Preoperative Endocrine Therapy Research Articles

A Case of Luminal B Breast Cancer in Which Preoperative Chemotherapy Was Used Due to Ineffective Preoperative Hormone Therapy

A Case of Luminal B Breast Cancer in Which Preoperative Chemotherapy Was Used Due to Ineffective Preoperative Hormone Therapy

Locally advanced breast cancer

Locally advanced breast cancer (LABC) is defined here as inoperable breast adenocarcinoma without distant metastases. Patients with LABC require a multidisciplinary approach. Given the risk of distant metastasis, staging exams are necessary. The incidence of LABC (stages IIIB and IIIC) has decreased in recent years. LABC has rarely been investigated separately: patients with LABC have participated both in clinical trials of palliative and of neoadjuvant therapy. Most trials did not analyze responses and long-term outcomes independently; thus, the treatment of patients with LABC is extrapolated from studies of patients with less or more advanced disease. Pathologic confirmation and molecular profiling are essential for the choice of neoadjuvant chemotherapy. Preoperative endocrine therapy may be considered in certain clinical situations; the addition of a CDK4/6 inhibitor is being investigated. HER2 positive LABCs are targeted with anti-HER2 agents combined with chemotherapy. PD-1 and PD-L1 antibodies in ‘triple-negative’ LABC are promising. Excellent responses to neoadjuvant therapy enable conservative surgery in many patients; however, inflammatory breast cancer may still indicate mastectomy. Postoperative radiotherapy is usually indicated. Target volumes include breast/chest wall, axillary, supraclavicular and internal mammary nodal basins. Preoperative radiation therapy can be useful in patients without response to systemic therapies. Palliative surgery for poor responders after neoadjuvant systemic and radiation therapy can be considered. Multidisciplinary teams can optimize local control and prevent relapses. However, modest improvement in survival was achieved between 2000 and 2014 underscoring the unmet need in patients with LABC who will benefit from specific research efforts in this disease entity.

TP53 mutations are associated with primary endocrine resistance in luminal early breast cancer.

BackgroundWhereas the genomic landscape of endocrine‐resistant breast cancer has been intensely characterized in previously treated cases with local or distant recurrence, comparably little is known about genomic alterations conveying primary non‐responsiveness to endocrine treatment in luminal early breast cancer.MethodsIn this study, 622 estrogen receptor‐expressing breast cancer cases treated with short‐term preoperative endocrine therapy (pET) from the WSG‐ADAPT trial (NCT01779206) were analyzed for genetic alterations associated with impaired endocrine proliferative response (EPR) to 3‐week pET with tamoxifen or aromatase inhibitors. EPR was categorized as optimal (post‐pET Ki67 <10%) versus slightly, moderately, and severely impaired (post‐pET Ki67 10%–19%, 20%–34%, and ≥35%, respectively). Recently described gene mutations frequently found in previously treated advanced breast cancer were analyzed (ARID1A, BRAF, ERBB2, ESR1, GATA3, HRAS, KRAS, NRAS, PIK3CA, and TP53) by next‐generation sequencing. Amplifications of CCND1, FGFR1, ERBB2, and PAK1 were determined by digital PCR or fluorescence in situ hybridization.Results ERBB2 amplification (p = 0.0015) and mutations of TP53 (p < 0.0001) were significantly associated with impaired EPR. Impaired EPR in TP53‐mutated breast cancer cases was independent from the Oncotype DX Recurrence Score group and was seen both with tamoxifen‐ and aromatase inhibitor‐based pET (p = 0.0005 each).ConclusionWe conclude that impaired EPR to pET is suitable to identify cases with primary endocrine resistance in early luminal breast cancer and that TP53‐mutated luminal cancers might not be sufficiently treated by endocrine therapy alone.

Effect of “Time To Surgery” On The Endometrial Cancer Prognosis

OBJECTIVE: Endometrial cancer is the most common gynecological cancer in developed countries. Our study aims to determine the effect of the time between diagnosis and surgery of endometrial cancer on the prognosis of the disease. STUDY DESIGN: Patients who were diagnosed with epithelial type endometrial cancer and did not receive preoperative chemotherapy, radiotherapy, or hormonal therapy were included in the study. RESULTS: Two hundred eighty-five patients were included in the study. We divided the patients into two groups regarding before and after 8 weeks from diagnosis to surgery. Clinical characteristics of the patients were comparable between the groups, except for comorbid conditions and body mass index. Using cox-regression analysis, time to operation did not have a significant effect on both recurrence and cancer-associated death risk. The log-rank test analysis also showed that there was no significant difference in progression-free survival and disease-specific survival between the patients. There was no significant difference between the groups in terms of progression-free survival and disease-specific survival for cases with endometrioid type grade 1-2 tumors. There was also no significant difference between the groups regarding progression-free survival and disease-specific survival in the patients with tumors of endometrioid type grade 3 and non-endometrioid histology. CONCLUSION: Time delay between diagnosis to surgery of the patients with endometrial cancer has no prognostic importance for recurrence and survival outcomes.

Clinicopathological Analysis of the ISUP Grade Group And Other Parameters in Prostate Cancer: Elucidation of Mutual Impact of the Various Parameters.

