Association of PALB2 sequence variants with the risk of familial and early-onset breast cancer in a South-American population.

BACKGROUND: Germline mutations in PALB2 have been identified in approximately 1% of familial breast cancer (BC) in several populations. Nevertheless its contribution in the South-American population is unknown. The goal of this study was to determine the prevalence of PALB2 mutations in the Chilean population. METHODS: 100 Chilean BRCA1/2-negatives familial BC cases were included for the PALB2 mutation analysis. We use conformational sensitive gel electrophoresis and direct sequencing. Using a case-control design, we studied the identified variants in 436 BC cases and 809 controls to evaluate their possible association with BC risk. RESULTS: No pathogenic mutations were detected. We identified three variants, the variant c.1861C > A not previously described was found in one of the 436 cases and none of the 809 controls. The bioinformatic analyses indicate that this variant probably is not pathogenic. PALB2 c.1676A > G (rs152451A/G) and c.2993C > T (rs45551636C/T) variants were significantly associated with increased BC risk only in cases with a strong family history of BC (OR = 1.9 [CI 95% 1.3-2.8] p < 0.01 and OR = 3.3 [CI 95% 1.4-7.3] p < 0.01, respectively). The rs152451A/G-rs45551636C/T composite genotype produce increase of the BC risk in cases with a strong family history of BC (OR = 3.6 [CI 95% 1.7-8.0] p = 0.003). The rs152451-G/rs45551636-C and rs152451-G/rs45551636-T haplotypes were associated with an increased BC risk only in cases with a strong family history of BC (OR = 1.6 [CI 95% 1.0-2.5] p = 0.05 and OR = 3.7 [CI 95% 1.8-7.5] p < 0.001, respectively). CONCLUSION: Our results suggest that PALB2 c.1676A > G and c.2993C > T play roles in BC risk in women with a strong family history of BC.

Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomised trial.

BACKGROUND: For women with oestrogen receptor (ER)-positive early breast cancer, treatment with tamoxifen for 5 years substantially reduces the breast cancer mortality rate throughout the first 15 years after diagnosis. We aimed to assess the further effects of continuing tamoxifen to 10 years instead of stopping at 5 years. METHODS: In the worldwide Adjuvant Tamoxifen: Longer Against Shorter (ATLAS) trial, 12,894 women with early breast cancer who had completed 5 years of treatment with tamoxifen were randomly allocated to continue tamoxifen to 10 years or stop at 5 years (open control). Allocation (1:1) was by central computer, using minimisation. After entry (between 1996 and 2005), yearly follow-up forms recorded any recurrence, second cancer, hospital admission, or death. We report effects on breast cancer outcomes among the 6846 women with ER-positive disease, and side-effects among all women (with positive, negative, or unknown ER status). Long-term follow-up still continues. This study is registered, number ISRCTN19652633. FINDINGS: Among women with ER-positive disease, allocation to continue tamoxifen reduced the risk of breast cancer recurrence (617 recurrences in 3428 women allocated to continue vs 711 in 3418 controls, p=0·002), reduced breast cancer mortality (331 deaths vs 397 deaths, p=0·01), and reduced overall mortality (639 deaths vs 722 deaths, p=0·01). The reductions in adverse breast cancer outcomes appeared to be less extreme before than after year 10 (recurrence rate ratio [RR] 0·90 [95% CI 0·79­1·02] during years 5­9 and 0·75 [0·62­0·90] in later years; breast cancer mortality RR 0·97 [0·79­1·18] during years 5­9 and 0·71 [0·58­0·88] in later years). The cumulative risk of recurrence during years 5­14 was 21·4% for women allocated to continue versus 25·1% for controls; breast cancer mortality during years 5­14 was 12·2% for women allocated to continue versus 15·0% for controls (absolute mortality reduction 2·8%). Treatment allocation seemed to have no effect on breast cancer outcome among 1248 women with ER-negative disease, and an intermediate effect among 4800 women with unknown ER status. Among all 12,894 women, mortality without recurrence from causes other than breast cancer was little affected (691 deaths without recurrence in 6454 women allocated to continue versus 679 deaths in 6440 controls; RR 0·99 [0·89­1·10]; p=0·84). For the incidence (hospitalisation or death) rates of specific diseases, RRs were as follows: pulmonary embolus 1·87 (95% CI 1·13­3·07, p=0·01 [including 0·2% mortality in both treatment groups]), stroke 1·06 (0·83­1·36), ischaemic heart disease 0·76 (0·60­0·95, p=0·02), and endometrial cancer 1·74 (1·30­2·34, p=0·0002). The cumulative risk of endometrial cancer during years 5­14 was 3·1% (mortality 0·4%) for women allocated to continue versus 1·6% (mortality 0·2%) for controls (absolute mortality increase 0·2%). INTERPRETATION: For women with ER-positive disease, continuing tamoxifen to 10 years rather than stopping at 5 years produces a further reduction in recurrence and mortality, particularly after year 10. These results, taken together with results from previous trials of 5 years of tamoxifen treatment versus none, suggest that 10 years of tamoxifen treatment can approximately halve breast cancer mortality during the second decade after diagnosis. FUNDING: Cancer Research UK, UK Medical Research Council, AstraZeneca UK, US Army, EU-Biomed.

