[Show abstract][Hide abstract] ABSTRACT: Treatment of diabetics with metformin is associated with decreased breast cancer risk in observational studies, but it remains unclear if this drug has clinical antineoplastic activity. In a recent presurgical trial, we found a heterogeneous effect of metformin on breast cancer proliferation (ki-67) depending upon insulin resistance (HOMA index). Here, we determined the associations of additional serum biomarkers of insulin resistance, tumor subtype, and drug concentration with ki-67 response to metformin. Two-hundred non-diabetic women were randomly allocated to metformin (850 mg/bid) or placebo for 4 weeks prior to breast cancer surgery. The ki-67 response to metformin was assessed comparing data obtained from baseline biopsy (ki-67 and tumor subtype) and serum markers (HOMA index, C-peptide, IGF-I, IGFBP-1, IGFBP-3, free IGF-I, hs-CRP, adiponectin) with the same measurements at definitive surgery. For patients with a blood sample taken within 24 h from last drug intake, metformin level was measured. Compared with placebo, metformin significantly decreased ki-67 in women with HOMA > 2.8, those in the lowest IGFBP-1 quintile, those in the highest IGFBP-3 quartile, those with low free IGF-I, those in the top hs-CRP tertile, and those with HER2-positive tumors. In women with HOMA index > 2.8, drug levels were positively correlated with the ki-67 decrease, whereas no trend was noted in women with HOMA < 2.8 (p-interaction = 0.07). At conventional antidiabetic doses, the effect of metformin on tumor ki-67 of non-diabetic breast cancer patients varies with host and tumor characteristics. These findings are relevant to design breast cancer prevention and treatment trials with metformin.
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The online version of this article (doi:10.1007/s10549-014-3141-1) contains supplementary material, which is available to authorized users.
Breast Cancer Research and Treatment 09/2014; 148(1). DOI:10.1007/s10549-014-3141-1 · 3.94 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Introduction:
The St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2013 recognized substantial progress in the pathological characterization of breast cancer subtypes. A useful surrogate definition was developed to distinguish luminal A-like breast cancer from luminal B-like disease based on a combination of estrogen receptor (ER), progesterone receptor (PgR) and Ki-67 status, without a requirement for molecular diagnostics. Differences depend upon the choice of the threshold value for Ki-67 and the requirement for substantial PgR positivity. We aimed to verify the suitability of the new surrogate definitions of luminal subtypes in terms of distant disease control in a large series of patients.
We studied 9,415 women with a median follow-up of 8.1 years who (1) had ER-positive, human epidermal growth factor receptor 2 (HER2)-negative early breast cancer and (2) had undergone surgery at the European Institute of Oncology between 1994 and 2006. We evaluated distant disease-free survival of patients with "low" (<14%), "intermediate" (14% to 19%) or "high" (≥20%) Ki-67 positivity stratified by PgR expression (negative or low versus high). We calculated the cumulative incidence of distant events, considered competing events and performed multivariable analysis adjusted for pathologic tumor stage, pathologic node stage, tumor grade, peritumoral vascular invasion and menopausal status.
Lack of substantial PgR positivity was associated with poorer outcomes only for patients with an intermediate Ki-67 level (P<0.001). The 4,890 patients (51.9%) with low Ki-67 level (any PgR expression level) or with intermediate Ki-67 level but substantial PgR positivity had comparably good outcomes and thus may represent a most advantageous grouping of those with luminal A-like disease.
The updated pathological definition of intrinsic molecular subtypes may maximize the number of patients classified as having the luminal A-like intrinsic subtype of breast cancer and for whom the use of cytotoxic drugs could mostly be avoided.
Breast cancer research: BCR 06/2014; 16(3):R65. DOI:10.1186/bcr3679 · 5.49 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We previously demonstrated that 1 or 5 mg per day of tamoxifen (T) given for 4 weeks before surgery reduces Ki-67 in breast cancer (BC) patients to the same extent as the standard 20 mg/d. Given the long half-life of T, a weekly dose (10mg/w) may be worth testing. Also, raloxifene (R) has shown Ki-67 reduction in post menopausal patients in a preoperative setting, but data in premenopausal women are limited. We conducted a randomized trial testing T 10mg per week (w), vs R 60 mg/d vs placebo in a pre-surgical model.