BackgroundProstate cancer has become increasingly common worldwide. Although Grade group (GG) is widely accepted as an indicator of prostate cancer grade, there are malignancies that cannot be defined by GG alone. Moreover, the relationship between GG and other parameters remains unclear. Herein, we aimed to explore the biological characteristics of prostate cancer.MethodsThis study included 299 radical prostatectomy cases. The Chi-square test and analysis of variance were used to analyze the association of GG with binary and continuous variables. We then conducted morphological analyses. Multivariate analyses were performed to extract the data on risk factors for biochemical recurrence (BCR) and lymph node metastasis.ResultsThe lymphatic, venous, perineural, and seminal vesicle invasion rates were 37/299 (12.4%), 25/299 (8.4%), 280/299 (93.6%), and 23/299 (7.7%), respectively. The extraprostatic extension (EPE), positive surgical margin, tertiary Gleason pattern 5, intraductal carcinoma of the prostate gland, and lymph node metastasis rates were 89/299 (29.8%), 106/299 (35.5%), 33/260 (12.7%), 56/299 (18.7%), and 23/299 (7.7%), respectively. As GG increased, various parameters became easier to visualize; however, there were differences between the parameters. Postoperative BCR was observed in 31/242 (12.8%) cases without preoperative hormone therapy; GG2, GG3, GG4, and GG5 accounted for 4, 7, 7, and 13 cases, respectively. Multivariate analyses revealed that GG and tumor diameter were significant risk factors for early BCR, whereas lymphatic invasion, EPE, and seminal vesicle invasion were significant risk factors for lymph node metastasis. For BCR, the odds ratios (ORs) for GG and tumor diameter were 2.253 (95% confidence interval (CI]): 1.297–3.912; P=0.004) and 1.074 (95% CI: 1.011–1.142; P=0.022), respectively. For lymph node metastasis, ORs for the presence of lymphatic invasion, EPE, and seminal vesicle invasion were 7.425 (95% CI: 1.688–22.583; P=0.004), 4.391 (95% CI: 1.037–18.589; P=0.044), and 5.755 (95% CI: 1.308–25.316; P=0.021), respectively.ConclusionsWe summarized various parameters correlating with each GG. Through multivariate analyses, we established the independent risk factors for early BCR and lymph node metastasis. In addition to GG, other important indices of malignancy were determined and weighted to provide a basis for future investigations.

Determination of endocrine sensitivity by response of the proliferative marker KI67 after short-term preoperative endocrine therapy and their correlation to oncotype score platform.

e12609 Background: Endocrine sensitivity (ES) determined by response to the Ki67 index to short-term preoperative endocrine therapy (ET) is accepted but not included in adjuvant treatment decision. However, genomic platforms have been incorporated into decision guides. Therefore, it would be interesting to analyze the correlation between both tools to improve the determination of endocrine sensitivity. Methods: A prospective series of 129 patients with early N0/N1 ES breast cancer was analyzed and Oncotype Dx platform was performed. Clinicopathological variables, and changes in ki67 index less than 10% (ES) were correlated with Oncotype Dx Recurrence Score (RS). Results: Median age was of 58 (23-84), 32% were premenopausal, median tumor size was of 22mm (7-90), nodal involvement was of 31%, 20% were progesterone receptor negative and initial median ki67 index of 24% (5-70). RS distribution: 27% RS 0-11, 29% RS 11-18, 23% RS 18-25, 21% RS &gt; 26. All premenopausal patients received Tamoxifeno as preoperative ET and letrozole for postmenopausal. Globally, 62% of patients had ES with a decrease &lt; 10% of ki67 after preoperative ET: 24/41 in premenopausal and 56/87 in postmenopausal. In all series ES according to RS was distributed: 80% in RS &lt; 11, 61% RS 11-18, 55% RS 18-25 and 50% RS &gt; 26. In premenopausal patients, ES and RS distribution was: 75% RS &lt; 11, 62% RS 11-18, 57% RS 18-25 and 33% RS &gt; 26. In postmenopausal patients, ES and RS distribution was: 83% RS &lt; 11, 61% RS 11-18, 55% RS 18-25 and 58% RS &gt; 26. ES results were not conditioned by tumor size or nodal involvement. RS &gt; 26 was strongly associated with less ES with an OD of 4 (p = 0.014) and RS 18-25 with an OD of 3.25 (p = 0.037). The sensitivity and specificity for ES and RS &lt; 11, was of 80% and 44%, respectively. Conclusions: We have found an ES of 62% in the whole population with the following distribution according RS: 80% in RS &lt; 11, 61% RS 11-18, 55% RS 18-25 and 50% RS &gt; 26. Of note, in premenopausal patients, ES rate in RS &gt; 26 is only of 33%. Determination of ES by response of ki67 is feasible and correlates with data of genomic platforms. Both tools could help to predict ES in this setting.