Association of genetic variants at TOX3, 2q35 and 8q24 with the risk of familial and early-onset breast cancer in a South-American population.

Recent Genome-Wide Association Studies have identified several single nucleotide polymorphisms (SNPs) associated with breast cancer (BC) among women of Asian, European, and African-American ancestry. Nevertheless, the contribution of these variants in the South American population is unknown. Furthermore, there is little information about the effect of these risk alleles in women with early BC diagnosis. In the present study, we evaluated the association between rs3803662 (TOX3, also known as TNRC9), rs13387042 (2q35), and rs13281615 (8q24) with BC risk in 344 Chilean BRCA1/2-negative BC cases and in 801 controls. Two SNPs, rs3803662 and rs13387042, were significantly associated with increased BC risk in familial BC and in non-familial early-onset BC. The risk of BC increased in a dose-dependent manner with the number of risk alleles (P-trend < 0.0001 and 0.0091, respectively). The odds ratios for BC in familial BC and in early-onset non-familial BC were 3.76 (95%CI 1.02-13.84, P = 0.046) and 8.0 (95%CI 2.20-29.04, P = 0.002), respectively, for the maximum versus minimum number of risk alleles. These results indicate an additive effect of the TOX3 rs3803662 and 2q35 rs13387042 alleles for BC risk. We also evaluated the interaction between rs3803662 and rs13387042 SNPs. We observed an additive interaction only in non-familial early-onset BC cases (AP = 0.72 (0.28-1.16), P = 0.001). No significant association was observed for rs13281615 (8q24) with BC risk in women from the Chilean population. The strongly increased risk associated with the combination of low-penetrance risk alleles supports the polygenic inheritance model of BC.

Genetic variants in FGFR2 and MAP3K1 are associated with the risk of familial and early-onset breast cancer in a South-American population.

Genome-Wide Association Studies have identified several loci associated with breast cancer (BC) in populations of different ethnic origins. One of the strongest associations was found in the FGFR2 gene, and MAP3K1 has been proposed as a low-penetrance BC risk factor. In this study, we evaluated the associations among FGFR2 SNPs rs2981582, rs2420946, and rs1219648; and MAP3K1 rs889312, with BC risk in 351 BRCA1/2-negative Chilean BC cases and 802 controls. All the SNPs studied were significantly associated with increased BC risk in familial BC and in non-familial early-onset BC, in a dose-dependent manner. Subjects with 3 risk alleles were at a significantly increased risk of BC compared with subjects with 0-2 risk alleles, in both familial BC and early-onset non-familial BC (OR = 1.47, 95 % CI 1.04-2.07, P = 0.026 and OR = 2.04 95 % CI 1.32-3.24, P < 0.001, respectively). In the haplotype analysis, the FGFR2 rs2981582 T / rs2420946 T / rs1219648 G haplotype (ht2) was associated with a significantly increased BC risk compared with the rs2981582 C / rs2420946 C / rs1219648 A haplotype in familial BC and in non-familial early-onset BC (OR = 1.32, 95 % CI 1.06-1.65, P = 0.012; OR = 1.46, 95 % CI 1.11-1.91, P = 0.004, respectively). When the FGFR2 ht2 and MAP3K1 rs889312 were evaluated as risk alleles, the risk of BC increased in a dose-dependent manner as the number of risk alleles increased (P trend <0.0001), indicating an additive effect. Nevertheless, there is no evidence of an interaction between FGFR2 ht2 and the MAP3K1 rs889312 C allele. These findings suggest that genetic variants in the FGFR2 and MAP3K1 genes may contribute to genetic susceptibility to BC.

