Search

Adjuvant therapy; Breast cancer; Olaparib Terapia adyuvante; Cáncer de mama; Olaparib Teràpia adjuvant; Càncer de mama; Olaparib Background The randomized, double-blind OlympiA trial compared 1 year of the oral poly(adenosine diphosphate-ribose) polymerase inhibitor, olaparib, to matching placebo as adjuvant therapy for patients with pathogenic or likely pathogenic variants in germline BRCA1 or BRCA2 (gBRCA1/2pv) and high-risk, human epidermal growth factor receptor 2-negative, early breast cancer (EBC). The first pre-specified interim analysis (IA) previously demonstrated statistically significant improvement in invasive disease-free survival (IDFS) and distant disease-free survival (DDFS). The olaparib group had fewer deaths than the placebo group, but the difference did not reach statistical significance for overall survival (OS). We now report the pre-specified second IA of OS with updates of IDFS, DDFS, and safety. Patients and methods One thousand eight hundred and thirty-six patients were randomly assigned to olaparib or placebo following (neo)adjuvant chemotherapy, surgery, and radiation therapy if indicated. Endocrine therapy was given concurrently with study medication for hormone receptor-positive cancers. Statistical significance for OS at this IA required P < 0.015. Results With a median follow-up of 3.5 years, the second IA of OS demonstrated significant improvement in the olaparib group relative to the placebo group [hazard ratio 0.68; 98.5% confidence interval (CI) 0.47-0.97; P = 0.009]. Four-year OS was 89.8% in the olaparib group and 86.4% in the placebo group (Δ 3.4%, 95% CI −0.1% to 6.8%). Four-year IDFS for the olaparib group versus placebo group was 82.7% versus 75.4% (Δ 7.3%, 95% CI 3.0% to 11.5%) and 4-year DDFS was 86.5% versus 79.1% (Δ 7.4%, 95% CI 3.6% to 11.3%), respectively. Subset analyses for OS, IDFS, and DDFS demonstrated benefit across major subgroups. No new safety signals were identified including no new cases of acute myeloid leukemia or myelodysplastic syndrome. Conclusion With 3.5 years of median follow-up, OlympiA demonstrates statistically significant improvement in OS with adjuvant olaparib compared with placebo for gBRCA1/2pv-associated EBC and maintained improvements in the previously reported, statistically significant endpoints of IDFS and DDFS with no new safety signals. Funding for this work, which was conducted as a collaborative partnership among the Breast International Group, NRG Oncology, Frontier Science, AstraZeneca, and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, U.S.A. (MSD), was provided by the National Institutes of Health (grant numbers: U10CA 180868, UG1CA 189867, and U10CA 180822) and by AstraZeneca as part of an alliance between AstraZeneca and MSD. Provision of olaparib and placebo was from AstraZeneca. more...

