Background: The presurgical model is a useful tool to test drug activity on surrogate biomarkers ... more Background: The presurgical model is a useful tool to test drug activity on surrogate biomarkers of breast cancer, including proliferation measured by Ki-67. We previously demonstrated that 1 or 5 mg/per day of tamoxifen (T) given for 4 weeks before surgery reduced Ki-67 to the same extent than the standard 20 mg/d. Given the long half-life of T and its metabolites, a weekly dose (10 mg/w) may be worth testing. Raloxifene (R), another SERM, has been shown to reduce Ki-67 in a preoperative setting and to be an effective breast cancer (BC) preventive agent in postmenopausal women. Methods: 125 premenopausal estrogen receptor positive BC patients were randomly assigned to either T 10mg/w or R 60 mg/d or placebo (P) for 6 weeks before surgery in a 2:2:1 ratio. The primary endpoint was tissue change of Ki67. Secondary endpoints were other tissue and circulating biomarkers. Results: The median age was 44, 46, 44 and the median BMI was 23, 22, 22 in the P, R and T group, respectively. Tissue biomarkers (Ki-67, ER, PgR) were not significantly modulated by treatment. Only PgR was modestly down regulated by T and more by R but with not statistically significance. More evident were the effects on the circulating biomarkers. Both SERMs significantly reduced IGF-I/BP-3 ratio (mean change P:0; T:-0.01; R:-0.02; p=0.007) and cholesterol (mean change P: 13.73; T: -10.82; R: -8.96; p<.0001) with no difference between the two drugs. Both T and R modulated significantly fibrinogen level (mean change P: 9.3; T: -14.24; R: -35.88 p=0.002) and in particular R was more effective than T (p=0.034). Antithrombin III showed a significant reduction by treatment vs. placebo (mean change P: -2.28; T: -6.19; R: -6.85; P=0.04). SHBG levels were positively influenced by both T and R (mean change P: -10.21; T: 5.95; R: 6.2; p=0.002). Overall compliance measured with pill count was above 80%. No severe adverse events occurred. Conclusions: Our findings show a lack of effect of both SERMs on breast cancer cells proliferation, possibly due to insufficient doses in premenopausal women with elevated estrogen levels. In contrast, both T at very low dose and R at the standard dose were effective on circulating biomarkers. Interestingly, R was more active than T in reducing fibrinogen level, in line with its safer vascular profile. Citation Information: Cancer Prev Res 2010;3(1 Suppl):A78.
ImportanceSuccessful therapeutic cancer prevention requires definition of the minimal effective d... more ImportanceSuccessful therapeutic cancer prevention requires definition of the minimal effective dose. Aromatase inhibitors decrease breast cancer incidence in high-risk women, but use in prevention and compliance in adjuvant settings are hampered by adverse events.ObjectiveTo compare the noninferiority percentage change of estradiol in postmenopausal women with estrogen receptor–positive breast cancer given exemestane, 25 mg, 3 times weekly or once weekly vs a standard daily dose with a noninferiority margin of −6%.Design, Setting, and ParticipantsThis multicenter, presurgical, double-blind phase 2b randomized clinical trial evaluated 2 alternative dosing schedules of exemestane. Postmenopausal women with estrogen receptor–positive breast cancer who were candidates for breast surgery were screened from February 1, 2017, to August 31, 2019. Blood samples were collected at baseline and final visit; tissue biomarker changes were assessed from diagnostic biopsy and surgical specimen. Biomarkers were measured in different laboratories between April 2020 and December 2021.InterventionsExemestane, 25 mg, once daily, 3 times weekly, or once weekly for 4 to 6 weeks before surgery.Main Outcomes and MeasuresSerum estradiol concentrations were measured by solid-phase extraction followed by liquid chromatography–tandem mass spectrometry detection. Toxic effects were evaluated using the National Cancer Institute terminology criteria, and Ki-67 was assessed by immunohistochemistry.ResultsA total of 180 women were randomized into 1 of the 3 arms; median (IQR) age was 66 (60-71) years, 63 (60-69) years, and 65 (61-70) years in the once-daily, 3-times-weekly, and