The BARD1 Cys557Ser variant and risk of familial breast cancer in a South-American population.

Since the discovery of the BRCA1 and BRCA2 genes, much work has been carried out to identify further breast cancer (BC) susceptibility genes. BARD1 (BRCA1-associated ring domain) was originally identified as a BRCA1-interacting protein but has also been described in tumor-suppressive functions independent of BRCA1. Some association studies have suggested that the BARD1 Cys557Ser variant might be associated with increased risk of BC, but others have failed to confirm this finding. To date, this variant has not been analyzed in Spanish or South-American populations. In this study, using a case-control design, we analyzed the C-terminal Cys557Ser change in 322 Chilean BC cases with no mutations in BRCA1 or BRCA2 and in 570 controls in order to evaluate its possible association with BC susceptibility. BARD1 Cys557Ser was associated with an increased BC risk (P = 0.04, OR = 3.4 [95 % CI 1.2-10.2]) among cases belonging to families with a strong family history of BC. No difference between single cases affected with age <50 years at diagnosis (n = 117) and controls was observed for carriers of Cys/Ser genotype. It is likely that this variant is not involved in BC risk in this group of women. We also analyzed a possible interaction between BARD1 557Ser/XRCC3 241Met variants considering the role of both genes in the maintenance of genome integrity. The combined genotype Cys/Ser-carrier with the XRCC3 241Met allele was associated with an increased BC risk (P = 0.02, OR = 5.01 [95 % CI 1.36-18.5]) among women belonging to families with at least three BC and/or ovarian cancer cases. Our results suggest that BARD1 557Ser and XRCC3 241Met may play roles in BC risk in women with a strong family history of BC. Nevertheless there is no evidence of an interaction between the two SNPs. These findings should be confirmed by other studies and in other populations.

Spectrum of BRCA1/2 point mutations and genomic rearrangements in high-risk breast/ovarian cancer Chilean families.

The distribution of BRCA1/2 germline mutations in breast/ovarian cancer (BC/OC) families varies among different populations. In the Chilean population, there are only two reports of mutation analysis of BRCA1/2, and these included a low number of BC and/or OC patients. Moreover, the prevalence of BRCA1/2 genomic rearrangements in Chilean and in other South American populations is unknown. In this article, we present the mutation-detection data corresponding to a set of 326 high-risk families analyzed by conformation-sensitive gel electrophoresis and heteroduplex analysis. To determine the contribution of BRCA1/2 LGRs in Chilean BC patients, we analyzed 56 high-risk subjects with no pathogenic BRCA1/2 point mutations. Germline BRCA1/2 point mutations were found in 23 (7.1%) of the 326 Chilean families. Families which had at least three BC and/or OC cases showed the highest frequency of mutations (15.9%). We identified 14 point pathogenic mutations. Three recurrent mutations in BRCA1 (c.187_188delAG, c.2605_2606delTT, and c.3450_3453delCAAG) and three in BRCA2 (c.4969_4970insTG, c.5374_5377delTATG, and c.6503_6504delTT) contributed to 63.6 and 66.7% of all the deleterious mutations of each gene, which may reflect the presence of region-specific founder effects. Taken together BRCA1/2 recurrent point mutations account for 65.2% (15/23) of the BRCA1/2 (+) families. No large deletions or duplications involving BRCA1/2 were identified in a subgroup of 56 index cases negative for BRCA1/2 point mutations. Our study, which is the largest conducted to date in a South American population, provides a comprehensive analysis on the type and distribution of BRCA1/2 mutations and allelic variants.

Variants in DNA double-strand break repair genes and risk of familial breast cancer in a South American population.

