Evolving indications and long-term oncological outcomes of risk-reducing bilateral nipple-sparing mastectomy.

Background: Bilateral nipple-sparing mastectomy (NSM) is a technically feasible operation and is associated with excellent cosmetic outcomes. The aim of this study was to evaluate trends in patient characteristics, indications for surgery and long-term outcomes of bilateral NSM for breast cancer risk reduction over time. Methods: A review of a single-centre experience with bilateral NSM performed between 2001 and 2017 for breast cancer risk reduction in patients without breast cancer was performed. Trends in patient characteristics and indications for surgery were evaluated over four time intervals: 2001-2005, 2006-2009, 2010-2013 and 2014-2017. Statistical analysis was performed using χ2 tests. Results: Over the study period, 272 NSMs were performed in 136 patients; their median age was 41 years. The number of bilateral NSMs performed increased over time. The most common indication was a mutation in breast cancer-associated genes (104 patients, 76·5 per cent), which included BRCA1 (62 patients), BRCA2 (35), PTEN (2), TP53 (3) and ATM (2). Other indications were family history of breast cancer (19 patients, 14·0 per cent), lobular carcinoma in situ (10, 7·4 per cent) and a history of mantle irradiation (3, 2·2 per cent). The proportion of patients having a bilateral NSM for mutation in a breast cancer-associated gene increased over time (2001-2005: 2 of 12; 2006-2009: 9 of 17; 2010-2013: 34 of 41; 2014-2017: 61 of 66; P < 0·001). Mean follow-up was 53 months; no breast cancers were found during follow-up. Conclusion: The use of bilateral NSM for breast cancer risk reduction is increasing and the indications have evolved over the past 16 years. These excellent long-term oncological results suggest that bilateral NSM is a good option for surgical breast cancer risk reduction.

Effect of tamoxifen on preneoplastic cell proliferation in N-nitroso-N-methylurea-induced mammary carcinogenesis.

N-Nitroso-N-methylurea (NMU) is an effective carcinogen for the induction of mammary carcinoma in the rat. Tamoxifen (TAM), used as a chemopreventive agent to reduce tumor incidence, has been well studied using this model. We have utilized the rat mammary carcinoma model to assess the effect of TAM on preneoplastic changes. Fifty-day-old virgin female Sprague-Dawley rats were randomized by weight and divided into the following five groups: Group 1, normal controls (n = 24); Group 2, TAM (n = 20); Group 3, NMU-short term (n = 24); Group 4, NMU-short term + TAM (n = 26); and Group 5, NMU-long term (n = 23). Seven weeks after the exposure to NMU, rats in Groups 1, 2, 3, and 4 were given injections of [3H]thymidine and sacrificed 4 h later for autoradiographic determination of thymidine labeling index (TLI). The rats from Group 5 were observed for 30 weeks after NMU exposure to confirm mammary tumor development. TLI in both terminal ducts and terminal end buds was modulated by treatment with TAM. Carcinogen administration induced higher TLI relative to the normal controls [18.3 +/- 1.8% (SD) versus 15.5 +/- 2.1%, P less than 0.001] in terminal end buds. The effect of carcinogen on TLI was also apparent in the terminal ducts (15.8 +/- 1.1% versus 9.5 +/- 1.1%, P less than 0.001). TAM administration was able to suppress both constitutive and NMU-induced TLI increases in terminal end buds (15.5 +/- 2.1% versus 2.8 +/- 1.1% and 18.3 +/- 1.8% versus 6.8 +/- 1.4%, respectively, P less than 0.001). Similar effects were observed in terminal ducts. In addition to its antiproliferative effect on nontransformed mammary tissue, TAM was effective in suppressing NMU-induced mammary tumor incidence and frequency. NMU-induced hyperproliferation is an intermediate stage in NMU carcinogenesis in the rat and is suppressed by TAM. Mammary epithelial hyperproliferation may provide a useful quantitative intermediate end point to evaluate chemopreventive efficacy.

Asymptomatic giant cell arteritis.