Out of 204 screened subjects, 57 were not eligible, 22 refused to participate and 125 were included in the study. The participants were all premenopausal women with estrogen receptor-positive BC. They were randomly assigned to either T 10mg/w or R 60 mg/d or placebo for 6 weeks before surgery. The primary endpoint was tissue change of Ki67. Secondary endpoints were modulation of estrogen and progesterone receptors and several other circulating biomarkers.
Ki-67 was not significantly modulated by either treatment. In contrast, both selective estrogen receptor modulators (SERMs) significantly modulated circulating IGF-I/IGFBP-3 ratio, cholesterol, fibrinogen and anti-thrombin III. Estradiol was increased with both SERMs. Within the tamoxifen arm, CYP2D6 polymorphism analysis showed a higher concentration of N-desTamoxifen, one of the tamoxifen metabolites, in subjects with reduced CYP2D6 activity. Moreover, a reduction of Ki67 and a marked increase of sex hormone banding protein (SHBP) were observed in the active phenotype.
A weekly dose of tamoxifen and a standard dose of raloxifene did not inhibit tumor cell proliferation, measured as Ki67 expression, in premenopausal BC patients. However in the tamoxifen arm women with an extensive phenotype for CYP2D6 reached a significant Ki67 modulation.
Breast cancer research: BCR 06/2013; 15(3):R47. DOI:10.1186/bcr3439 · 5.49 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background:
The post-surgical management of ductal intraepithelial neoplasia (DIN) of the breast is still a dilemma. Ki-67 labelling index (LI) has been proposed as an independent predictive and prognostic factor in early breast cancer.
The prognostic and predictive roles of Ki-67 LI were evaluated with a multivariable Cox regression model in a cohort of 1171 consecutive patients operated for DIN in a single institution from 1997 to 2007.
Radiotherapy (RT) was protective in subjects with DIN with Ki-67 LI ≥14%, whereas no evidence of benefit was seen for Ki-67 LI <14%, irrespective of nuclear grade and presence of necrosis. Notably, the higher the Ki-67 LI, the stronger the effect of RT (P-interaction <0.01). Hormonal therapy (HT) was effective in both Luminal A (adjusted hazard ratio (HR)=0.56 (95% CI, 0.33–0.97)) and Luminal B/Her2neg DIN (HR 0.51 (95% CI, 0.27–0.95)).
Our data suggest that Ki-67 LI may be a useful prognostic and predictive adjunct in DIN patients. The Ki-67 LI of 14% could be a potential cutoff for better categorising this population of women at increased risk for breast cancer and in which adjuvant treatment (RT, HT) should be differently addressed, independent of histological grade and presence of necrosis.
British Journal of Cancer 04/2013; 108(8). DOI:10.1038/bjc.2013.147 · 4.84 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Metformin is associated with reduced breast cancer risk in observational studies in patients with diabetes, but clinical evidence for antitumor activity is unclear. The change in Ki-67 between pretreatment biopsy and post-treatment surgical specimen has prognostic value and may predict antitumor activity in breast cancer.
After tumor biopsy, we randomly allocated 200 nondiabetic women with operable breast cancer to either metformin 850 mg/twice per day (n = 100) or placebo (n = 100). The primary outcome measure was the difference between arms in Ki-67 after 4 weeks adjusted for baseline values.
Overall, the metformin effect on Ki-67 change relative to placebo was not statistically significant, with a mean proportional increase of 4.0% (95% CI, -5.6% to 14.4%) 4 weeks apart. However, there was a different drug effect depending on insulin resistance (homeostasis model assessment [HOMA] index > 2.8, fasting glucose [mmol/L] × insulin [mU/L]/22.5; P(interaction) = .045), with a nonsignificant mean proportional decrease in Ki-67 of 10.5% (95% CI, -26.1% to 8.4%) in women with HOMA more than 2.8 and a nonsignificant increase of 11.1% (95% CI, -0.6% to 24.2%) with HOMA less than or equal to 2.8. A different effect of metformin according to HOMA index was noted also in luminal B tumors (P(interaction) = .05). Similar trends to drug effect modifications were observed according to body mass index (P = .143), waist/hip girth-ratio (P = .058), moderate alcohol consumption (P = .005), and C-reactive protein (P = .080).