The double-strand break (DSB) DNA repair pathway has been implicated in breast cancer (BC). RAD51 and its paralogs XRCC3 and RAD51D play an important role in the repair of DSB through homologous recombination (HR). Some polymorphisms including XRCC3-Thr241Met, RAD51-135G>C, and RAD51D-E233G have been found to confer increased BC susceptibility. In order to detect novel mutations that may contribute to BC susceptibility, 150 patients belonging to 150 Chilean BRCA1/2-negative families were screened for mutations in XRCC3. No mutations were detected in the XRCC3 gene. In addition, using a case-control design we studied the XRCC3-Thr241Met, and RAD51D-E233G polymorphisms in 267 BC cases and 500 controls to evaluate their possible association with BC susceptibility. The XRCC3 Met/Met genotype was associated with an increased BC risk (P = 0.003, OR = 2.44 [95%CI 1.34-4.43]). We did not find an association between E233G polymorphism and BC risk. We also analyzed the effect of combined genotypes among RAD51-135G>C, Thr241Met, and E233G polymorphisms on BC risk. No interaction was observed between Thr241Met and 135G>C. The combined genotype Thr/Met-E/G was associated with an increased BC risk among women who (a) have a family history of BC, (b) are BRCA1/2-negative, and (c) were <50 years at onset (n = 195) (P = 0.037, OR = 10.5 [95%CI 1.16-94.5]). Our results suggested that the variability of the DNA HR repair genes XRCC3 and RAD51D may play a role in BC risk, but this role may be underlined by a mutual interaction between these genes. These findings should be confirmed in other populations.

Non-BRCA1/2 Variants Detected in a High-Risk Chilean Cohort With a History of Breast and/or Ovarian Cancer.

METHODS: Data were retrospectively collected from the registry of the High-Risk Breast and Ovarian Cancer Program at Clínica Las Condes, Santiago, Chile. Data captured included index case diagnosis, ancestry, family history, and genetic test results. RESULTS: Three hundred fifteen individuals underwent genetic testing during the study period. The frequency of germline pathogenic and likely pathogenic variants in a breast or ovarian cancer predisposition gene was 20.3%. Of those patients who underwent testing with a panel of both high- and moderate-penetrance genes, 10.5% were found to have pathogenic or likely pathogenic variants in non-BRCA1/2 genes. CONCLUSION: Testing for non-BRCA1 and -2 mutations may be clinically relevant for individuals who are suspected to have a hereditary breast or ovarian cancer syndrome in Chile. Comprehensive genetic testing of individuals who are at high risk is necessary to further characterize the genetic susceptibility to cancer in Chile.

Association of common ATM variants with familial breast cancer in a South American population.

BACKGROUND: The ATM gene has been frequently involved in hereditary breast cancer as a low-penetrance susceptibility gene but evidence regarding the role of ATM as a breast cancer susceptibility gene has been contradictory. METHODS: In this study, a full mutation analysis of the ATM gene was carried out in patients from 137 Chilean breast cancer families, of which 126 were BRCA1/2 negatives and 11 BRCA1/2 positives. We further perform a case-control study between the subgroup of 126 cases BRCA1/2 negatives and 200 controls for the 5557G>A missense variant and the IVS38-8T>C and the IVS24-9delT polymorphisms. RESULTS: In the full mutation analysis we detected two missense variants and eight intronic polymorphisms. Carriers of the variant IVS24-9delT, or IVS38-8T>C, or 5557G>A showed an increase in breast cancer risk. The higher significance was observed in the carriers of IVS38-8T>C (OR = 3.09 [95%CI 1.11-8.59], p = 0.024). The IVS24-9 T/(-T), IVS38-8 T/C, 5557 G/A composite genotype confered a 3.19 fold increase in breast cancer risk (OR = 3.19 [95%CI 1.16-8.89], p = 0.021). The haplotype estimation suggested a strong linkage disequilibrium between the three markers (D' = 1). We detected only three haplotypes in the cases and control samples, some of these may be founder haplotypes in the Chilean population. CONCLUSION: The IVS24-9 T/(-T), IVS38-8 T/C, 5557 G/A composite genotype alone or in combination with certain genetic background and/or environmental factors, could modify the cancer risk by increasing genetic instability or by altering the effect of the normal DNA damage response.

RAD51 135G>C polymorphism and risk of familial breast cancer in a South American population.