once-weekly arms, respectively. In the intention-to-treat population (n = 171), the least square mean percentage change of serum estradiol was −89%, −85%, and −60% for exemestane once daily (n = 55), 3 times weekly (n = 56), and once weekly (n = 60), respectively. The difference in estradiol percentage change between the once-daily and 3-times-weekly arms was −3.6% (P for noninferiority = .37), whereas in compliant participants (n = 153), it was 2.0% (97.5% lower confidence limit, −5.6%; P for noninferiority = .02). Among secondary end points, Ki-67 and progesterone receptor were reduced in all arms, with median absolute percentage changes of −7.5%, −5.0%, and −4.0% for Ki-67 in the once-daily, 3-times-weekly, and once-weekly arms, respectively (once daily vs 3 times weekly, P = .31; once daily vs once weekly, P = .06), and −17.0%, −9.0%, and −7.0% for progesterone receptor, respectively. Sex hormone–binding globulin and high-density lipoprotein cholesterol had a better profile among participants in the 3-times-weekly arm compared with once-daily arm. Adverse events were similar in all arms.Conclusions and RelevanceIn this randomized clinical trial, exemestane, 25 mg, given 3 times weekly in compliant patients was noninferior to the once-daily dosage in decreasing serum estradiol. This new schedule should be further studied in prevention studies and in women who do not tolerate the daily dose in the adjuvant setting.Trial RegistrationClinicalTrials.gov Identifier: NCT02598557; EudraCT: 2015-005063-16
Background: Low dose tamoxifen has shown comparable antiproliferative activity to 20 mg/day in bi... more Background: Low dose tamoxifen has shown comparable antiproliferative activity to 20 mg/day in biomarker trials, but its clinical efficacy is unclear. We assessed the effect of low dose tamoxifen, 10 mg on alternate day in most, on ipsilateral recurrence in high risk DCIS patients treated in a single institution. Methods: Following breast conserving surgery, women with DCIS received radiotherapy and/or low dose tamoxifen as per clinical judgment and patient preference. Multivariate Cox regression analyses adjusted for potential confounding variables were performed. Results: In a cohort of 1,091 women, median age was 53 years (IQR 46-62), 544 received radiotherapy versus 547 no radiotherapy. Of these, 883 had ER-positive DCIS, 467 received low-dose tamoxifen versus 416 no tamoxifen. After 7.7 years of median follow-up (IQR, 5.1-9.7), 235 ipsilateral recurrences and 62 contralateral tumors were observed. Low dose tamoxifen decreased any breast event (HR = 0.70, 95% CI, 0.54-0.91) and ipsilateral DCIS recurrence (HR = 0.66, 95% CI, 0.49-0.88), but not ipsilateral invasive recurrence (HR = 0.78, 95% CI, 0.56-1.09) or contralateral tumors (HR = 0.89, 95% CI, 0.51-1.55). Radiotherapy decreased any breast event (HR = 0.55, 95% CI, 0.42-0.72). Low dose tamoxifen was more effective in women aged >50 years for all events (HR = 0.51, 95% CI, 0.33-0.77) and ipsilateral recurrences (HR = 0.43, 95% CI, 0.26-0.72) than in women aged 50 or younger (HR = 0.84, 95% CI, 0.60-1.18 and HR = 0.80, 95% CI, 0.55-1.16, respectively, p-interaction = 0.03). Young age or premenopausal status, positive margins, high Ki67, high grade and low BMI were independent predictors of ipsilateral recurrence. No increase in endometrial cancers was observed and fewer deaths occurred in women on low dose tamoxifen. Conclusions: In high risk ER-positive DCIS, low-dose tamoxifen seems to be safe and effective in reducing ipsilateral recurrence, and represents a valuable option in women aged >50 years. A randomized clinical trial is underway to confirm these results. Supported by Lega Italiana per la Lotta contro i Tumori, AIRC, Italian Ministry of Health (RFPS-2006-1-339898), Gruppo bancario Credito Valtellinese. Citation Format: Aliana Guerrieri-Gonzaga, Ivana Sestak, Matteo Lazzeroni, Davide Serrano, Nicole Rotmensz, Massimiliano Cazzaniga, Clara Varricchio, Mangesh A. Thorat, Giancarlo Pruneri, Maria Cristina Leonardi, Viviana Galimberti, Bernardo Bonanni, Andrea DeCensi. Benefit of low-dose tamoxifen in a large, single-institution cohort of high-risk ER-positive DCIS. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1788.