Metformin before surgery did not significantly affect Ki-67 overall, but showed significantly different effects according to insulin resistance, particularly in luminal B tumors. Our findings warrant further studies of metformin in breast cancer with careful consideration to the metabolic characteristics of the study population.
[Show abstract][Hide abstract] ABSTRACT: To evaluate late toxicity and cosmetic outcome after intraoperative radiotherapy using electrons (ELIOT) as sole treatment modality in early breast cancer patients.
A total of 119 patients selected randomly among 1200 cases was analyzed. Late toxicities were documented using the LENT-SOMA scoring system, cosmesis was evaluated with the Harvard scale, and a numeric rating scale was used to assess symptoms.
After a median follow-up of 71 months, grade II fibrosis was observed in 38 patients (31.9%) and grade III fibrosis in 7 patients (5.9%). Postoperative complications (12.6%) did not correlate with late toxicity. Physicians and patients scored cosmesis as excellent or good in 84% and 77.3% of the cases, respectively. Patient satisfaction was higher than 90%.
In the study, ELIOT gives low and acceptable long-term toxicity. A longer follow-up and a larger number of patients are needed to confirm these promising results.
[Show abstract][Hide abstract] ABSTRACT: Breast cancer is the most common cancer in women. Primary treatment is surgery, with mastectomy as the main treatment for most of the twentieth century. However, over that time, the extent of the procedure varied, and less extensive mastectomies are employed today compared to those used in the past, as excessively mutilating procedures did not improve survival. Today, many women receive breast-conserving surgery, usually with radiotherapy to the residual breast, instead of mastectomy, as it has been shown to be as effective as mastectomy in early disease. The relatively new skin-sparing mastectomy, often with immediate breast reconstruction, improves aesthetic outcomes and is oncologically safe. Nipple-sparing mastectomy is newer and used increasingly, with better acceptance by patients, and again appears to be oncologically safe. Breast reconstruction is an important adjunct to mastectomy, as it has a positive psychological impact on the patient, contributing to improved quality of life.
International Journal of Surgical Oncology 06/2011; 2011(5):980158. DOI:10.1155/2011/980158
[Show abstract][Hide abstract] ABSTRACT: We analyzed 382 patients with pure lobular carcinoma treated up to 2002 with sufficient follow-up to draw prognostic conclusions, all treated by conservative surgery. Our aim was to evaluate the influence of margin status on outcomes with a view assessing the appropriateness of conservative surgery in this breast cancer subtype.
We assessed locoregional relapse, distant metastasis, contralateral breast cancer, breast cancer-related event free survival, disease-free survival and overall survival according to margin status categorized as at least 10 mm versus less than 10 mm (usually considered negative).
The proportions of patients with less than 10 mm margins varied significantly with age (P = 0.02), menopausal status (P = 0.006), and tumor size (P = 0.02) but no other characteristic was significantly related to margin status. As regards unfavorable events during follow-up, none differed significantly between at least 10 mm and less than 10 mm margin groups. In particular, there were 11 (3.7%) local relapses in the same quadrant in at least 10 mm margin group compared to 4 (4.6%) in the less than 10 mm margin group, and 7 (2.4%) ipsilateral breast cancers in the 10 mm or more margin group but none in the less than 10 mm group. These findings indicate that minimal residual disease as evidenced by margins less than 10 mm is eradicated by radiotherapy (backed up in selected cases by reexcision, which in this series was always conservative). The rate of contralateral breast cancer was low at 2.9% indicating that prophylactic contralateral mastectomy is not justified.
We conclude that the surgical approach and criteria for adjuvant hormonal and systemic treatment in lobular carcinoma should be the same as for ductal carcinoma, provided that adequate preoperative investigations exclude extensive multifocal and contralateral disease.
Annals of surgery 03/2011; 253(3):580-4. DOI:10.1097/SLA.0b013e31820d9a81 · 8.33 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In recent decades, a steady improvement in imaging diagnostics has been observed together with a rising adherence to regular clinical breast examinations. As a result, the detection of small clinically occult (nonpalpable) lesions has progressively increased. At present in our institution some 20% of the cases are treated when nonpalpable. The aim of the present study is to analyze the characteristics and prognosis of such tumors treated in a single institution.
The analysis focused on 1,258 women who presented at the European Institute of Oncology with a primary clinically occult carcinoma between 2000 and 2006. All patients underwent radioguided occult lesion localization (ROLL), axillary dissection when appropriate, whole breast radiotherapy, or partial breast intraoperative irradiation and received tailored adjuvant systemic treatment.