Background: As the development and use of oral anticancer agents increases, it is critical to understand patient adherence to both standard and investigational agents. The open label, phase 3 multicenter PALLAS trial investigates whether adding 2 years of the CDK4/6 inhibitor palbociclib (P) to adjuvant endocrine therapy (ET) improves invasive disease-free survival (iDFS) over adjuvant ET alone in patients (pts) with HR- positive, HR2-negative, stage II-III breast cancer. Pts were randomly assigned to either Palbociclib (125 mg/day, 3 weeks on, 1 week off, in a 28-day cycle) plus ongoing provider/patient-choice adjuvant ET (P+ET) versus ET alone. We examined patient-reported adherence to ET +/- P during the first two years of study treatment. Methods: Adherence outcomes were measured in English-speaking pts in the U.S., UK, Ireland and Australia, Spanish-speaking pts in Spain and Mexico, and German-speaking pts in Germany and Austria. Adherence measures included drug diaries completed at each cycle, pill counts (for P only) collected at each study visit, and the Morisky Medication Adherence Scale-4 item and the McHorney Adherence Estimator questionnaires completed at cycles 2, 3, 6, 12, 18, and 24 (22 months). Mean adherence for each cycle was defined as the average proportion of prescribed pills taken (via drug diary) across all patients who initiated that cycle. Persistence was defined as the duration of drug initiation to treatment cessation (via drug diary). Generalized estimating equations were used to model the “most adherent” pts on the Morisky (score = 5 vs score 0) to compare the average difference between arms over time for ET, adjusting for baseline demographic and clinical variables. Results: 81% (N=4688) of PALLAS pts were included in this analysis. Median persistence to ET was 23.6 months in P + ET (n=2169), 23.7 months in ET alone (2136) and 20.4 months for P (n=2194). The number of pts who initiated each cycle for ET declined over time and was similar between arms; the decline was more marked for P (Table 1). Mean adherence range as measured by drug diary was 98.2-99.3% for ET in P+ET and 98.0 - 99.4% in ET alone; and for P, ranged from 93.4 - 98.8%. The adherence and persistence results were nearly identical whether measured by drug diary or pill count for P. The observed percent “most adherent” for P measured by the Morisky scale ranged from 71.9% - 79.6% and the percent “low risk” for adherence problems measured by the McHorney scale, 64.0% - 73.4%. The percent of pts “most adherent” and “low risk” for adherence problems to ET was higher, on average over time, in the P+ET group compared to ET alone (75% vs 68%, p Table 1.Adherence and persistence in PALLAS over the 24 month treatment periodPalbocicilb + ETETPalbociclibETETTreatment cycleMean Adherence (SD)N*Mean Adherence (SD)NMean Adherence (SD)N193.4 (13.8)229098.7 (6.1)230999.0 (5.2)2343294.7 (13.3)218198.8 (6.4)220398.4 (7.1)2206397.4 (10.1)211298.7 (7.3)214298.8 (6.3)2168497.6 (10.2)203598.6 (7.8)211099.0 (5.7)2154597.6 (11.1)197598.3 (7.9)209398.1 (8.3)2148698.1 (8.7)189998.7 (6.6)203798.5 (8.2)2116798.1 (9.3)185599.0 (6.3)201298.6 (7.3)2102898.0 (9.1)181098.2 (8.2)199798.1 (8.2)2092998.4 (7.4)173399.0 (6.4)196298.8 (6.8)20511098.3 (8.6)171499.2 (4.9)194699.0 (5.5)20381198.3 (8.0)169198.5 (7.3)193798.2 (8.2)20311298.7 (6.2)161299.1 (5.3)191098.7 (7.5)19861398.5 (7.7)159698.9 (6.4)189398.8 (7.1)19691497.9 (9.3)157698.4 (7.3)188298.0 (9.1)19611598.5 (6.9)151499.2 (4.6)185499.0 (6.0)19281698.2 (8.7)148699.1 (4.6)183599.1 (5.7)19131798.1 (9.8)147998.3 (7.8)182698.5 (6.4)19031898.7 (6.8)141699.3 (4.1)176899.2 (5.3)18601998.7 (7.3)140899.3 (3.8)175699.4 (3.1)18482098.4 (8.9)139798.9 (5.3)174298.7 (5.8)18382198.5 (7.5)130199.0 (6.1)167698.8 (7.1)17842297.8 (9.7)124698.8 (6.2)164799.2 (5.7)17692398.1 (8.8)118098.2 (8.5)161998.4 (8.0)17552498.8 (7.2)108699.0 (6.3)146898.9 (7.1)16192598.8 (6.7)99699.2 (5.2)143298.8 (7.1)15892697.9 (11.2)84599.1 (5.7)140998.6 (8.8)1578ET=Endocrine therapy * Number of pts who initiated the treatment cycle. Citation Format: Eileen Shinn, David Zahrieh, Angela DeMichele, Nick Zdenkowski, Julie Lemieux, Jun Mao, Vesna Bjelic-Radisic, Michelle Naughton, Georg Pfeiler, Karen Gelmon, Ingrid Mayer, Daniel Egle, Gabriele Zoppoli, Tiffany Traina, Miguel Martin Jiménez, Silvia Antolin Novoa, Tufia Haddad, Arlene Chan, Alistair Edward Ring, Antonio Wolff, Jose JuanPonce Lorenzo, Dhanusha Sabanathan, Hal Burstein, Zbigniew Ireneusz Nowecki, Gunda Pristauz-Telsnigg, Adam Brufsky, Meritxell Bellet-Ezquerra, Theodoros Foukakis, Yelena Novik, Gabor Rubovszky, Karoline Muehlbacher, Otto Metzger, Theodora Goulioti, Ernest Law, Ann Partridge, Lisa Carey, Alex Zoroufy, Dominik Hlauschek, Christian Fesl, Erica Mayer, Michael Gnant. Adherence with adjuvant endocrine therapy with or without Palbociclib in the PALLAS trial [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-12-01. more...