A 71-year-old asymptomatic man was investigated because of anemia and an elevated erythrocyte sedimentation rate. Temporal artery biopsy showed that he had active giant cell arteritis. To our knowledge, this is the first report of giant cell arteritis in an asymptomatic patient. Giant cell arteritis may remain undiagnosed during life in many cases and may be an important cause of unexplained anemia in the elderly.

Does 40 mg omeprazole daily offer additional benefit over 20 mg daily in patients requiring more than 4 weeks of treatment for symptomatic reflux oesophagitis?

This study was designed to establish whether 40 mg omeprazole once daily exhibits sufficient additional efficacy over that of 20 mg omeprazole once daily in patients with symptomatic reflux oesophagitis requiring more than an initial 4-week course of 20 mg omeprazole once daily (o.m.) to warrant routine use of the higher dose. Three hundred and thirteen patients were randomized to receive either 20 mg omeprazole (4 weeks) then 20 mg (second 4 weeks if not both healed and symptom-free after 4 weeks), or 20 mg omeprazole (4 weeks) then 40 mg omeprazole o.m. (second 4 weeks). One hundred and twenty-seven patients were healed and symptom-free after 4 weeks and left the study at that point. Taking the second treatment period in isolation, the healing rate (64% vs. 45%, P < 0.02) and relief of heartburn (72% vs. 60%, P < 0.002) were greater among patients receiving 40 mg omeprazole o.m., demonstrating the existence of a dose-response relationship for omeprazole. However, on completion, there were no significant differences between the patients randomized to the 20/20 mg (healed 65%, asymptomatic 69%) or the 20/40 mg (healed 74%, asymptomatic 74%: both not significant differences compared with 20/20 mg) regimens. The magnitude of the difference in efficacy between 20 and 40 mg omeprazole in symptomatic reflux oesophagitis is insufficient to warrant the routine use of 40 mg in patients requiring more than 4 weeks' treatment with 20 mg omeprazole o.m.; continued treatment with 20 mg omeprazole for 4-8 weeks is the preferred option.

Symptom relief and duodenal ulcer healing with omeprazole or cimetidine. Opus (Omeprazole Peptic Ulcer Study) Research Group.

In a double-blind parallel-group study, 98 patients with symptomatic duodenal ulcer received omeprazole 20 mg o.m. and 91 cimetidine 800 mg nocte for 2 or, if then not healed, 4 weeks. After 2 weeks the healing rates on an intention-to-treat basis were: for omeprazole 62% and for cimetidine 33% (P less than 0.001), and at 4 weeks 85% and 61%, respectively (P less than 0.001). The proportions symptom-free at 2 weeks were 83% of the omeprazole and 63% of the cimetidine-group (P less than 0.01) and at 4 weeks 84% and 72% (P = 0.01). Patients receiving omeprazole took fewer antacid tablets than those receiving cimetidine. Patient tolerance of both drugs was similar and good. In the treatment of duodenal ulcer, omeprazole 20 mg o.m. gives faster symptom relief than cimetidine 800 mg nocte, as well as healing a greater proportion of ulcers within 2 and 4 weeks.

Maintenance of remission of ulcerative colitis: a comparison between balsalazide 3 g daily and mesalazine 1.2 g daily over 12 months. ABACUS Investigator group.

BACKGROUND: Despite widespread use of aminosalicylates as maintenance treatment for ulcerative colitis (UC), patients still report troublesome symptoms, often nocturnally. AIM: To compare the efficacy and safety of balsalazide (Colazide) with mesalazine (Asacol) in maintaining UC remission. METHODS: A randomized, double-blind comparison of balsalazide 3 g daily (1.04 g 5-ASA) and mesalazine 1.2 g daily for 12 months, in 99 (95 evaluable) patients in UC remission. RESULTS: Balsalazide patients experienced more asymptomatic nights (90% vs. 77%, P=0.0011) and days (58% vs. 50%, N.S.) during the first 3 months. Balsalazide patients experienced more symptom-free nights per week (6.4+/-1.7 vs. 4.7+/-2.8; P=0.0006) and fewer nights per week with blood on their stools or on the toilet paper, mucus with their stools or with sleep disturbance resulting from symptoms or lavatory visits (each P < 0.05). Fewer balsalazide patients relapsed within 3 months (10% vs. 28%; P=0.0354). Remission at 12 months was 58%, in both groups. Similar proportions of patients reported adverse events (61% balsalazide vs. 65% mesalazine). There were five serious adverse events (two balsalazide, three mesalazine) and four withdrawals due to unacceptable adverse events (three balsalazide, one mesalazine), of which one in each group was also a serious adverse event. CONCLUSIONS: Balsalazide 3 g/day and mesalazine 1.2 g/ day effectively maintain UC remission and are equally well tolerated over 12 months. At this dose balsalazide prevents more relapses during the first 3 months of treatment and controls nocturnal symptoms more effectively.