Disseminated peritoneal leiomyomatosis and malignant transformation: A case series in a single referral center

ObjectiveThe aim of this study was to describe one of the largest series of disseminated peritoneal leiomyomatosis (DPL) and its malignant counterpart, evaluating possible risk factors for both the benign and malignant condition, and highlighting any differences between them in terms of surgical and clinical management. Study DesignClinical, surgical and histopathological characteristics of patients diagnosed with DPL (group 1) and malignant-DPL (group 2), between July 2010 and July 2020, were retrospectively retrieved. ResultsA total of 14 benign and 5 malignant cases were selected. The duration of preoperative hormonal therapy was significantly longer in the benign condition while malignant DPL showed significantly larger lesions (median nodule size: 12 cm). However, surgical procedures and surgical outcomes did not differ among the two conditions, with highly complex surgery and relatively high post-operative complications in both groups. ConclusionPreoperative discrimination between benign and malignant DPL is challenging. Given the high surgical complexity required in both cases, addressing patients to referral cancer centers is strictly recommend, in order to offer them the best possible treatment and allowing a continuous and accurate collection of clinical information that might be crucial for further studies.

Time to Treatment Initiation for Breast Cancer During the 2020 COVID-19 Pandemic.

PURPOSE:The COVID-19 pandemic has posed significant pressures on healthcare systems, raising concern that related care delays will result in excess cancer-related deaths. Because data regarding the impact on patients with breast cancer are urgently needed, we aimed to provide a preliminary estimate of the impact of COVID-19 on time to treatment initiation (TTI) for patients newly diagnosed with breast cancer cared for at a large academic center.METHODS:We conducted a retrospective study of patients with newly diagnosed early-stage breast cancer between January 1, 2020, and May 15, 2020, a time period during which care was affected by COVID-19, and an unaffected cohort diagnosed between January 1, 2018 and May 15, 2018. Outcomes included patient volume, TTI, and initial treatment modality. Adjusted TTI was compared using multivariable linear regression.RESULTS:Three hundred sixty-six patients were included. There was an 18.8% decrease in patient volume in 2020 (n = 164) versus 2018 (n = 202). There was no association between time of diagnosis (pre-COVID-19 or during COVID-19) and adjusted TTI (P = .926). There were fewer in situ diagnoses in the 2020 cohort (P = .040). There was increased use of preoperative systemic therapy in 2020 (43.9% overall, 20.7% chemotherapy, and 23.2% hormonal therapy) versus 2018 (16.4% overall, 12.4% chemotherapy, and 4.0% hormonal therapy) (P < .001).CONCLUSION:TTI was maintained among patients diagnosed and treated for breast cancer during the COVID-19 pandemic at a single large academic center. There was a decrease in patient volume, specifically in patients with in situ disease and a shift in initial therapy toward the use of preoperative hormonal therapy.

Abstract PS5-38: Short course of preoperative tamoxifen in premenopausal breast cancer patients: Biomarker changes and survival

Abstract Background: Luminal HER2 negative breast cancer is a highly heterogeneous disease, which complicates the choice of optimal systemic treatment in early stage disease. It is known that in postmenopausal patients (pts) Ki67 level after short course of preoperative endocrine therapy (PET) correlates with survival in contrast to baseline level. We performed the trial of PET in premenopausal early stage breast cancer pts.Patients and methods: This is a non-randomized, open-label, single-arm, phase II study of short course of preoperative tamoxifen in premenopausal pts. Primary objective was a decline in Ki67 level below 10%, secondary objectives were biomarker changes and disease free survival. Between 2011 and 2017 74 pts with T1-2N0-1M0 ER+ HER2 negative breast cancer were included in the study, median age was 45 (range, 32-55), median baseline Ki67 30% (range, 5-96), median stromal TILs 5% (range, 0-40). All pts were treated with tamoxifen for 2-3 weeks before surgery. Median follow-up was 56 months (range, 29.6-124.3).Results: There was a statistically significant decline in Ki67 during the short course of endocrine therapy (p&amp;lt;0,001), median Ki67 level after PET was 20% (range 3-75). Also we noticed significant decline in estrogen receptor (ER) expression level (p=0,001), but not in progesterone receptor (PR) expression. There was an increase in the level of stromal TILs (p=0.09). Baseline level of Ki67 and tumor grade had significant impact on decline in Ki67 below 10%. None of 28 pts with baseline Ki67&amp;gt;30% had post-PET Ki67&amp;lt;10% in comparison with 20,5% (9/44) with baseline Ki67 10-30%. No pts with baseline TILs≥20% had decline in Ki67 below 10%. Baseline level of Ki67 did not correlate with survival, 3-year DFS with baseline Ki67≤30 was 94,4%, Ki67&amp;gt;30% - 92,6% (p=0.54). Also there was no difference in survival according to Ki67 level after the course of endocrine therapy: with post-PET Ki67&amp;lt;10% 3-year DFS was 100% (none of pts was treated with chemotherapy), 10-30 – 92,4%, &amp;gt;30 – 94,4% (p=0.61). We explain this with the changes in adjuvant treatment in pts with high (&amp;gt;30%) level of Ki67 after endocrine therapy – all pts were receiving adjuvant chemotherapy and, what is more important, they also had ovarian suppression and tamoxifen has been changed to aromatase inhibitors (AI). Conclusion: to our knowledge this is the first study of the short course of PET in premenopausal pts. We demonstrated that post-PET Ki67 level can be used for individualization of adjuvant therapy (intensification with chemotherapy, ovarian suppression, AI in poor responders and avoiding of chemotherapy in good responders). Further prospective randomized trials are warranted. Citation Format: Mona Frolova, Marina Stenina, Alexander Petrovsky, Olga Krohina, Sergei Tjulandin. Short course of preoperative tamoxifen in premenopausal breast cancer patients: Biomarker changes and survival [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS5-38.