Several studies have reported that mutations in genes involved in maintenance of genome integrity may be responsible for increased cancer risk. Human RAD51, known to function in DNA repair, interacts with a number of proteins implicated in breast cancer (BC), including BRCA1 and BRCA2. Few studies have investigated the role of RAD51 gene variations in familial BC. To detect potential novel gene defects that may contribute to hereditary BC susceptibility, 143 patients belonging to 143 Chilean families tested for BRCA1 and BRCA2 mutations were screened for mutations in RAD51, using conformational sensitive gel electrophoresis (CSGE) and DNA sequencing. No mutations were detected in the exon or splice-boundary regions of the RAD51 gene in these families. The RAD51 135G>C polymorphism (c.-98G>C, rs1801320) was studied in a case-control design, to evaluate its possible association with BC susceptibility. The frequency of the RAD51 135C allele was established in 143 cases and 247 controls, using restriction fragment length polymorphism-polymerase chain reaction. RAD51 135C genotypes (G/C and C/C) were associated with an increased BC risk only among women with (a) a family history of BC, (b) BRCA1/2 negative (n = 131), and (c) age at onset <50 years (P = 0.020; OR = 2.17, 95% CI = 1.11-4.24). Thus, we propose that RAD51 135G>C polymorphism presents an increased risk of familial BC in women with age < 50 years at diagnosis, and this polymorphism may be a BC risk variant. This finding should be confirmed in other populations.

Increased risk of recurrence after hormone replacement therapy in breast cancer survivors.

BACKGROUND: Hormone replacement therapy (HT) is known to increase the risk of breast cancer in healthy women, but its effect on breast cancer risk in breast cancer survivors is less clear. The randomized HABITS study, which compared HT for menopausal symptoms with best management without hormones among women with previously treated breast cancer, was stopped early due to suspicions of an increased risk of new breast cancer events following HT. We present results after extended follow-up. METHODS: HABITS was a randomized, non-placebo-controlled noninferiority trial that aimed to be at a power of 80% to detect a 36% increase in the hazard ratio (HR) for a new breast cancer event following HT. Cox models were used to estimate relative risks of a breast cancer event, the maximum likelihood method was used to calculate 95% confidence intervals (CIs), and chi(2) tests were used to assess statistical significance, with all P values based on two-sided tests. The absolute risk of a new breast cancer event was estimated with the cumulative incidence function. Most patients who received HT were prescribed continuous combined or sequential estradiol hemihydrate and norethisterone. RESULTS: Of the 447 women randomly assigned, 442 could be followed for a median of 4 years. Thirty-nine of the 221 women in the HT arm and 17 of the 221 women in the control arm experienced a new breast cancer event (HR = 2.4, 95% CI = 1.3 to 4.2). Cumulative incidences at 5 years were 22.2% in the HT arm and 8.0% in the control arm. By the end of follow-up, six women in the HT arm had died of breast cancer and six were alive with distant metastases. In the control arm, five women had died of breast cancer and four had metastatic breast cancer (P = .51, log-rank test). CONCLUSION: After extended follow-up, there was a clinically and statistically significant increased risk of a new breast cancer event in survivors who took HT.

Scintimammography in the evaluation of axillary lymph node invasion in patients with breast cancer

Purpose. To correlate axillary Technetium-99m-sestamibi uptake with the axillary histology in patients with proven breast cancer. Secondly, to correlate the breast scintimammography results with the tumor histology. Materials and methods. Fifty-one patients with operable breast cancer T1, T2 or T3 and N0 or N1 had a scintimammography before surgery. Images were interpreted directly from the computer screen by two specialists who did not have knowledge about clinical or radiological information concerning the patients. Surgical treatment included conservative surgery or mastectomy, both followed by axillary dissection for malignant tumors (45 patients) and only excision for benign lesions (6 patients). Statistical analysis correlated scintimammography and histologic results. Results. The sensitivity and specificity of Tc99m-sestamibi to assess histologic lymph node involvement in patients with operable breast cancer was 35 percent (95 percent CI:14-61 percent) and 57 percent (95 percent CI:37-75 percent) respectively. The positive predictive value was 33 percent (95 percent CI:13-58 percent) and the negative predictive value was 59 percent ( 95 percent CI: 38-77 percent). The sensitivity and specificity of Tc99-sestamibi to assess breast tumor malignancy was 97 percent (95 percent CI:88-99 percent) and 33 percent (95 percent CI: 4-77 percent) respectively, calculated in only six patients. The positive predictive value was 91 percent (95 percent CI: 80-97 percent) and the negative predictive value was 66 percent (95 percent CI:9-99 percent). Conclusion. Our findings regarding the preoperative axillary assessment with Tc99m-sestamibi do not support the use of this imaging modality for this purpose