Retinoids have been studied as chemopreventive compounds because of their role in regulating cell... more Retinoids have been studied as chemopreventive compounds because of their role in regulating cell growth, differentiation and apoptosis in preclinical models. Induction of apoptosis is a unique feature of fenretinide (4-hydroxyphenylretinamide, 4-HPR) the most studied retinoid in clinical trials of breast cancer (BC) prevention for its selective accumulation in the breast tissue and its low toxicity. Fenretinide is effective in inhibiting the growth of BRCA1 mutated BC cell lines. Recent studies showed that it modulates gene expression in ovarian cells, with an up-regulation of expression of proapoptotic genes in OVCA433 cells. The fifteen-year follow up of a randomized phase III trial of fenretinide to prevent second BC indicates that it induced a 17% reduction of second BC incidence. More importantly, when stratified by menopausal status, the analysis showed a 38%, statistically significant reduction of second BC in premenopausal women and this effect persisted for up to 15 years. Interestingly, the younger were the women (≤ 40 years), the greater was the trend of benefit by fenretinide. When considering the protective activity of fenretinide on second BC and a similar trend on ovarian cancer (OC) it appears that young women at high risk for both diseases such as carriers of germline BRCA1 and BRCA2 mutations or those with a high family risk may be ideal candidates for further investigation on this retinoid. Since a reduction of second BC might be a surrogate marker of primary prevention, a favorable effect of fenretinide provides strong rationale for a primary prevention trial in unaffected women at high-risk for BC. The European Institute of Oncology (IEO, Milan, Italy) has promoted a multi-centric (15 centres nationwide), randomized phase III placebo-controlled study with fenretinide in healthy young women: 758 healthy women, 25-44 years old, at increased BC risk (BRCA1/2 mutation carriers or subjects with mutation probability ≥20% acc. to BRCAPRO), will be randomized to 4-HPR 200 mg/day vs placebo for 5 years followed by a 10 years follow up period. We will perform a clinical examination every 6 months, and annual breast ultrasound and breast MRI. For subjects ≥ 35 years old also an annual mammography is requested. All subjects will undergo a transvaginal ultrasound at least once a year. At each visit, safety tests (β-HCG, AST, ALT, blood count, creatinine, glycemia, lipid profile, CA-125), and blood samples for biomarkers evaluation at baseline, 12, 36, and 60 months. Enrollment started at the IEO in December 2009. The other centers are expected to start within early 2011. The primary endpoint of the trial is to assess the efficacy of fenretinide in reducing the incidence of invasive BC and ductal intraepithelial neoplasia (DIN). Secondary endpoints are the incidence of non-invasive breast disorders, OC, other cancers and the study of various risk biomarkers. In particular, we will evaluate the change in circulating biomarkers of the IGF system, androgens, retinol binding protein (RBP-4), insulin, blood glucose and VEGF. Genotyping of single nucleotide polymorphisms (SNPs) linked to BC risk (MTHFR, COMT, GH, IGFBP-3, AR, TGF-β genes), degree of methylation of RASSAF1 and RARβ and circulating progranulin will be assessed. The results will be correlated with mammographic instrumental measurements, plasma and tissue biomarkers after 1 year treatment. Citation Information: Cancer Prev Res 2010;3(12 Suppl):A71.
A59 The presurgical model is a useful tool to screen and evaluate drug activity and select new ch... more A59 The presurgical model is a useful tool to screen and evaluate drug activity and select new chemopreventive agents. Cancer cell proliferation measured by ki-67 is considered to be a reliable surrogate biomarker in assessing the efficacy of chemopreventive agents. Exemestane (Exe), a highly specific steroidal aromatase inactivator, has shown clinical efficacy in the treatment of postmenopausal breast cancer (BC) patients. Epidemiologic evidence suggests that anti-inflammatory drugs reduce the risk of BC. Celecoxib (Cel) is a selective inhibitor of the enzyme COX-2 (Cyclooxygenase-2), which is overexpressed in human breast tumors, BC cell lines, and rodent mammary tumors, and it has shown significant antiproliferative and proapoptotic properties. No clinical data are known so far on the antiproliferative activity of Cel in breast cancer cells. The primary endpoint of the present study is to assess the antiproliferative activity (as measured by ki-67 percentage change) of Exe 25mg/d or Cel 800 mg/d relative to placebo in postmenopausal ER positive BC patients treated for 6 weeks before surgery. Estimating a 20% increase in the placebo arm and a 25 % decrease in the treatment arms with 80% power and two-tailed significance at 5 %, a total of 90 subjects (18 in the placebo arm and 36 in each treatment arm) was required. Secondary endpoints were changes in ER and PgR expression, apoptosis, gene expression profile focusing on nuclear receptor coregulators (AIB1, SRC1, TIF-2/GRIP1, N-CoR and SMRT) on frozen tissue, circulating biomarkers (sex hormones, markers of inflammation and hemostasis, insulin-like growth factors, bone markers) and genomic DNA analyses of genetic polymorphisms related to BC, hormone metabolism, response to DNA damage, and cardiovascular events. One hundred and one patients were randomized to either Exe 25 mg/d (n=41), or Cel 800 mg/d (n=40) or placebo (n=20). Baseline median age and BMI were 62, 65, 61 years, 26, 25, 27 in the Exe, Cel and placebo group, respectively. At baseline median ki67% was 21, 18, 18 in the Exe, Cel and placebo arm, respectively. After adjustment for baseline values, Ls means of changes of ki67 were -11.5 (-14.1, -8.9), 1.3 (-1.4, 3.9), 3.2 (-0.5, 6.8) (P among arms <.001; P among active treatments <.001). After adjustment for baseline values, ls means of changes of PgR were -26.2 (-34.1, -18.4), -6.3 (-14.3, 1.7), 2.1 (-8.8, 13.1) (P among arms <.001; P among active treatments <.001). After adjustment for baseline values, ls means of changes of ER were -2.6 (-7.8, 2.7), 0.8 (-4.5, 6.1), -0.7 (-8.0, 6.7) (P among arms 0.671; P among active treatments 0.374). Compliance was higher than 75% and no severe AEs were observed. In this postmenopausal population, Exe has shown a significant reduction of cell proliferation and PgR expression. Bone biomarkers are currently being measured as long as the other secondary endpoints and final results will be helpful to plan further prevention studies with Exe in high-risk subjects. Conversely, only a modest non significant modulation of PgR expression was observed in the Cel arm despite the relatively high dose of the drug. Evaluation of secondary endpoints, including expression of Cox-2 activity, will help to better elucidate the activity of both agents. Citation Information: Cancer Prev Res 2008;1(7 Suppl):A59.