There are few data on complications with gender affirming surgery. The aim of this study was to assess peri- and postoperative complications of laparoscopic hysterectomy and mastectomy performed in a single sitting in transgender men. Assessment of intra- and postoperative complications in a series of 65 transgender men (mean age 27, range 18–47) undergoing concomitant mastectomy and laparoscopic hysterectomy with salpingo-oophorectomy. Mean operating time was 292 ± 47 min. Thirty-four (52%) patients experienced complications: 28 (41%) DINDO grade I, 0 DINDO grade 2, 6 (11%) DINDO grade III. The six grade 3 complications consisted of 5 hematomas requiring evacuation after mastectomy and 2 vaginal tears requiring transvaginal repair. Three patients were readmitted within 30 days, all for postoperative bleeding/hematoma. In transgender men, performing laparoscopic hysterectomy and mastectomy at a single sitting has a modest rate of perioperative complications, and may improve resource utilization. Supplementary Information The online version contains supplementary material available at 10.1007/s43032-021-00724-x. more...

After the first case of COVID-19 pneumonia was reported in Wuhan, Hubei Province, China, in December 2019, the infection quickly spread to the rest of China and then to the wider world. The available information on pregnant women infected with COVID-19 is now significantly greater. There are now several case series and systematic reviews of cohorts, some of which include more than 100 cases. This review evaluates the scientific literature available until May 1, 2020 and discusses common questions about COVID-19 in the context of pregnancy and the postpartum period. more...

PURPOSE The PALLAS study investigated whether the addition of palbociclib, an oral CDK4/6 inhibitor, to adjuvant endocrine therapy (ET) improves invasive disease-free survival (iDFS) in early hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2–) breast cancer. In this analysis, we evaluated palbociclib exposure and discontinuation in PALLAS. METHODS Patients with stage II-III HR+, HER2– disease were randomly assigned to 2 years of palbociclib with adjuvant ET versus ET alone. The primary objective was to compare iDFS between arms. Continuous monitoring of toxicity, dose modifications, and early discontinuation was performed. Association of baseline covariates with time to palbociclib reduction and discontinuation was analyzed with multivariable competing risk models. Landmark and inverse probability weighted per-protocol analyses were performed to assess the impact of drug persistence and exposure on iDFS. RESULTS Of the 5,743 patient analysis population (2,840 initiating palbociclib), 1,199 (42.2%) stopped palbociclib before 2 years, the majority (772, 27.2%) for adverse effects, most commonly neutropenia and fatigue. Discontinuation of ET did not differ between arms. Discontinuations for non–protocol-defined reasons were greater in the first 3 months of palbociclib, and in the first calendar year of accrual, and declined over time. No significant relationship was seen between longer palbociclib duration or ≥ 70% exposure intensity and improved iDFS. In the weighted per-protocol analysis, no improvement in iDFS was observed in patients receiving palbociclib versus not (hazard ratio 0.89; 95% CI, 0.72 to 1.11). CONCLUSION Despite observed rates of discontinuation in PALLAS, analyses suggest that the lack of significant iDFS difference between arms was not directly related to inadequate palbociclib exposure. However, the discontinuation rate illustrates the challenge of introducing novel adjuvant treatments, and the need for interventions to improve persistence with oral cancer therapies. more...