Mastopatía fibroquística: modificaciones clínicas y hormonales con la administración continua de acetato de medroxiprogesterona / Fibrocystic mastopathy: clinical and hormonal modifications with the continuous administration of medroxy-progesterone acetate

Se analizan 41 mujeres portadoras de mastopatía fibroquística severa, que fueron divididas al azar en los grupos. Uno recibió A.M.P. por vía oral en dosis de 100 mg diarios durante 90 días, y el otro, placebo en igual forma. El grupo con A.M.P. obtuvo un número significativamente mayor de respuesta clínicas favorables: 95,7% sobre molestias subjetivas (54,5% con placebo) y 100% sobre signología (9,9%) con placebo). Se determinaron los niveles plasmáticos de FSH. LH, estrógenos y progesterona en el ciclo previo al tratamiento, durante los 90 días de tratamiento (más medroxiprogesterona), y en 7 mujeres hasta 6 semanas después del tratamiento, se concluye que todas las pacientes con MFO presentaron ciclos ovulatorios, probablemente con fase lútea inadecuada. La A.M.P., en las dosis empleadas, consiguió niveles plasmáticos de 8-10 ng/ml y produjo un significativo descenso, precoz y mantenido, de los niveles de estrógenos y progesterona, que se recuperaron antes de las 6 semanas de finalizado el tratamiento

Patología anexial no inflamatoria durante el uso de implantes de levonorgestrel (Norplant) o dispositivos intrauterinos / Annexial pathology non inflammatory during levonorgestrel implant use (Norplant) or intrauterine devices

Se revisan las fichas clínicas de 477 mujeres usuarias de Norplant y 200 portadoras de T-Cobre que reúnen 28548 y 9752 meses de exposición, respectivamente. Se evaluó la presencia de masas anexiales no inflamatorias iguales o mayores de 5 cm, analizando su frecuencia, evolución natural y terminaciones. En 54 usuarias de Norplant (11,3%) se diagnosticaron 62 episodios de masas anexiales que corresponden a 2,6 episodios por 1.200 meses de uso. En 7 usuarias de T-Cobre (3,5%) se diagnosticaron 8 episodios, con una tasa de 1,0 episodios por 1.200 meses de uso. Las masas fueron casi siempre ováricas y unilaterales y se interpretaron en su mayoría como quístes ováricos funcionales por sus características clínicas y ecográficas y por su evolución. En 2 mujeres de cada grupo la masa se ubicó en la trompa y correspondió a embarazos tubarios. La incidencia de embarazo tubario en el grupo Norplant fue de 1 por 100 años mujer, inferior a lo ocurrido en el grupo T-Cobre y a lo referido con otras progestinas. En la mayoría de los casos (72,6% en el grupo Norplant y 62,5% en el grupo T-Cobre) la masa anexial era asintomática y se detectó en un control ginecológico de rutina. Los motivos de consulta en los otros casos fueron algia pelviana y sangrado anormal. Los episodios regresaron espontáneamente en el 90,4% de las usuarias de Norplant y en el 62,5% del grupo T-Cobre, la mayoría de ellos en los 60 días que siguieron al diagnóstico. Las indicaciones quirúrgicas en usuarias de Norplant fueron 2 embarazos tubarios, 2 quistes foliculares y 2 tumores neoplásicos. En el grupo T-Cobre las indicaciones quirúrgicas fueron 2 embarazos ectópicos y un quiste ovárico simple. Se concluye que los quistes funcionales ováricos son más frecuentes en mujeres portadoras de implantes Norplant que en los controles, que generalmente son asintomáticos y regresan espontáneamente. Deben ser vigilados hasta su desaparición por la posibilidad que se trate de una masa anexial de otra etiología que requiera tratamiento quirúrgico