Median age was 56 years. Imaging showed a breast nodule in half of the cases and a breast nodule accompanied by microcalcifications in 9%. Microcalcifications alone were present in 17.1% of the cases, whereas suspicious opacity, distortion, or thickening represented the remaining 24.6%. Most tumors were characterized by low proliferative rates (68.9%), positive estrogen receptors (92.3%), and non-overexpressed Her2/neu (91.3%). After a median follow-up of 60 months, we observed 19 local events (1.5%), 12 regional events (1%), and 20 distant metastases (1.6%). Five-year overall survival was 98.6%.
Clinically occult (nonpalpable) carcinomas show very favorable prognostic features and high survival rates, showing the important role of modern imaging techniques.
The Oncologist 12/2010; 15(12):1248-52. DOI:10.1634/theoncologist.2010-0123 · 4.87 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Few data exist on the potential role of circulating tumor cells (CTCs) in patients with operable breast cancer. If the presence of CTCs in early breast cancer could predict an increased risk for relapse, it might be an early marker for treatment efficacy and could help in deciding treatment continuation.
Thirty milliliters of peripheral blood was taken from 56 breast cancer patients before surgery and again 5 days after surgery, and the presence of CTCs was evaluated. In case of positivity of one of the perioperative samples, another sample was taken after 30 days. The presence of CTCs was assessed with the CellSearch System (Veridex, Warren, NJ).
One to three CTCs were found in 16 (29%) of 56 patients before surgery, in 14 (30%) of 47 patients at day 5, and in 8 (30%) of 27 at day 30. No association with pathological characteristics was found, apart a borderline significant association between presence of CTCs at baseline and vascular invasion (P = 0.07). When we looked at concordance between CTCs at baseline and after day 5 (47 patients), we found 40% discordant samples (10 negative at baseline and positive at day 5, and 9 vice versa).
This study provides evidence of the presence of CTCs in approximately 30% of patients with localized breast cancer both before and after surgery, with change from positive to negative and vice versa in 40% of cases. No association with the pathological variables was found, except for vascular invasion and presence of preoperative CTCs. Long-term follow-up will be required to understand the significance of these data.
[Show abstract][Hide abstract] ABSTRACT: Tamoxifen's cost-benefit ratio for breast ductal intraepithelial neoplasia (DIN) is unclear. Since low-dose tamoxifen showed a favorable modulation of breast cancer biomarkers in phase II trials, a monoinstitutional cohort of women with DIN treated with low-dose tamoxifen or no systemic treatment was analyzed.
A total of 309 patients with DIN received low-dose tamoxifen as part of institutional guidelines and were compared with 371 patients with DIN who received no systemic treatment after surgery.
Women with estrogen receptor (ER)/progesterone receptor (PgR) >50% DIN who were not treated had a higher incidence of breast events than women on tamoxifen [hazard ratio (HR) 1.76; 95% confidence interval (CI) 1.00-3.12] or women with ER/PgR <50% DIN (HR 1.72; 95% CI 1.14-2.58). Among untreated patients with ER >50% DIN, recurrence was higher in PgR > or =50% DIN than in PgR <50% DIN, whereas it was similar among low PgR (<50%) DIN against which tamoxifen had no effect. No difference in endometrial cancer incidence was noted.
High ER and especially high PgR expression is a significant adverse prognostic indicator of DIN, and low-dose tamoxifen appears to be an active treatment. Women with low-expression ER or PgR DIN do not seem to benefit from tamoxifen. A definitive clinical trial is warranted.
Annals of Oncology 10/2009; 21(5):949-54. DOI:10.1093/annonc/mdp408 · 7.04 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Idiopathic granulomatous mastitis clinically and histologically mimics an inflammatory carcinoma. A correct approach including ultrasound, clinical and histological analysis can safely identify a patient with this pathology, orienting to adequate therapy with anti-inflammatory and antibiotic drugs and leaving the surgical approach only for case unresponsive to medical therapy.
[Show abstract][Hide abstract] ABSTRACT: Diagnosis of breast ductal intraepithelial neoplasia (DIN) has increased over the last decades, but proper postsurgical treatment remains controversial. We analyzed risk factors and treatment outcome in a large series of women treated at one institution.
