohort analysis among women listed as incident cases of breast malignancy in the Kaiser Permanente Northern California Cancer Registry during 2003 (n = 2830). Type and duration of hormone used (none, estrogen, progesterone, or combined) before breast cancer diagnosis was obtained from electronic pharmacy records. The association between type and duration of hormone use with characteristics of subsequent breast cancers was examined. RESULTS: Among women aged >50 years (n = 1701), any use of estrogen, progesterone, or combination therapy was not associated with an increased risk of estrogen receptor (ER)-positive disease. However, >6 months' use of combined HRT increased the odds of ER-positive tumors (odds ratio, 1.65; 95% confidence interval, 1.07-2.5; P = .02). Estrogen HRT patients were more likely than nonusers to present with low-grade (P = .05), and early-stage tumors (P = .03). This trend was not seen in combined HRT users. CONCLUSIONS: Short-duration HRT did not increase the likelihood of ER-positive breast cancer. However, prolonged duration of combined HRT, but not estrogen or progesterone alone, resulted in a marked increase in ER-positive disease. Our findings suggest that the effect of combined HRT on breast cancer incidence or progression is not immediate and that long-term use is more likely to affect breast cancer histology.