Tratamiento con bromocriptina de la mastopatía fibroquística / Treatment of fibrocystic mastopathy with bromocriptine

Se estudia el efecto de bromocriptina administrada en forma continua o rítmica en mujeres con mastopatía fibroquística sintomática. 90 mujeres seleccionadas configuraron tres grupos al azar: Grupo 1 (bromocriptina continua) recibió bromocriptina 5 mg diarios del 1o al 25o día del ciclo, durante tres ciclos. Grupo 2 (bromocriptina rítmica), placebo desde el 1o al 25o día por tres ciclos. Los tratamientos se administraron según doble ciego 1/2 tableta 4 veces al día. El seguimiento fué cada 30 días, hasta completar siete meses de observación. La evolución del cuadro clínico en cada control se objetivó con diferentes medidas para la mastalgia, nodularidad y sensibilidad. Se determinaron niveles plasmáticos de prolactina, estrógenos o progesterona en la fase lútea del ciclo previo al tratamiento y durante el segundo mes de tratamiento. Resultados: 75% a 90% de las mujeres que recibieron bromocriptina continua o rítmica presentaron respuestas favorables. Quedaron asitomáticas 50% del grupo 1 y 35% del grupo 2. La respuesta fue significativamente mejor que con placebo, que presentó 35% de respuestas favorables y sólo 10% queda asintomática. El grupo bromocriptina continua respondió discretamente mejor que el rítmico, pero no fue estadísticamente significativo. Con bromocriptina de observó un notorio descenso de la prolactina plasmática, que coincidió con un significativo ascenso de los niveles de progesterona. Los efectos colaterales más relevantes fueron decaimiento, mareos, náuseas, vómitos y cefalea, que ocurrieron aproximadamente en un 30%. Estas molestias fueron disminuyendo durante el transcurso del tratamiento. Se correlaciona la respuesta clínica favorable con el aumento de progesterona plasmática y el descenso de la prolactina

Programa de screening y tratamiento de cáncer de mama / Screening and treatment program of breast cancer

En enero de 1988 comenzamos un programa piloto de screening en cáncer de mama para mujeres asintomáticas. Una mamografía con dos proyecciones se planificó cada 2 años para las mujeres entre 40 y 50 años y anualmente para aquéllas con 50 años o más. Si en esta mamografía se encontraban hallazgos anormales, las mujeres fueron evaluadas con estudios localizados y examen físico realizado por un comité constituído por un radiólogo, un cirujano y un oncólogo. Si luego de esta evaluación la anormalidad del estudio persiste, a juicio del comité, la paciente se planifica para biopsia excisional. Si el resultado de la biopsia es positivo y la enfermedad es localizada, la paciente es tratada conservadoramente con radioterapia. Hasta el 31 de enero de 1990 en 1.742 mujeres se ha realizado este screening y 2.573 mamografías han sido tomadas (en 831 se ha realizado 2 exámenes), 42% de las mujeres tienen 50 años o menos. Después del primer examen 32 mujeres fueron seleccionados para biopsia (24 tenían una lesión no-palpable). Después de la biopsia 4 cánceres fueron diagnosticadas (sólo una palpable) y en otra mujer, una hiperplasia epitelial atípica con lesión no palpable. Después del segundo examen 20 mujeres fueron a biopsia (12 con lesiones no palpables) y 5 cánceres se diagnosticaron (tres no-palpables). De estos 5 cánceres, 2 podrían haber sido vistos en el examen previo, ambos no palpables y tres eran nuevas lesiones. El screening de cáncer de mama es posible de realizar, detecta lesiones pequeñas, permitiendo un tratamiento conservador de las mismas y mejora la sobrevida del cáncer de mama

Influencia de los implantes anticonceptivos Norplant (R) en la lactancia y el crecimiento de los niños / Influence of Norplant contraceptive implants on lactation and infant growth