Abstract GS4-04: Endocrine therapy alone in patients with intermediate or high-risk luminal early breast cancer (0-3 lymph nodes), Recurrence Score &amp;lt;26 and Ki67 response after preoperative endocrine therapy: Primary outcome results from the WSG-ADAPT HR+/HER2- trial

Abstract Background: In HR+/HER2- N0 early breast cancer (EBC), patients (pts) with Recurrence Score™ (RS)&amp;lt;26 (postmenopausal) and &amp;lt;16 (premenopausal) have excellent prognosis and do not benefit fromadditional chemotherapy. However, prognostic impact of RS in N+ disease and importance of Ki67response after short preoperative endocrine therapy (ET) in the context of genomic signatures remainunclear. For the first time, we present survival results from the large prospective phase III WSG-ADAPTHR+/HER- trial combining both static (RS in baseline core biopsy) and dynamic (Ki67 response)biomarkers to optimize adjuvant therapy in luminal EBC. Methods: 5625 pts were registered and 4691 finally treated by ET (n=2356) or CT (n=2335) within ADAPTHR+/HER2-. ET-trial ITT population comprised 2290 pts: n=868 RS0-11, n=1422 RS12-25/ET-response(30% premenopausal, 26% N1). 5y-iDFS was 93.9% (95%-CI: [91.8% to 95.4%]) in RS0-11 and 92.6%(95%-CI: [90.8% to 94.0%]) in RS12-25/ET-responders. Since the one-sided upper 95% confidence limitof the 5y-iDFS difference was 3.3%, the pre-specified criterion to accept the primary NI-hypothesis wasmet (p=.05).5y-dDFS was 96.3% [94.6% to 97.5%] vs. 95.6% [94.2% to 96.7%]) in RS0-11 vs. RS12-25/ET-responders,respectively (95%-CI for 5y-dDFS difference: [-1.2% to 2.6%]). 5y-OS was also excellent and similar(98.0% [96.7% to 98.9%] vs. 97.3% [96.1 to 98.1%]) in RS0-11 vs. RS12-25/ET-responders, respectively(95% CI for the 5y-OS difference: [-0.7% to 2.2%]). Results: 5625 pts were registered and 4691 finally treated by ET (n=2356) or CT (n=2335) within ADAPTHR+/HER2-. ET-trial ITT population comprised 2290 pts: n=868 RS0-11, n=1422 RS12-25/ET-response(30% premenopausal, 26% N1). 5y-iDFS was 93.9% (95%-CI: [91.8% to 95.4%]) in RS0-11 and 92.6%(95%-CI: [90.8% to 94.0%]) in RS12-25/ET-responders. Since the one-sided upper 95% confidence limit of the 5y-iDFS difference was 3.3%, the pre-specified criterion to accept the primary NI-hypothesis was met (p=.05) 5y-dDFS was 96.3% [94.6% to 97.5%] vs. 95.6% [94.2% to 96.7%]) in RS0-11 vs. RS12-25/ET-responders, respectively (95%-CI for 5y-dDFS difference: [-1.2% to 2.6%]). 5y-OS was also excellent and similar (98.0% [96.7% to 98.9%] vs. 97.3% [96.1 to 98.1%]) in RS0-11 vs. RS12-25/ET-responders, respectively (95% CI for the 5y-OS difference: [-0.7% to 2.2%]). Conclusions: In pN0-1 luminal EBC pts receiving ET alone, pts with RS12-25/ET-response had 5y-iDFSwell above 90% and very close to RS0-11 pts. Both groups had excellent similar dDFS and OS. DynamicET response thus complements RS as a key selection criterion for omission of chemotherapy in pN0-1HR+/HER2- EBC. Citation Format: Nadia Harbeck, Oleg Gluz, Sherko Kuemmel, Matthias Christgen, Michael Braun, Bahriye Aktas, Kerstin Luedtke-Heckenkamp, Helmut Forstbauer, Eva-Maria Grischke, Claudia Schumacher, Maren Darsow, Katja Krauss, Benno Nuding, Marc Thill, Jochem Potenberg, Christoph Uleer, Mathias Warm, Hans H. Fischer, Wolfram Malter, Michael Hauptmann, Ronald Kates, Monika Graeser, Rachel Wuerstlein, Steve Shak, Rick Baehner, Hans Kreipe, Ulrike Nitz, West German Study Group. Endocrine therapy alone in patients with intermediate or high-risk luminal early breast cancer (0-3 lymph nodes), Recurrence Score &amp;lt;26 and Ki67 response after preoperative endocrine therapy: Primary outcome results from the WSG-ADAPT HR+/HER2- trial [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr GS4-04.