Women undergoing surgery for DIN at the European Institute of Oncology between 1996 and 2005, with follow-up until December 2006, were included.
We evaluated the postsurgical treatment outcome of 974 and 293 patients who underwent breast-conserving surgery (BCS) or mastectomy, respectively. The 5-year cumulative incidence of breast cancer (BC) events was 11.8%, with a significant trend according to age (from 43% in women <36 years to 8% in women >65 years). Among the 727 BCS patients with DIN2-DIN3 histology, 414 (57%) received radiotherapy (RT), and they were both younger and with worse prognostic factors than the 313 patients who did not receive it. In these groups, the adjusted hazard ratio (HR) for RT versus non-RT was 0.40 (95% confidence interval [CI], 0.26-0.63). Among the 691 BCS patients with estrogen receptor (ER)(+) disease, 329 (48%) received low-dose tamoxifen (either 5 mg/day or 20 mg once a week) and they were younger than the 362 who did not receive it. In these groups, the adjusted HR for tamoxifen versus no tamoxifen was 0.68 (95% CI, 0.43-1.07), and the HR was 0.55 (95% CI, 0.32-0.97) after excluding human epidermal growth factor receptor (HER)2/neu-overexpressing DIN.
BC events were more frequent in young patients. RT was associated with a lower incidence of BC events. Low-dose tamoxifen was associated with a lower incidence of BC events in patients with ER(+) disease when HER-2 was not overexpressed. Further prospective studies should confirm our observations.
The Oncologist 03/2009; 14(3):201-12. DOI:10.1634/theoncologist.2008-0203 · 4.87 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Conservative surgery represents the standard care for patients with early breast cancer. The aim of this review was to discuss the extension of conservative surgery in controversial fields such as after primary chemotherapy for large tumours or the possibility to repeat conservative surgery for a local reappearance. The project of a conservative approach to breast cancers continues with sentinel node biopsy which is worldwide performed more and more frequently. In our institute sentinel node biopsy is the standard procedure in the axillary staging of breast cancer even in those clinical scenarios which were previously considered either controversial or a contraindication such as in multicentric breast cancer, during pregnancy, in intra-ductal neoplasias, after primary chemotherapy, and male breast cancer. This conservative approach is completed by the possibility to deliver a partial breast irradiation and to provide patients with more personalized adjuvant treatments tailored on the biological features of the tumour.
[Show abstract][Hide abstract] ABSTRACT: We evaluated the risks and benefits of nipple-sparing mastectomy in a multiinstitutional experience in the settings of risk-reducing surgery and breast cancer treatment.
We analyzed data on 123 patients who had undergone nipple-sparing mastectomy with breast reconstruction for prophylaxis (n=55), treatment of breast cancer (n=41), or both (n=27) at four large centers.
Median patient age was 45 years (range 22 to 70 years). There were 192 procedures (69 bilateral, 54 unilateral). Forty-four patients had invasive cancer; 20 had ductal carcinoma in situ (DCIS); 4 had phyllodes tumor. In all of these patients, the nipple tissue was cancer free on pathologic review. Median followup was 24.6 months (range 2.0 to 570.4 months). Local recurrence developed in two patients: one had DCIS in the upper-outer quadrant, with 71.8 months of followup; the other's cancer was invasive, in the upper-outer quadrant, with 6 months of followup. Distant metastasis developed in a third patient, who died 50 months after the procedure. Breast cancer developed in two patients after prophylactic mastectomy: one in the upper-outer quadrant at 61.8 months; one in the axillary tail at 24.4 months. No patients had recurrences in the nipple-areolar complex. Necrosis of the nipple was reported in 22 of 192 patients (11%) and it was judged minimal (less than one-third total skin of nipple) in 13 of 22 patients (59%). Overall cosmesis was judged by the patient and surgeon as good to excellent in the majority of patients. Level of satisfaction with cosmetic results was similar between prophylactic and treatment patients.
The risk of local relapse was very low in our series of nipple-sparing mastectomies performed for DCIS or invasive cancer. Nipple-sparing mastectomy in the risk-reducing and breast cancer-treatment settings may be feasible in selected patients and should be the subject of additional prospective clinical trials.
Journal of the American College of Surgeons 12/2006; 203(5):704-14. DOI:10.1016/j.jamcollsurg.2006.07.015 · 5.12 Impact Factor