Urogenital atrophy affects50 % of women after breast cancer (BC) and there is reluctance to use local estrogen for this group. Hormone-free therapies like intravaginal laser therapy and hyaluronic acid suppositories have been shown to produce symptom relief in women with BC and urogenital atrophy, but have not been tested against each other. The aim of this study was to compare these nonhormonal modalities in women with urogenital atrophy after BC in a randomized fashion.We randomly assigned 43 women (aged 49-58 years, mean age 54 years) with urogenital atrophy and a history of BC to receive intravaginal laser therapy (2 courses within 1 month) or hyaluronic acid suppositories (3 times/week continuously for three months). The primary endpoint was score on the Vaginal Health Index after 3 months. Secondary endpoints were subjective bother on a numeric rating scale for all urogenital atrophy domains, quality of life, sexual health and pelvic organ prolapse symptoms using validated questionnaires.Of the 43 women who participated, 22 were randomized to intravaginal laser therapy, and 21 to vaginal suppositories. At 3 months score on the Vaginal Health Index had improved significantly in both groups (p = 0.001), without a significant difference between treatment groups (p = 0.232). Significant improvement was also seen in both groups for subjective bother of urogenital atrophy, quality of life and sexual health, without significant differences between laser or hyaluronic acid therapy.Both intravaginal laser therapy and hyaluronic acid suppositories are effective treatment options for women after BC suffering from urogenital atrophy. No difference was found between treatment regimens.gov identifier: NCT03816735, https://clinicaltrials.gov/ct2/show/NCT03816735. more...

Background: High grade serous ovarian cancer (HGSC), the most common and aggressive type of ovarian cancer, is nearly always driven by TP53 mutations, which can be detected in uterine lavages using ultra-deep duplex sequencing. While this finding supports the development of a uterine lavage assay for early HGSC detection, age-related TP53 mutations compromise specificity. The goal of this study was to thoroughly characterize the nature of TP53 mutations identified in uterine lavage of women with and without HGSC to better understand TP53 clonal evolution during aging and to determine its association to HGSC. Methods: Uterine lavages were collected preoperatively in 54 “average-risk” women undergoing gynecological surgery for suspicious masses (34 women ultimately had HGSC, 20 were cancer free) and in 98 “high-risk” women undergoing risk-reducing salpingo-oopherectomy (17 were found to have HGSC or serous tubal intraepithelial carcinomas (STICs), 81 were cancer-free). Ultra-deep (>10,000x), ultra-accurate sequencing of TP53 was performed on uterine lavage DNA using duplex sequencing. Tumors and STICs were also duplex sequenced to determine TP53 tumor-driving mutations. The frequency of TP53 mutations and large TP53 mutant clones (those found in >2 duplex reads) was compared between women with and without HGSC. Results: The tumor-specific TP53 mutation was detected in 53% of lavages from average-risk women with HGSC and in 22% of lavages from high-risk women with HGSC/STICs. As in prior studies, TP53 biological background mutations were identified in nearly all women and their frequency was age-related. TP53 background mutations, however, were more abundant in women with prior chemotherapy, regardless of their cancer status or age. In women without prior chemotherapy and without high-risk of HGSC, having HGSC was associated with a significantly higher frequency of large TP53 mutant clones (p=0.007) and large TP53 mutant clones containing pathogenic mutations (p=0.007) or TP53 mutations commonly found in cancer (p=0.001). Interestingly, women at high risk of HGSC also carried high frequency of large and pathogenic TP53 mutant clones in lavage, even in those cases in which cancer or STICs were not identified. Conclusions: Ultra-sensitive duplex sequencing enabled detection of a patient’s HGSC or STIC driver mutations, respectively, in about half and a quarter of uterine lavages. However, of even greater interest, we observed a significant excess of large and pathogenic TP53 mutant clones in lavages of women with HGSC that were not present in the tumor. These results indicate that TP53 somatic evolution is associated with HGSC development and suggest that the measurement of TP53 mutant clones in uterine lavages harbors value as a predictor of ovarian cancer risk. Citation Format: Rosana Risques, Thomas H. Smith, Zachary K. Norgaard, Roniz Katz, Fang Yin Lo, Elizabeth K. Schmidt, Jacob E. Higgins, Martin Filipits, Intidhar Labidi-Galy, David Cibula, Lukáš Dostálek, Gabriel Jelenek, Magdalena Plch, Jiří Bouda, Alexander Mustea, Mateja Condic, Sabine Grill, Noreen Gleeson, Peter Oppelt, Gunda Pristauz-Telsnigg, Adriaan Vanderstichele, Siel Obrecht, Adam Rosenthal, Paul Speiser, Jesse Salk. TP53 field defects in uterine fluid are associated with ovarian cancer risk [abstract]. In: Proceedings of the AACR Special Conference on the Evolutionary Dynamics in Carcinogenesis and Response to Therapy; 2022 Mar 14-17. Philadelphia (PA): AACR; Cancer Res 2022;82(10 Suppl):Abstract nr PR005. more...