Abstract GS4-03: Neoadjuvant nab-paclitaxel weekly versus dose-dense paclitaxel followed by dose-dense EC in high risk HR+/HER2- early BC by: Results from the neoadjuvant part of ADAPT HR+/HER2- trial

Abstract Background: Pathological complete response (pCR) is associated with improved outcome in patients with high-risk HR+/HER2- breast cancer (BC) but the use of (neo)adjuvant chemotherapy in early HR+/HER2- BC remains controversial. Oncotype DX / Recurrence Score (RS) and dynamic Ki67 response after short preoperative endocrine therapy are potentially predictive for pCR. Still, no prospective data are available so far to predict chemotherapy efficacy in this key patient group. Use of dose-dense chemotherapy is associated with improved outcome in meta-analysis, but its use in the neoadjuvant setting is less studied. Furthermore, use of nab-paclitaxel instead of solvent-based paclitaxel has shown promising results in some studies. Here, we present for the first time data from a randomized prospective trial comparing these risk-selection strategies according to RS and Ki67 decrease in high-risk HR+/HER2- BC. Methods: High-risk BC patients [cN0-1 with RS&amp;gt;25 or (RS 12-25 AND (centrally measured) post-endocrine Ki67 &amp;gt;10%] OR [cN2-3 status] OR [G3 AND Ki67&amp;gt;40%] were randomized to (neo)adjuvant 4x paclitaxel175 q2w or 8xnab-paclitaxel 125 mg/m2q1w followed by 4x E90C600 q2w. pCR was defined as no invasive tumor in breast and lymph nodes. Results: 858 patients with available surgery data randomized to neoadjuvant Pac-EC (N=423) or nab-Pac-EC (N=435) were analyzed. Median age was 51 years; median RS was 30 (N=572); 34% had node-positive; 46% (locally) G3 tumors. Baseline characteristics were well balanced between study arms. Patients receiving nab-Pac-EC had higher pCR than those with Pac-EC (20.3% vs. 12.3%, p=.002); patients with RS&amp;lt;25 (about 27%) had a lower pCR rate than those with RS&amp;gt;25 (6.5% vs. 15.8%, p=.003). The association of RS with pCR appeared more pronounced in premenopausal women, but a test of interaction was not significant; RS was about 3 points higher (mean 32.9 vs. 29.8, p&amp;lt;.001) in postmenopausal cases (p=.001). Clinical tumor stage cT2-4 was reported in 65%, with a lower pCR rate than in cT1 tumors (14% vs. 20%, p=.02). RS was moderately correlated (R=.45) with baseline Ki67. In multivariable analysis with tumor stage, RS, Ki67, menopausal status, and ER and PR positivity, higher RS and cT1 stage were favorable for pCR. Excluding RS, higher Ki67 and lower ER (as well as cT1) were favorable. In patients with RS&amp;lt;25, there was no pCR with Pac-EC (0/72 pCR); pCR was almost 20% with RS&amp;gt;25 and nab-Pac-EC. Further details and data including impacts of Ki67 dynamics and additional markers on pCR will be presented at the meeting. Conclusions: Use of neoadjuvant nab-paclitaxel instead of solvent-based paclitaxel appears promising within a short (16-weeks) dose-dense chemotherapy schedule in high-risk HR+/HER2- BC. For the first time, data from a large neoadjuvant randomized trial confirm RS could help to select patients for neoadjuvant chemotherapy in high-risk HR+/HER2- breast cancer (BC). Citation Format: Sherko Kuemmel, Oleg Gluz, Ulrike Nitz, Michael Braun, Matthias Christgen, Kerstin Luedtke-Heckenkamp, Raquel von Schumann, Maren Darsow, Helmut Forstbauer, Jochem Potenberg, Eva-Maria Grischke, Bahriye Aktas, Claudia Schumacher, Ronald Kates, Monika Graeser, Rachel Wuerstlein, Christoph Uleer, Michael Hauptmann, Steve Shak, Rick Baehner, Hans Kreipe, Nadia Harbeck, West German Study Group. Neoadjuvant nab-paclitaxel weekly versus dose-dense paclitaxel followed by dose-dense EC in high risk HR+/HER2- early BC by: Results from the neoadjuvant part of ADAPT HR+/HER2- trial [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr GS4-03.

Abstract SP012: Convergent evolution of resistance pathways during early stage breast cancer treatment with combination cell cycle (CDK) and endocrine signaling inhibitors