Background: Metformin has been associated with decreased breast cancer (BC) incidence in diabetic... more Background: Metformin has been associated with decreased breast cancer (BC) incidence in diabetic patients in epidemiological studies. Moreover, this drug results in initiation of an AMPK-dependent energy stress response which can adversely affect survival of breast cancer cell lines and inhibition of PI3K/Akt/mTOR signaling leading to reduced proliferation of BC cell lines. Methods: We conducted a randomized, pre-surgical, phase IIb, placebo-controlled, biomarker trial in women with stage I-III BC candidate to elective surgery. The primary endpoint was the change in cell proliferation in malignant, dysplastic and hyperplastic tissue as measured by Ki-67 labeling index (LI). With 150 subjects, the study was 80% powered to test for the interaction between metformin activity and ER status. Two interim analyses are being planned after 100 and 200 women enrolled. Results: As of June 18, 2010, 175 subjects have been randomized and 162 have completed treatment. Here we report data on the first 100 women enrolled. At the symposium, full data on the first 200 women enrolled will be available. As of December 31, 2009, a total of 163 women were screened, 26 were not eligible and 40 refused to participate, 6 dropped out during the study for AEs (n=2) or refusal to continue treatment (n=4), thus leaving 95 subjects assessable for the primary endpoint. The main subject and tumor characteristics blinded as to the allocated arm were mean age 52 (31-77), Pre/postmenopause, 54/41, mean BMI, 23.6 (18.0-40.2). At baseline, median Ki-67LI was 18% (range 4%-65%) at biopsy and 19% (4%-70%) after 4 weeks at surgery. All adverse events except for 1 SAE were grade 1 or 2, consisting of G2 nausea and G2 diarrhea in 4% and 6% of the cases, respectively. The prevalence of ductal intraepithelial neoplasia was 91% (median Ki-67 LI, 10%) in samples both adjacent and distant from the tumor, whereas the prevalence of ductal hyperplasia was 77% (median Ki-67LI, 2%) in samples distant from the tumor. Conclusions: Our preliminary results show the feasibility, high compliance and safety of a metformin trial in breast cancer patients. Assessment of tissue and circulating biomarkers is currently ongoing to characterize the whole spectrum of metformin activity in malignant and dysplastic tissue. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr PD03-02.
1514 Background: Primary prevention trials have shown that tamoxifen (T) lowers ER+ breast cancer... more 1514 Background: Primary prevention trials have shown that tamoxifen (T) lowers ER+ breast cancer (BC) incidence by 48%. While the IBIS I update showed mixed findings, the Italian trial showed an interesting positive risk/benefit ratio in T and hormone replacement therapy (HRT) users: fewer BC, endometrial cancer comparable to placebo, and no cardiovascular diseases (CVD) excess. In a phase II study, low dose T and HRT showed a safe gynecological profile and did not increase menopausal symptoms. Moreover low dose T maintains the same antiproliferative effects as the standard dose. To improve BC prevention and quality of life (QoL) in menopausal women we started a multicentric, phase III trial of low dose T in HRT users. Methods: current or de novo HRT users are randomized to T 5 mg/day or placebo for 5 yrs. The primary aim is the reduction of invasive or in situ BC. Secondary aims are: safety, gene polymorphisms (SNPs) correlated to BC risk and T activity. In a subgroup transvaginal ultrasound (TvUS) and endometrial biopsy is being performed after 3 years of treatment to monitor endometrial effects. Results: as of December 31 2006, 1870 women were enrolled, of which 21% were hysterectomized. Median age is 53 years (33–72), BMI is <25 in 66%, =25<30 in 26%, >30 in 8%. Current or de novo users are 80% and 20%. 84% participants have at least one follow-up visit. 128 subjects performed already the 3 years TvUS and endometrial biopsy: so far no atypical hyperplasia or cancer was found. A modest increase of menopausal symptoms was observed (hot flashes 42% vs 52%, night sweating 39% vs 44%). Drop-outs are 23%, of which 13% due to AE including: 21 cancers (12 invasive BC, 1 DCIS), 13 CVD (3 VTE), 9 gynecological (5 endometrial polyps). Conclusions: combination of low dose T and HRT has reasonable safety profile, we have reached almost 1,900 women on study and AE rate is very low. These unblinded findings support the safety of the association of HRT and T. No significant financial relationships to disclose.