El presente trabajo estudia la influencia de Norplant (R) sobre la lactancia y sobre el crecimiento del lactante durante el primer año post parto. 100 mujeres en lactancia exclusiva recibieron Norplant (R) el día 55 + ou - 3 post parto y a 100 mujeres con similares características se les insertó una T cobre. No hubo diferencias significativas en la evolución de la lactancia entre los dos grupos hasta el 12§ mes post parto en que el grupo Norplant observó un menor porcentaje de mujeres en lactancia exclusiva. Los niños presentaron un crecimiento ponderal normal en los dos grupos, aunque las hijas del grupo Norplant crecieron significativamente menos durante el 4§ mes de vida, al compararlas con las hijas de mujeres portadoras de DIU. No se diagnosticaron embarazos ni efectos colaterales relevantes. En la leche materna se detectaron concentraciones variables de levonorgestrel con valores que fluctuaron entre 23 y 311 pc/ml. La dosis recibida por el niño se estimó en 15 a 18 ng/Kg/día durante el primer mes de uso de Norplant (R), dosis baja que probablemente no representa riesgo para la salud de los niños, aunque se necesita más investigación sobre el tema. Hasta el momento, el uso de Norplant durante la lactancia debería limitarse a aquellos casos que necesitan protección efectiva y que otros métodos anticonceptivos no hormonales estén contraindicados o no sean aceptados

Ensayo clínico de anillos vaginales liberadores de progesterona como anticonceptivos en la lactancia / Clinical trial of progesterone releasing vaginal rings as contraceptives during lactation

El objetivo de este ensayo fue investigar los niveles plasmáticos de progesterona y la eficacia anticonceptiva de anillos vaginales liberando progesterona durante la lactancia. Se probaron dos tipos de anillos, que liberaban un promedio aproximado de 5 ó 10 mg. diarios, respectivamente, en 165 mujeres sanas, en plena lactancia. Se constituyó un grupo control de 162 portadores de DIU - T/Cobre. Los anillos fueron insertados el día 60- posparto, y renovados cada tres meses por otros. Al comienzo del ensayo, los niveles plasmáticos de progesterona eran, aproximadamente, 10 nmol/L y 15 nmol/L para anillos que liberaban, respectivamente, 5 y 10 mg por día, y se reducían ligeramente después de 30 días. Los niveles en períodos de uso subsecuentes, observados, se acercaban a los del primer período o etapa. Estos niveles varían dentro de la amplitud eficaz para inhibir la fertilidad de mujeres en lactancia. Se diagnosticó un embarazo en 1005 meses-mujer de uso del anillo de progesterona, y no ocurrió ninguno en 1075 meses-mujer de uso de T/Cu. Esto contrasta con la alta incidencia de embarazos comprobada en un grupo de mujeres en lactancia, sin tratamiento, en quienes se gestaron 19 embarazos, o sea, una incidencia en 677 meses-mujer. No se detectaron efectos deletéreos sobre la lactancia ni sobre el crecimiento de los niños, como tampoco sobre la salud materna o infantil. La conclusión es que el anillo vaginal de progesterona es un método adecuado para el suministro de progesterona como anticonceptivo para madres en lactancia

Amenorrea, anovulación e infertilidad asociadas a la lactancia en un grupo seleccionado de mujeres urbanas / Amenorrhea, anovulation and infertility associated with breast feeding in a selected group of urban women

Se midió la influencia del amamantamiento sobre la duración de la amenorrea en un grupo de mujeres altamente motivadas para amamantar en libre demanda por un tiempo prolongado. Se calculó la probabilidad de presentar el primer sangrado en 676 mujeres en lactancia exclusiva al segundo mes postparto. El 52% presentó el primer sangrado estando en lactancia exclusiva, antes del término del sexto mes postparto. El tiempo transcurrido desde el parto y la suplementación influyeron negativamente en la duración de la amenorrea. Frecuencias de ocho o más mamadas en 24 hooras no lograron prolongar la amenorrea en todos los casos. El reinicio de los ciclos ovulatorios se estudió en 48 mujeres en amenorrea y lactancia exclusiva al tercer mes postparto. El 28% de las mujeres presentó el primer sangrado, y el 26% de los casos ovuló antes del término del sexto mes postparto. La probabilidad acumulada de embarazo fue de 9,4% al sexto mes postparto en las mujeres en lactancia exclusiva que no usaron métodos anticonceptivos. El riesgo fue menor del 2% en aquellos casos que permanecieron en amenorrea durante este período. En la población estudiada la lactancia no resultó un método eficaz para espaciar los nacimientos, con excepción de los casos que se mantuvieron con lactancia exclusiva y amenorrea