Abstract Combining cyclin-dependent kinase (CDK) inhibitors with endocrine therapy improves outcomes for metastatic estrogen receptor positive (ER+), HER2 negative, breast cancer patients. However, the value of this combination in potentially curable earlier stage patients is not clear. Using single cell transcriptomic profiling, we examined the evolutionary trajectories of early stage breast cancer tumors using serial tumor biopsies from a clinical trial of preoperative endocrine therapy alone (letrozole) or in combination with the cell cycle inhibitor ribociclib. Applying hierarchical regression and Gaussian process mathematical modelling, we classified each tumor by whether it shrinks or persists with therapy and determined cancer phenotypes related to evolution of resistance and cell cycle transcriptional rewiring. We found that all patients’ tumors undergo subclonal evolution during therapy, irrespective of the clinical response. However, tumors subjected to endocrine therapy alone showed reduced diversity over time, those facing combination therapy exhibited increased diversity. Despite different diversity, single nuclei RNA sequencing uncovered common phenotypic changes in tumor cells that persist following treatment. In these tumors, accelerated loss of estrogen signaling is convergent with up-regulation of the JNK pathway, while persistent tumors that maintain estrogen signaling during therapy show potentiation of CDK4/6 activation consistent with ERBB4 and ERK signaling up-regulation. Cell cycle reconstruction identified that these tumors can rebound during combination therapy treatment, indicating stronger selection and promotion of a proliferative state. These results indicate that combination therapy in early stage ER+ breast cancers with ER and CDK inhibition drives rapid evolution of resistance via a shift from estrogen signaling to alternative growth factor receptor mediated proliferation and JNK signaling activation, concordant with a bypass in the G1 checkpoint. Citation Format: JI Griffiths, J Chen, PA Cosgrove, A O'Dea, P Sharma, CX Ma, M Trivedi, K Kalinsky, KB Wisinski, R O'Reagan, I Makhoul, LM Spring, A Bardia, FR Adler, AL Cohen, JT Chang, QJ Khan, AH Bild. Convergent evolution of resistance pathways during early stage breast cancer treatment with combination cell cycle (CDK) and endocrine signaling inhibitors [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr SP012.

No Venous Thromboembolism Increase Among Transgender Female Patients Remaining on Estrogen for Gender-Affirming Surgery.

Both surgery and exogenous estrogen use are associated with increased risk of venous thromboembolism (VTE). However, it is not known whether estrogen hormone therapy (HT) exacerbates the surgery-associated risk among transgender and gender nonbinary (TGNB) individuals. The lack of published data has contributed to heterogeneity in perioperative protocols regarding estrogen HT administration for TGNB patients undergoing gender-affirming surgery. A single-center retrospective chart review was performed on all TGNB patients who underwent gender-affirming surgery between November 2015 and August 2019. Surgery type, preoperative HT regimen, perioperative HT regimen, VTE prophylaxis management, outcomes, and demographic data were recorded. A total of 919 TGNB patients underwent 1858 surgical procedures representing 1396 unique cases, of which 407 cases were transfeminine patients undergoing primary vaginoplasty. Of the latter, 190 cases were performed with estrogen suspended for 1 week prior to surgery, and 212 cases were performed with HT continued throughout. Of all cases, 1 patient presented with VTE, from the cohort of transfeminine patients whose estrogen HT was suspended prior to surgery. No VTE events were noted among those who continued HT. Mean postoperative follow-up was 285 days. Perioperative VTE was not a significant risk in a large, homogenously treated cohort of TGNB patients independent of whether HT was suspended or not prior to surgery.

“Bridge” Neoadjuvant Endocrine Therapy for Early Stage Breast Cancer Patients During COVID-19 at an Academic Hospital in NYC: Lessons Learned and Future Directions

<i>Background</i>: The COVID-19 pandemic presented a unique challenge to our healthcare system and rapidly changed the delivery of cancer care. During the height of the pandemic in New York State, non-emergent surgery, including cancer surgery, was postponed. For patients with hormone receptor positive breast cancer, “bridge” neoadjuvant hormonal therapy was initiated until surgery could be safely performed. <i>Objective</i>: We present our institutional experience with this approach and lessons learned, including oncologic outcomes and factors which may lead to increased medication compliance. <i>Method</i>: This is a single institution, retrospective, observational chart review. Using data from the NYU Perlmutter Cancer Center, we created a database of patients who were diagnosed with ER+ stage 0, I, or II breast cancer and were offered preoperative endocrine therapy (tamoxifen or aromatase inhibitors) between March 12, 2020 and June 1, 2020. Variables collected included demographics, tumor characteristics, as well as the rates of medication uptake and compliance. Patients eligible for review were adult (age>18) males and females who had initial visits at our two cancer centers between March 12, 2020 and June 1, 2020, during the height of the COVID-19 pandemic in New York. <i>Results</i>: Of 192 newly diagnosed breast cancer patients seen at the NYU Perlmutter Cancer Center during the study time period, 136 (71%) patients had early stage ER positive breast cancer. Forty-five patients (23%) had not yet undergone surgery, and were recommended to receive presurgical hormonal therapy as a bridge. Average age: 60.5 +/- 13.8 years old (range 31-89). Thirty-four patients (75.6%) had invasive cancer, 8 had DCIS (17.8%), 3 had DCIS with microinvasion (6.7%). There were 9 patients (20%) who did not take the medication. Thirty-six patients (80%) took medication for an average of 43.6 +/- 27.3 days (range 9-101 days) prior to surgery. Twenty-eight patients (77.8%) took an aromatase inhibitor, and 8 (22.2%) took tamoxifen. Forty-two patients have now undergone surgery (93.3%) – the remaining patients include one who is refusing all treatment, one patient who relocated out of state, and another patient who has not yet scheduled surgery, but is still taking an aromatase inhibitor. <i>Conclusion</i>: Despite traditionally low uptake and adherence to endocrine therapy, acceptance of neo-adjuvant bridge therapy during the COVID-19 pandemic was high (80%). We plan to investigate our patient population further, especially psychosocial and behavioral factors that influence willingness to take endocrine therapy – and apply these lessons to management of early-stage ER positive breast cancer.