Breast cancer survival and perioperative blood transfusion.

The effect of perioperative blood transfusion on disease-free and overall survival was studied in 812 patients with stages I and II breast cancer, followed up prospectively in a multicenter study. All patients initially underwent a modified radical mastectomy. Patients with axillary node-negative, stage I cancer were followed up without additional therapy. Patients with axillary node-positive, stage II cancer were randomized to receive adjuvant chemoendocrine therapy. Transfusion was done in 35.8% of the patients with stage I and in 37.3% of the patients with stage II cancer. For the patients with stage II cancer, perioperative blood transfusion did not affect disease-free or overall survival. For the patients with stage I cancer, perioperative blood transfusion resulted in a worse disease-free and overall survival (p = 0.05 and 0.02, respectively), which was particularly evident for those patients who received more than 1 unit. This study suggests that stage of disease, adjuvant therapy, number of transfusions, and duration of follow-up must be considered in further analyses.

The interaction of estrogen receptor status and race in predicting prognosis for stage I breast cancer patients.

As part of a multi-institutional breast cancer data base, 501 stage I, node negative patients have been followed prospectively with a median of 89 months. Patients were treated by a modified radical mastectomy without postoperative therapy. Estrogen receptor (ER) content of the primary tumor was determined in all cases. For the entire patient group at 10 years, the disease-free survival (DFS) rate is 72% and the overall survival (OS) rate is 85%. Both ER value and race (black versus white) were found to be significant prognostic variables for DFS (p = 0.008 and 0.02, respectively) and for OS (p = 0.0001 and 0.01, respectively). ER positive patients had a better DFS and OS rate compared with ER negative patients (74% versus 66% and 90% versus 68%, respectively). Black patients had significantly worse DFS and OS rates compared with white patients (64% versus 74% and 75% versus 86%, respectively). Statistical interaction between the ER and race variables was apparent when comparing the similar DFS for ER positive white (75%), ER negative white (72%), and ER positive black (73%) patients in contrast to a DFS of less than 42% at 10 years for the ER negative black patients. An analysis of the data for the ER negative black patients suggested that the postmenopausal ER negative black patients are at particularly high risk of recurrence and death from breast cancer.

Recurrence patterns in a prospective study of patients with stage II breast cancer treated with endocrine-chemotherapy.

Local-regional versus distant recurrence patterns were investigated for 311 patients with stage II node-positive breast cancer who were part of an endocrine-chemotherapy adjuvant breast cancer trial. After mastectomy patients were randomized to receive either cytoxan, methotrexate, and 5-fluorouracil (CMF) (1 year) or CMF with tamoxifen (1 year) with or without bacillus Calmette-Guérin (BCG). With a median follow-up of 92.1 months, 55.3% of the patients had recurrences. The first site of recurrence was local-regional for 31.4% of patients and distant for 68.6%. This pattern of first recurrence was not associated with treatment groups, menopausal status, race, estrogen receptor value, number of positive lymph nodes, or tumour diameter. Although patients with a first local-regional recurrence had a better overall prognosis compared with those with a first distant recurrence, 52.2% of those patients with an initial local-regional recurrence developed a distant recurrence within 12 months. Among patients who had a recurrence, 48.3% had a local-regional recurrence at some time during their follow-up. Conclusions from this study are (1) patterns of recurrence were not affected by the addition of antiestrogen therapy to chemotherapy; (2) for the variables tested, including number of positive nodes and tumor diameter, no association with recurrence patterns was found; and (3) most patients (52.2%) with a first local-regional recurrence will develop a distant recurrence within 1 year.