Background: The presurgical model is a useful tool to test drug activity on surrogate biomarkers ... more Background: The presurgical model is a useful tool to test drug activity on surrogate biomarkers of breast cancer, including proliferation measured by Ki-67. We previously demonstrated that 1 or 5 mg/per day of tamoxifen (T) given for 4 weeks before surgery reduced Ki-67 to the same extent than the standard 20 mg/d. Given the long half-life of T and its metabolites, a weekly dose (10 mg/w) may be worth testing. Raloxifene (R), another SERM, has been shown to reduce Ki-67 in a preoperative setting and to be an effective breast cancer (BC) preventive agent in postmenopausal women. Methods: 125 premenopausal estrogen receptor positive BC patients were randomly assigned to either T 10mg/w or R 60 mg/d or placebo (P) for 6 weeks before surgery in a 2:2:1 ratio. The primary endpoint was tissue change of Ki67. Secondary endpoints were other tissue and circulating biomarkers. Results: The median age was 44, 46, 44 and the median BMI was 23, 22, 22 in the P, R and T group, respectively. Tissue biomarkers (Ki-67, ER, PgR) were not significantly modulated by treatment. Only PgR was modestly down regulated by T and more by R but with not statistically significance. More evident were the effects on the circulating biomarkers. Both SERMs significantly reduced IGF-I/BP-3 ratio (mean change P:0; T:-0.01; R:-0.02; p=0.007) and cholesterol (mean change P: 13.73; T: -10.82; R: -8.96; p<.0001) with no difference between the two drugs. Both T and R modulated significantly fibrinogen level (mean change P: 9.3; T: -14.24; R: -35.88 p=0.002) and in particular R was more effective than T (p=0.034). Antithrombin III showed a significant reduction by treatment vs. placebo (mean change P: -2.28; T: -6.19; R: -6.85; P=0.04). SHBG levels were positively influenced by both T and R (mean change P: -10.21; T: 5.95; R: 6.2; p=0.002). Overall compliance measured with pill count was above 80%. No severe adverse events occurred. Conclusions: Our findings show a lack of effect of both SERMs on breast cancer cells proliferation, possibly due to insufficient doses in premenopausal women with elevated estrogen levels. In contrast, both T at very low dose and R at the standard dose were effective on circulating biomarkers. Interestingly, R was more active than T in reducing fibrinogen level, in line with its safer vascular profile. Citation Information: Cancer Prev Res 2010;3(1 Suppl):A78.
ImportanceSuccessful therapeutic cancer prevention requires definition of the minimal effective d... more ImportanceSuccessful therapeutic cancer prevention requires definition of the minimal effective dose. Aromatase inhibitors decrease breast cancer incidence in high-risk women, but use in prevention and compliance in adjuvant settings are hampered by adverse events.ObjectiveTo compare the noninferiority percentage change of estradiol in postmenopausal women with estrogen receptor–positive breast cancer given exemestane, 25 mg, 3 times weekly or once weekly vs a standard daily dose with a noninferiority margin of −6%.Design, Setting, and ParticipantsThis multicenter, presurgical, double-blind phase 2b randomized clinical trial evaluated 2 alternative dosing schedules of exemestane. Postmenopausal women with estrogen receptor–positive breast cancer who were candidates for breast surgery were screened from February 1, 2017, to August 31, 2019. Blood samples were collected at baseline and final visit; tissue biomarker changes were assessed from diagnostic biopsy and surgical specimen. Biomarkers were measured in different laboratories between April 2020 and December 2021.InterventionsExemestane, 25 mg, once daily, 3 times weekly, or once weekly for 4 to 6 weeks before surgery.Main Outcomes and MeasuresSerum estradiol concentrations were measured by solid-phase extraction followed by liquid chromatography–tandem mass spectrometry detection. Toxic effects were evaluated using the National Cancer Institute terminology criteria, and Ki-67 was assessed by immunohistochemistry.ResultsA total of 180 women were randomized into 1 of the 3 arms; median (IQR) age was 66 (60-71) years, 63 (60-69) years, and 65 (61-70) years in the once-daily, 3-times-weekly, and