Risk-adapted adjuvant therapy of luminal early breast cancer in 2020.

The present review summarizes recent original publications addressing the topic of risk-adapted adjuvant therapy in early breast cancer (EBC). As neoadjuvant therapy has become a standard for triple negative and HER2+ EBC, it focusses on luminal EBC. Gene expression assays have become standard of care in luminal EBC, at least for patients with node negative disease. Two prospective randomized clinical trials, TAILORx (Oncotype DX) and MINDACT (MammaPrint) have presented additional analyses underlining the clinical utility of the tests. In times of COVID-19, immunohistochemically determined ER, PR, and Ki67 and early Ki67 response to endocrine therapy can be used to safely allocate patients for preoperative endocrine therapy and delay surgeries if resources are scarce. In patients with luminal high-risk disease, adding a CDK 4/6 inhibitor (abemaciclib) improves patient outcome already after short-term follow-up. Determination of recurrence risk will remain important in luminal EBC for optimal therapy decisions. In the future, risk-adapted treatment concepts will include decision making for chemotherapy but also for endocrine-based approaches.

Preoperative topical testosterone for penile hypospadias repair `a comparative study`

BackgroundAlthough the outcome of hypospadias repair has much improved, repair of a small-sized phallus is still challenging. Whether preoperative hormonal therapy is beneficial remains controversial.In this report, we prospectively conducted a clinical trial comparing two groups of patients regarding the effect of preoperative topical testosterone application on the outcome of primary hypospadias repair.ResultsThe study included 40 cases of primary hypospadias with a small glans. Their age ranged from 6 months to 3 years. Patients were divided into two equal groups. Group A were treated by local application of testosterone topical gel 1% for 30–40 days and stopped one month before operation, while cases in group B did not receive preoperative hormonal treatment. Genital skin biopsies were taken for histopathological examination. For group A, penile measurements were documented before and after hormonal therapy.There was a significant increase in all penile parameters after hormonal stimulation in group A. Interestingly, the ventral penile length proximal to the meatus showed more growth in response to hormonal stimulation compared to ventral penile length distal to meatus.We did not find significant difference between both groups regarding the rate of postoperative complications. Also, the cosmesis and parent satisfaction were ‘more or less’ similar. On the histopathological level, we could not detect a difference between both groups regarding micro-vessel density using CD31, which is a vascular marker indicating neovascularization supposed to play a fundamental role in the healing process.ConclusionThe use of preoperative topical testosterone significantly increases the size of the hypospadiac phallus. However, this increase in size appears to be disproportionate on the ventral penile surface and has not been reflected on improving the surgical outcome.Level of evidenceThis is a case control study (level III evidence).

Implementing preoperative endocrine therapy in breast cancer.

[ ]substantial heterogeneity exists in hormone receptor-positive, HER2-negative disease regarding patient prognosis and treatment benefit 1 To date, tools available before any systemic intervention has taken place, such as the Ki67 proliferation-related tumour biomarker2 or gene expression-based tests, predict long-term prognosis in early-stage, hormone receptor-positive, HER2-negative breast cancer 3 Among them, genomic tests are recommended by the ASCO clinical practice guidelines and the St Gallen International Consensus Guidelines to decrease the use of (neo)adjuvant chemotherapy 3 However, new tools or approaches to discriminate the individual's prognosis and treatment benefit are needed, especially in patients with intermediate-risk or high-risk hormone receptor-positive, HER2-negative disease [ ]the third group, which represents 31·9% of all patients with hormone receptor-positive, HER2-negative disease, had low Ki67 (≤10%) at baseline and week 2, and the 5-year risk of recurrence was less than 5% [ ]if we want to improve precision medicine in early-stage, hormone receptor-positive disease, primary surgery should not be the first option for most patients, similar to those with triple-negative and HER2-positive breast cancer

Comparison of effect of preoperative dienogest and gonadotropin-releasing hormone agonist administration on laparoscopic cystectomy for ovarian endometriomas.

To compare the effects of preoperative dienogest (DNG) and gonadotropin-releasing hormone (GnRH) agonist administration on the improvement of preoperative symptoms and surgical outcomes in patients who underwent laparoscopic cystectomy for ovarian endometriomas. Seventy patients who were scheduled for laparoscopic surgery were enrolled in the study. They were divided into two groups: 35 patients who received DNG for 4months preoperatively (group D) and 35 patients who received low-dose sustained-release goserelin acetate for 4months preoperatively (group G). Preoperative outcomes, including pain score associated with endometriosis, using the numerical rating scale (NRS), adverse events of hormonal therapy and Kupperman index (KI) before and after treatment, surgical outcomes including total surgical duration and blood loss, and postoperative recurrence of endometrioma were compared between the two groups. Regarding preoperative symptoms, NRS and KI at 4months after preoperative hormonal therapy were significantly lower in group D than in group G (NRS, 5.3 ± 5.5 vs. 2.7 ± 3.9; P = 0.01; KI, 16.0 ± 11.0 vs. 9.2 ± 7.6; P = 0.006). Regarding adverse events, the incidence of hot flashes was significantly lower in group D than in group G (P < 0.001). Meanwhile, the incidence of breast pain and metrorrhagia was significantly higher in group D than in group G (P = 0.04 and P < 0.001, respectively). The total surgical duration and blood loss were not significantly different between the groups. At 12months after surgery, ovarian endometrioma did not recur in either group. Preoperative administration of DNG is more valuable for patients with endometriosis and scheduled for laparoscopic surgery to improve symptoms with good efficacy and tolerability than the administration of GnRH agonist.