Short-term tamoxifen plus chemotherapy: superior results in node-positive breast cancer.

Three hundred eleven patients with node-positive breast cancer were randomized to one of three adjuvant treatments: cyclophosphamide (Cytoxan), methotrexate, and 5-fluorouracil; all of the above with tamoxifen citrate; or all of the above with tamoxifen and bacillus Calmette-Guerin vaccination. Local therapy for all patients was a modified radical mastectomy. Estrogen receptors were measured on all primary tumors. Patients were stratified by the number of positive nodes (one to three nodes and more than three nodes) and estrogen-receptor value (less than 3 femtomole/mg and greater than or equal to 3 femtomole/mg). Follow-up is available, with a mean of 9.1 and maximum of 14.2 years. In this study the efficacy of short-term tamoxifen is apparent over that of chemoimmunotherapy alone and continues to be significant with prolonged follow-up. The addition of tamoxifen to chemoimmunotherapy significantly prolonged disease-free survival among patients with estrogen receptor-positive tumors who were postmenopausal, who had larger tumors (greater than 3 cm), or who had more extensive axillary node involvement (more than three nodes). Tamoxifen improved overall survival for patients with estrogen receptor-positive tumors larger than 3 cm. The addition of bacillus Calmette-Guerin Cytoxan, methotrexate, 5-fluorouracil, and tamoxifen did not significantly alter disease-free or overall survival.

Antiestrogen-cytotoxic chemotherapy and bacillus Calmette-Guerin vaccination in stage II breast cancer: seventy-two-month follow-up.

A prospective, randomized clinical trial of adjuvant treatment of 312 stage II breast cancer patients with use of chemotherapy, antiestrogen therapy, and immunotherapy is reported after 72 months of follow-up. The stratification of patients was based on nodal involvement and estrogen receptor (ER) assay of the primary tumors. Findings at 72 months indicate that antiestrogen therapy (tamoxifen, Nolvadex) added to chemotherapy with cyclophosphamide (Cytoxan), methotrexate, and fluorouracil (5-Fluorouracil) (CMF) resulted in significant delayed recurrence in ER-positive postmenopausal patients, ER-positive patients with four or more positive nodes, and ER-positive patients with tumors greater than 3 cm in diameter. The addition of nonspecific immunotherapy with bacillus Calmette-Guerin had no effect on disease-free survival. ER and progesterone receptor measurements in patients with primary breast cancer provide valuable prognostic information on subsequent recurrence and overall survival and should be documented in future clinical trials.

Inflammatory breast cancer.

Historically, the prognosis of inflammatory breast cancer has been poor. We conducted a retrospective review to evaluate the recent Memorial Sloan-Kettering Cancer Center experience, to evaluate the role of combination chemotherapy, and to compare the effect of surgery and radiation on local/regional failure. Fifty-six patients with local/regional inflammatory breast cancer diagnosed between 1975 and 1984 were identified. All were treated with combination chemotherapy. Overall 5-year survival was 45% with a 5-year disease-free survival rate of 37%. Twenty-one patients were treated with induction chemotherapy followed by mastectomy and adjuvant chemotherapy. Survival and disease-free survival rates were similar to those achieved in patients treated with mastectomy followed by chemotherapy. Residual cancer was found in all 21 patients treated with induction chemotherapy, with extensive disease present in 18, including six of seven complete responders. The local/regional failure rate was 34%.

Not all nonpalpable breast cancers are alike.