once-weekly arms, respectively. In the intention-to-treat population (n = 171), the least square mean percentage change of serum estradiol was −89%, −85%, and −60% for exemestane once daily (n = 55), 3 times weekly (n = 56), and once weekly (n = 60), respectively. The difference in estradiol percentage change between the once-daily and 3-times-weekly arms was −3.6% (P for noninferiority = .37), whereas in compliant participants (n = 153), it was 2.0% (97.5% lower confidence limit, −5.6%; P for noninferiority = .02). Among secondary end points, Ki-67 and progesterone receptor were reduced in all arms, with median absolute percentage changes of −7.5%, −5.0%, and −4.0% for Ki-67 in the once-daily, 3-times-weekly, and once-weekly arms, respectively (once daily vs 3 times weekly, P = .31; once daily vs once weekly, P = .06), and −17.0%, −9.0%, and −7.0% for progesterone receptor, respectively. Sex hormone–binding globulin and high-density lipoprotein cholesterol had a better profile among participants in the 3-times-weekly arm compared with once-daily arm. Adverse events were similar in all arms.Conclusions and RelevanceIn this randomized clinical trial, exemestane, 25 mg, given 3 times weekly in compliant patients was noninferior to the once-daily dosage in decreasing serum estradiol. This new schedule should be further studied in prevention studies and in women who do not tolerate the daily dose in the adjuvant setting.Trial RegistrationClinicalTrials.gov Identifier: NCT02598557; EudraCT: 2015-005063-16
Background: Low dose tamoxifen has shown comparable antiproliferative activity to 20 mg/day in bi... more Background: Low dose tamoxifen has shown comparable antiproliferative activity to 20 mg/day in biomarker trials, but its clinical efficacy is unclear. We assessed the effect of low dose tamoxifen, 10 mg on alternate day in most, on ipsilateral recurrence in high risk DCIS patients treated in a single institution. Methods: Following breast conserving surgery, women with DCIS received radiotherapy and/or low dose tamoxifen as per clinical judgment and patient preference. Multivariate Cox regression analyses adjusted for potential confounding variables were performed. Results: In a cohort of 1,091 women, median age was 53 years (IQR 46-62), 544 received radiotherapy versus 547 no radiotherapy. Of these, 883 had ER-positive DCIS, 467 received low-dose tamoxifen versus 416 no tamoxifen. After 7.7 years of median follow-up (IQR, 5.1-9.7), 235 ipsilateral recurrences and 62 contralateral tumors were observed. Low dose tamoxifen decreased any breast event (HR = 0.70, 95% CI, 0.54-0.91) and ipsilateral DCIS recurrence (HR = 0.66, 95% CI, 0.49-0.88), but not ipsilateral invasive recurrence (HR = 0.78, 95% CI, 0.56-1.09) or contralateral tumors (HR = 0.89, 95% CI, 0.51-1.55). Radiotherapy decreased any breast event (HR = 0.55, 95% CI, 0.42-0.72). Low dose tamoxifen was more effective in women aged >50 years for all events (HR = 0.51, 95% CI, 0.33-0.77) and ipsilateral recurrences (HR = 0.43, 95% CI, 0.26-0.72) than in women aged 50 or younger (HR = 0.84, 95% CI, 0.60-1.18 and HR = 0.80, 95% CI, 0.55-1.16, respectively, p-interaction = 0.03). Young age or premenopausal status, positive margins, high Ki67, high grade and low BMI were independent predictors of ipsilateral recurrence. No increase in endometrial cancers was observed and fewer deaths occurred in women on low dose tamoxifen. Conclusions: In high risk ER-positive DCIS, low-dose tamoxifen seems to be safe and effective in reducing ipsilateral recurrence, and represents a valuable option in women aged >50 years. A randomized clinical trial is underway to confirm these results. Supported by Lega Italiana per la Lotta contro i Tumori, AIRC, Italian Ministry of Health (RFPS-2006-1-339898), Gruppo bancario Credito Valtellinese. Citation Format: Aliana Guerrieri-Gonzaga, Ivana Sestak, Matteo Lazzeroni, Davide Serrano, Nicole Rotmensz, Massimiliano Cazzaniga, Clara Varricchio, Mangesh A. Thorat, Giancarlo Pruneri, Maria Cristina Leonardi, Viviana Galimberti, Bernardo Bonanni, Andrea DeCensi. Benefit of low-dose tamoxifen in a large, single-institution cohort of high-risk ER-positive DCIS. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1788.