This abstract is being presented as a short talk in the scientific program. A full abstract is available in the Proffered Abstracts section (PR005) of the Conference Proceedings. Citation Format: Rosana Risques, Thomas H. Smith, Zachary K. Norgaard, Roniz Katz, Fang Yin Lo, Elizabeth K. Schmidt, Jacob E. Higgins, Martin Filipits, Intidhar Labidi-Galy, David Cibula, Lukáš Dostálek, Gabriel Jelenek, Magdalena Plch, Jiří Bouda, Alexander Mustea, Mateja Condic, Sabine Grill, Noreen Gleeson, Peter Oppelt, Gunda Pristauz-Telsnigg, Adriaan Vanderstichele, Siel Obrecht, Adam Rosenthal, Paul Speiser, Jesse Salk. TP53 field defects in uterine fluid are associated with ovarian cancer risk [abstract]. In: Proceedings of the AACR Special Conference on the Evolutionary Dynamics in Carcinogenesis and Response to Therapy; 2022 Mar 14-17. Philadelphia (PA): AACR; Cancer Res 2022;82(10 Suppl):Abstract nr A008. more...

75% of ovarian cancer (OC) cases are detected at an advanced stage. State–of–the–art diagnostic tools don't show sufficient sensitivity, especially in diagnosing early–stage disease. Still, due to lack in alternatives, these methods are used for monitoring BRCA mutation carriers, who face a high penetrance of OC. A 41–year old BRCA1 mutation carrier decided to undergo risk–reducing bilateral salpingo–oophorectomy (rrBSO), currently the only effective way of reducing the OC risk. The day before surgery, 20ml of peripheral blood were drawn to test for the presence of circulating tumor cells (CTCs) by applying a microfluidic device (Parsortix system) and subsequent qPCR. Furthermore, a lavage of the uterine cavity was performed as previously described. According to state–of–the–art techniques, no signs of cancer were present. However, microscopic malignant lesions at both ovaries and the right diaphragm were observed, and final histopathology revealed FIGO IIIB serous OC. Multiple precursor lesions (STICs) were observed in the fallopian tube. qPCR of preoperative enriched cell fraction indicated the presence of CTCs. Analysis of the lavage sample using TP53 mutation analysis revealed 17% mutant allelic fraction. The same mutation was identified in different STIC and invasive lesions. This case shows that early detection of high–grade serous OC does not necessarily translate into a stage shift, but easier to resect disease. Considering the lag–time between STIC to clinically–overt OC development, both described methods present an opportunity for monitoring high–risk patients to delay rrBSO. Both methods proved to be able to diagnose occult OC, and even carry the potential of detecting STICs. Citation Format: Elisabeth Maritschnegg, Eva Obermayr, Barbara Holzer, Noreen Gleeson, Florian Heitz, Leon Massuger, Gunda Pristauz Telsnigg, Adam Rosenthal, Fabian Trillsch, Els Van Nieuwenhuysen, Michael Zikan, Paul Speiser, Robert Zeillinger. DETECTION OF A CLINICALLY OCCULT OVARIAN CARCINOMA BY NEW DIAGNOSTIC TOOLS – A CASE REPORT [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr DPOC-009. more...