ADAPTcycle: Adjuvant dynamic marker-adjusted personalized therapy (ADAPT) comparing endocrine therapy plus ribociclib versus chemotherapy in intermediate-risk HR+/HER2- early breast cancer (EBC).

TPS601 Background: The WSG ADAPT trial program represents the concept of individualization of (neo)-adjuvant decision-making in EBC in a subtype-specific manner. The first WSG ADAPT umbrella trial aimed to establish early predictive molecular surrogate markers for response after a short 3-week induction treatment. The goals of the WSG ADAPT trial program are early response assessment and subtype-specific therapy tailoring to those patients who are most likely to benefit. Methods: WSG-ADAPTcycle is a prospective, multi-center, interventional, two-arm, open-label, (neo)adjuvant, non-blinded, randomized, controlled phase III trial (NCT04055493). It investigates whether patients (pts.) with HR+/HER2- EBC identified during screening as intermediate risk (based on Oncotype DX and response to 3 weeks of preoperative endocrine therapy [ET]) derive additional benefit from 2 years of the CDK4/6 inhibitor ribociclib combined with ET compared to chemotherapy (CT) (followed by standard ET). Co-primary endpoints are disease-free survival (DFS) and distant DFS. It is planned to screen 5600 pts and to randomize 1670 pts in a 3:2 ratio (ribociclib + ET/CT). Study start was in July 2019 (80 sites, enrollment period 36 months) and until date of submission, 180 pts. have been screened and 40 randomized. Pts with HR+/HER2- EBC with clinically enhanced risk (cT2-4 or Ki67 20% or G3 or cN+) are eligible if they fulfill the ADAPT intermediate-risk group criteria: either Recurrence Score (RS) ≤25 and Ki67postendocrine&gt;10%, RS &gt;25 and Ki67postendocrine&lt;10% in p/cN0-1 pts, or RS ≤25 and Ki67postendocrine&lt;10% in c/pN2-3 pts. Treatment duration is 2 years for the ribociclib + ET (premenopausal: AI + GnRH) arm and 16-24 weeks for the CT arm; treatment is possible either in the neoadjuvant (ET + ribociclib duration 16 – 32 weeks) or adjuvant setting. ePROs are collected using CANKADO; ECG monitoring is performed using a novel cardiology-supported CANKADO-based eHealth method. Translational analyses: Exploratory tissue biomarker research will be conducted to assess alterations in molecular markers. In addition, ctDNA/ctRNA from optional blood samples will be assessed for mutations and gene expression. Conclusions: ADAPTcycle seeks to evaluate whether endocrine-based therapy with ET and a CDK 4/6 inhibitor is superior to CT followed by ET in patients with luminal EBC who may be undertreated with ET alone (based on either lack of endocrine responsiveness or high tumor burden). Clinical trial information: 2018-003749-40 .

PAX8: A Highly Sensitive Marker for the Glands in Extragenital Endometriosis

In cases of extragenital endometriosis or microscopic endometriosis lesions, pathological diagnosis can be challenging because endometriotic stroma and glands represent only a minor component of fibrotic endometriotic lesions. For better accuracy of diagnosis, the development of a sensitive and specific epithelial marker is beneficial. Previous studies showed that PAX8 is a highly sensitive and specific marker for primary and metastatic Mullerian epithelial tumors. Therefore, we sought to examine whether PAX8 is a highly sensitive marker for glands in extragenital endometriosis. Eight and 47 samples of ovarian endometrioma and extragenital endometriosis, respectively, were evaluated in this study. We calculated the percentage of samples positively immunostained for PAX8, CD10, estrogen receptor (ER), and progesterone receptor (PR). PAX8 was positive for endometriotic epithelial cells in 95.7% (45/47) of extragenital endometrioses and in 100% (8/8) of ovarian endometrioses. CD10 was positive for endometriotic stromal cells in 97.9% (46/47) of extragenital endometrioses. PAX8 was strongly positive for glands, even in a CD10-negative case. The expression of PAX8, CD10, and PR was not affected by preoperative hormonal therapy, and the positive rate of ER staining was significantly reduced by preoperative hormonal therapy. In conclusion, PAX8 is a highly sensitive epithelial marker for extragenital endometriosis. This specific expression was maintained under hormonal therapy. It is noteworthy that extragenital endometriosis maintains the expression of this lineage marker, although it occurs at various sites, and its cause and mechanism of development might be different. PAX8 nuclear expression can be useful in detecting extragenital endometriosis in clinical practice.