Retinoids have been studied as chemopreventive compounds because of their role in regulating cell... more Retinoids have been studied as chemopreventive compounds because of their role in regulating cell growth, differentiation and apoptosis in preclinical models. Induction of apoptosis is a unique feature of fenretinide (4-hydroxyphenylretinamide, 4-HPR) the most studied retinoid in clinical trials of breast cancer (BC) prevention for its selective accumulation in the breast tissue and its low toxicity. Fenretinide is effective in inhibiting the growth of BRCA1 mutated BC cell lines. Recent studies showed that it modulates gene expression in ovarian cells, with an up-regulation of expression of proapoptotic genes in OVCA433 cells. The fifteen-year follow up of a randomized phase III trial of fenretinide to prevent second BC indicates that it induced a 17% reduction of second BC incidence. More importantly, when stratified by menopausal status, the analysis showed a 38%, statistically significant reduction of second BC in premenopausal women and this effect persisted for up to 15 years. Interestingly, the younger were the women (≤ 40 years), the greater was the trend of benefit by fenretinide. When considering the protective activity of fenretinide on second BC and a similar trend on ovarian cancer (OC) it appears that young women at high risk for both diseases such as carriers of germline BRCA1 and BRCA2 mutations or those with a high family risk may be ideal candidates for further investigation on this retinoid. Since a reduction of second BC might be a surrogate marker of primary prevention, a favorable effect of fenretinide provides strong rationale for a primary prevention trial in unaffected women at high-risk for BC. The European Institute of Oncology (IEO, Milan, Italy) has promoted a multi-centric (15 centres nationwide), randomized phase III placebo-controlled study with fenretinide in healthy young women: 758 healthy women, 25-44 years old, at increased BC risk (BRCA1/2 mutation carriers or subjects with mutation probability ≥20% acc. to BRCAPRO), will be randomized to 4-HPR 200 mg/day vs placebo for 5 years followed by a 10 years follow up period. We will perform a clinical examination every 6 months, and annual breast ultrasound and breast MRI. For subjects ≥ 35 years old also an annual mammography is requested. All subjects will undergo a transvaginal ultrasound at least once a year. At each visit, safety tests (β-HCG, AST, ALT, blood count, creatinine, glycemia, lipid profile, CA-125), and blood samples for biomarkers evaluation at baseline, 12, 36, and 60 months. Enrollment started at the IEO in December 2009. The other centers are expected to start within early 2011. The primary endpoint of the trial is to assess the efficacy of fenretinide in reducing the incidence of invasive BC and ductal intraepithelial neoplasia (DIN). Secondary endpoints are the incidence of non-invasive breast disorders, OC, other cancers and the study of various risk biomarkers. In particular, we will evaluate the change in circulating biomarkers of the IGF system, androgens, retinol binding protein (RBP-4), insulin, blood glucose and VEGF. Genotyping of single nucleotide polymorphisms (SNPs) linked to BC risk (MTHFR, COMT, GH, IGFBP-3, AR, TGF-β genes), degree of methylation of RASSAF1 and RARβ and circulating progranulin will be assessed. The results will be correlated with mammographic instrumental measurements, plasma and tissue biomarkers after 1 year treatment. Citation Information: Cancer Prev Res 2010;3(12 Suppl):A71.
A59 The presurgical model is a useful tool to screen and evaluate drug activity and select new ch... more A59 The presurgical model is a useful tool to screen and evaluate drug activity and select new chemopreventive agents. Cancer cell proliferation measured by ki-67 is considered to be a reliable surrogate biomarker in assessing the efficacy of chemopreventive agents. Exemestane (Exe), a highly specific steroidal aromatase inactivator, has shown clinical efficacy in the treatment of postmenopausal breast cancer (BC) patients. Epidemiologic evidence suggests that anti-inflammatory drugs reduce the risk of BC. Celecoxib (Cel) is a selective inhibitor of the enzyme COX-2 (Cyclooxygenase-2), which is overexpressed in human breast tumors, BC cell lines, and rodent mammary tumors, and it has shown significant antiproliferative and proapoptotic properties. No clinical data are known so far on the antiproliferative activity of Cel in breast cancer cells. The primary endpoint of the present study is to assess the antiproliferative activity (as measured by ki-67 percentage change) of Exe 25mg/d or Cel 800 mg/d relative to placebo in postmenopausal ER positive BC patients treated for 6 weeks before surgery. Estimating a 20% increase in the placebo arm and a 25 % decrease in the treatment arms with 80% power and two-tailed significance at 5 %, a total of 90 subjects (18 in the placebo arm and 36 in each treatment arm) was required. Secondary endpoints were changes in ER and PgR expression, apoptosis, gene expression profile focusing on nuclear receptor coregulators (AIB1, SRC1, TIF-2/GRIP1, N-CoR and SMRT) on frozen tissue, circulating biomarkers (sex hormones, markers of inflammation and hemostasis, insulin-like growth factors, bone markers) and genomic DNA analyses of genetic polymorphisms related to BC, hormone metabolism, response to DNA damage, and cardiovascular events. One hundred and one patients were randomized to either Exe 25 mg/d (n=41), or Cel 800 mg/d (n=40) or placebo (n=20). Baseline median age and BMI were 62, 65, 61 years, 26, 25, 27 in the Exe, Cel and placebo group, respectively. At baseline median ki67% was 21, 18, 18 in the Exe, Cel and placebo arm, respectively. After adjustment for baseline values, Ls means of changes of ki67 were -11.5 (-14.1, -8.9), 1.3 (-1.4, 3.9), 3.2 (-0.5, 6.8) (P among arms <.001; P among active treatments <.001). After adjustment for baseline values, ls means of changes of PgR were -26.2 (-34.1, -18.4), -6.3 (-14.3, 1.7), 2.1 (-8.8, 13.1) (P among arms <.001; P among active treatments <.001). After adjustment for baseline values, ls means of changes of ER were -2.6 (-7.8, 2.7), 0.8 (-4.5, 6.1), -0.7 (-8.0, 6.7) (P among arms 0.671; P among active treatments 0.374). Compliance was higher than 75% and no severe AEs were observed. In this postmenopausal population, Exe has shown a significant reduction of cell proliferation and PgR expression. Bone biomarkers are currently being measured as long as the other secondary endpoints and final results will be helpful to plan further prevention studies with Exe in high-risk subjects. Conversely, only a modest non significant modulation of PgR expression was observed in the Cel arm despite the relatively high dose of the drug. Evaluation of secondary endpoints, including expression of Cox-2 activity, will help to better elucidate the activity of both agents. Citation Information: Cancer Prev Res 2008;1(7 Suppl):A59.