Clinical and mammographic data of 1009 consecutive patients were correlated with histopathologic data of 1144 biopsy specimens of nonpalpable breast lesions to better define the presentation and biologic behavior of early breast cancer. Patients with malignant neoplasms (269 [24%] of 1144 specimens) were older (mean age, 62.1 years) than patients with benign lesions (mean age, 54.9 years). Furthermore, patients with invasive disease were older (mean age, 63.3 years) than patients with noninvasive disease (mean age, 58.5 years) with an overall increased risk of invasive cancer per year of 1.035. A 58% incidence of invasive cancer was detected for lesions characterized by calcifications, while the incidence of invasive cancer was 84% for isolated mass lesions (relative risk, 4.31 for masses). Isolated mammographic calcifications associated with cancer appeared in a younger population and were significantly associated with noninvasive ductal cancer. Breast cancer presenting as a mammographic mass appeared in an older group and was highly associated with the presence of invasive disease.

Primary tumor size. Relevance to breast cancer survival.

In view of current emphasis on identifying prognostic factors for patients with early breast cancer, we studied the importance of tumor size to survival among 1392 patients with primary operable breast cancer who were followed up prospectively. All patients had modified radical mastectomies. Nine hundred seventeen patients had negative nodes and did not receive postoperative adjuvant therapy. Four hundred seventy-five patients had node involvement and received combination chemoendocrine therapy. In a Cox's proportional hazards model, tumor size was a significant predictor of disease-free and overall survival when the number of positive nodes, estrogen receptor status, menopausal status, and race were considered. Among the node-negative group, tumor size explained considerable variation in disease-free and overall survival, varying from a 10-year disease-free and overall survival of 80% and 99% for patients with estrogen receptor-positive tumors measuring 1 cm or less to a 10-year disease-free and overall survival of 51% and 59% for patients with tumors larger than 5 cm.

Local-regional breast cancer recurrence following mastectomy.

Local-regional recurrence patterns were investigated in 1392 patients with breast cancer. Primary treatment for all patients included a mastectomy. Nine hundred seventeen patients had negative nodes and did not receive systemic therapy. Four hundred seventy-five patients had node metastases and were randomized to receive different combinations of chemoendocrine therapy. Follow-up ranged between 5 and 16 years. Two hundred thirty (25.8%) node-negative patients have had recurrences, with the initial recurrence being local-regional in 9.2%. Two hundred forty-two (50.9%) node-positive patients have had recurrences, with the initial recurrence being local-regional in 17.1%. Larger tumors and more extensive node involvement were associated with more first local-regional recurrences. The relative percent of first local-regional recurrence among patients in whom cancer recurred was similar for node-negative and node-positive patients (35.4% and 33.5%, respectively). In 63.6% of patients in whom cancer recurred, first local-regional recurrence were distant. Larger tumors, more extensive node involvement, and a shorter disease-free interval after mastectomy were associated with more rapid appearance of distant recurrence among these patients.

Age does not predict breast cancer outcome.

OBJECTIVE: To determine whether age is a prognostic factor of breast cancer and should be used to make treatment recommendations, because younger patients are considered to have a poorer prognosis compared with that of older patients and, thus, often receive more aggressive therapy. DESIGN: A large group of patients with operable breast cancer, all of whom were followed up prospectively as part of two multicenter trials. SETTING: Case Western Reserve University, Cleveland, Ohio, was the primary hospital and study center, with 12 participating regional institutions. PATIENTS: All 1353 patients underwent uniform local-regional therapy that consisted of a modified radical mastectomy. Patients who were node negative were followed up, and patients who were node positive received systemic chemoendocrine therapy. MAIN OUTCOME MEASURES: Patients were followed up at regular intervals for either recurrence or death. RESULTS: Patients ranged in age from 22 to 75 years with a median age of 56 years. Younger patients had more estrogen receptor-negative tumors (P < .0001) and a greater number of positive lymph nodes (P < .0001). Of the 241 black patients in the study, a greater percentage were younger compared with white patients (P < .0001). Age was considered in a Cox's multivariate model, together with nodes, tumor diameter, estrogen receptor content, and race. Age was not a significant predictor of either disease-free (P = .33) or overall (P = .30) survival. Using mixture models with covariates, the estimated average hazards (where lambda indicates the force of mortality) of breast cancer deaths per year were similar (P, not significant) for patients 45 years old or younger (lambda = 0.061), older than 45 years but 65 years old or younger (lambda = 0.052), and older than 65 years (lambda = 0.061). CONCLUSIONS: In conclusion, younger patients as a group have more aggressive and advanced breast cancer at presentation compared with older patients. Considered in a multivariate model, together with other variables, age does not provide independent prognostic information and should not be used alone for management decisions.