Background: Metformin has been associated with decreased breast cancer (BC) incidence in diabetic... more Background: Metformin has been associated with decreased breast cancer (BC) incidence in diabetic patients in epidemiological studies. Moreover, this drug results in initiation of an AMPK-dependent energy stress response which can adversely affect survival of breast cancer cell lines and inhibition of PI3K/Akt/mTOR signaling leading to reduced proliferation of BC cell lines. Methods: We conducted a randomized, pre-surgical, phase IIb, placebo-controlled, biomarker trial in women with stage I-III BC candidate to elective surgery. The primary endpoint was the change in cell proliferation in malignant, dysplastic and hyperplastic tissue as measured by Ki-67 labeling index (LI). With 150 subjects, the study was 80% powered to test for the interaction between metformin activity and ER status. Two interim analyses are being planned after 100 and 200 women enrolled. Results: As of June 18, 2010, 175 subjects have been randomized and 162 have completed treatment. Here we report data on the first 100 women enrolled. At the symposium, full data on the first 200 women enrolled will be available. As of December 31, 2009, a total of 163 women were screened, 26 were not eligible and 40 refused to participate, 6 dropped out during the study for AEs (n=2) or refusal to continue treatment (n=4), thus leaving 95 subjects assessable for the primary endpoint. The main subject and tumor characteristics blinded as to the allocated arm were mean age 52 (31-77), Pre/postmenopause, 54/41, mean BMI, 23.6 (18.0-40.2). At baseline, median Ki-67LI was 18% (range 4%-65%) at biopsy and 19% (4%-70%) after 4 weeks at surgery. All adverse events except for 1 SAE were grade 1 or 2, consisting of G2 nausea and G2 diarrhea in 4% and 6% of the cases, respectively. The prevalence of ductal intraepithelial neoplasia was 91% (median Ki-67 LI, 10%) in samples both adjacent and distant from the tumor, whereas the prevalence of ductal hyperplasia was 77% (median Ki-67LI, 2%) in samples distant from the tumor. Conclusions: Our preliminary results show the feasibility, high compliance and safety of a metformin trial in breast cancer patients. Assessment of tissue and circulating biomarkers is currently ongoing to characterize the whole spectrum of metformin activity in malignant and dysplastic tissue. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr PD03-02.
1514 Background: Primary prevention trials have shown that tamoxifen (T) lowers ER+ breast cancer... more 1514 Background: Primary prevention trials have shown that tamoxifen (T) lowers ER+ breast cancer (BC) incidence by 48%. While the IBIS I update showed mixed findings, the Italian trial showed an interesting positive risk/benefit ratio in T and hormone replacement therapy (HRT) users: fewer BC, endometrial cancer comparable to placebo, and no cardiovascular diseases (CVD) excess. In a phase II study, low dose T and HRT showed a safe gynecological profile and did not increase menopausal symptoms. Moreover low dose T maintains the same antiproliferative effects as the standard dose. To improve BC prevention and quality of life (QoL) in menopausal women we started a multicentric, phase III trial of low dose T in HRT users. Methods: current or de novo HRT users are randomized to T 5 mg/day or placebo for 5 yrs. The primary aim is the reduction of invasive or in situ BC. Secondary aims are: safety, gene polymorphisms (SNPs) correlated to BC risk and T activity. In a subgroup transvaginal ultrasound (TvUS) and endometrial biopsy is being performed after 3 years of treatment to monitor endometrial effects. Results: as of December 31 2006, 1870 women were enrolled, of which 21% were hysterectomized. Median age is 53 years (33–72), BMI is <25 in 66%, =25<30 in 26%, >30 in 8%. Current or de novo users are 80% and 20%. 84% participants have at least one follow-up visit. 128 subjects performed already the 3 years TvUS and endometrial biopsy: so far no atypical hyperplasia or cancer was found. A modest increase of menopausal symptoms was observed (hot flashes 42% vs 52%, night sweating 39% vs 44%). Drop-outs are 23%, of which 13% due to AE including: 21 cancers (12 invasive BC, 1 DCIS), 13 CVD (3 VTE), 9 gynecological (5 endometrial polyps). Conclusions: combination of low dose T and HRT has reasonable safety profile, we have reached almost 1,900 women on study and AE rate is very low. These unblinded findings support the safety of the association of HRT and T. No significant financial relationships to disclose.
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