Predicting the likelihood of residual disease in women treated for ductal carcinoma in situ.

BACKGROUND: To identify women at risk for residual disease after excision of ductal carcinoma in situ (DCIS), we assessed the relationship between characteristics of the initial biopsy and the presence of residual DCIS at a subsequent operation. STUDY DESIGN: We identified 134 consecutive "paired" operations from 112 women who had undergone 2 or more operations for DCIS between February 1995 and December 1996. Cancer status of the margins, patient age and leading presentation, tumor subtype and grade, and the presence of multifocal-extensive disease were assessed as potential predictors. RESULTS: Residual DCIS was found in 60 patients (45%): in 2 of 12 patients (17%) with negative margins, in 11 of 36 (31%) with close margins (< 2 mm), in 30 of 52 (58%) with positive margins, and in 17 of 34 patients (50%) with margins of unknown status. Patients with positive or unknown margins were 7.7 and 8.3 times, respectively, more likely to have residual disease than patients with negative margins (95% CI 1.1-59.1; 1.1-66.4). Patients with clinical presentations were 8.0 times more likely to have residual disease than patients who presented with abnormal mammograms (95% CI 2.3-27.6). Multifocal-extensive DCIS was associated with residual disease (adjusted odds ratio [OR] = 7.7, 95% CI 2.9-20.5), as was comedo subtype (OR = 2.7, 95% CI 1.1-6.7). CONCLUSIONS: Positive or unknown biopsy margins, a clinical presentation, multifocal-extensive cancer, and the comedo subtype are associated with higher risk of residual DCIS.

Hormone receptors. An update and application.

The introduction of measurements of hormone receptors in breast cancer tumor specimens provides a major advance in selection of patients likely to have hormone-dependent cancers. Endocrine adjuvant treatment for estrogen-positive breast cancers in both pre- and postmenopausal women has been shown to be effective in delaying recurrence. Whenever possible, estrogen and progesterone receptors should be measured in tumor tissue from all patients with breast cancer.

Breast cancer evaluation and follow-up: a survey of The Ohio Chapter of The American College of Surgeons.

Preoperative evaluation and postoperative follow-up of breast cancer patients vary considerably. Recent literature suggests that routine surveillance studies for breast cancer patients can be reduced without compromising the outcome. The Ohio State Chapter of The American College of Surgeons Committee on Cancer sponsored a survey of its general surgeon fellows to determine their practice philosophies regarding these issues. The questions centered around breast cancer screening, evaluation and treatment, and follow-up. The fellows were also questioned as to their opinions regarding practice parameters and whether the State Chapter should take a role in this area. Of the 764 surveys sent out, 34.2% were appropriate for evaluation. For breast cancer screening, 96.1% believe yearly mammography is important. Newly diagnosed breast cancer patients are generally evaluated with history and physical exam, chest X-ray, complete blood cell count, and liver function tests. Bone scans are used by 38.6% of surgeons. Most patients with positive lymph nodes see a medical oncologist. About half of primary breast cancer treatment (44.7%) is by breast preservation. Essentially all surgeons follow their patients after treatment for breast cancer surveillance. Essentially all surgeons feel that physical exam and mammograms are important for post-treatment follow-up. Complete blood cell count, liver function studies, and chest X-rays are used less commonly but still by more than half of the surgeons. 44.4% of the surgeons have found difficulty with third-party payers covering the costs of surveillance studies. 87.7% of surgeons surveyed felt the State Chapter should become involved in establishing clinical guidelines or practice parameters.

An update on breast cancer: evolving treatments and persistent questions.

This review describes recent advances in imaging technology and treatment options, and discusses the persistent questions about the best strategies for preventing, diagnosing and treating breast cancer. Possible clinical implications of new research on the causes of breast cancer are also examined. The evolution of breast cancer management over the past century is summarized.