Preoperative Endocrine Therapy Research Articles

Unchartered waters: Significance of fall in Ki67 index after short-term preoperative endocrine therapy in early breast cancers.

Endocrine treatment for breast cancer acts largely by inhibiting tumor cell proliferation. The biomarker Ki67 is linked to the proliferative index of the tumour. To identify the factors affecting the fall in Ki67 value in early-stage hormone receptor (HR) positive breast cancer patients receiving short-term preoperative endocrine therapy in an Indian cohort. Women with hormone receptor positive, invasive, nonmetastatic, and early breast cancer (<T2, <N1) were assigned to short-term preoperative tamoxifen 20 mg daily (pre-menopausal women) or Letrozole 2.5 mg daily (post-menopausal women) for a minimum of 7 days after noting the baseline Ki67 value from the diagnostic core biopsy specimen. The postoperative Ki67 value was estimated from the surgical specimen, and the factors determining the extent of fall were evaluated. The short-term preoperative endocrine therapy resulted in a reduction in the median Ki67 index, which was significantly greater among postmenopausal women who received Letrozole (63.25 (31.94-80.5)) than among premenopausal women who received Tamoxifen (0 (-28.99-62.25)) (p-value 0.001). The fall in Ki67 value was particularly marked for patients with low-grade tumors with high Estrogen and progesterone receptor expression (p-value < 0.05). The duration of treatment (<2 week or 2-4 week or >4 week) did not affect the fall in Ki67. Preoperative therapy with Letrozole resulted in a more significant fall in Ki67, as compared to therapy with Tamoxifen. Determining the fall in Ki67 value in response to preoperative endocrine therapy could provide an insight into the response to endocrine therapy in luminal breast cancer.

A retrospective study to evaluate the effect of preoperative hormonal therapy on continence recovery.

To evaluate whether different preoperative hormonal therapy options affect postoperative continence and to identify risk/protective factors for continence recovery. This is a retrospective analysis of several clinical trials (NCT04356430, NCT04869371, NCT04992026 and NCT05406999). Data from patients treated with hormonal therapy followed by RARP were collected and analyzed. Continence was defined as 0 pad/day or one safety pad. The study included 230 patients with adequate information. The median time to continence recovery is 8 weeks. A total of 216 (93.9%) participants recovered to urinary continence within 12 months after surgery. 21 (9.1%) participants achieved immediate continence. 69, 85, 27 and 14 participants restored continence at 1 month, 1-3 month, 3-6 month, 6-12 month, accounting for 30.0%, 40.0%, 11.7% and 6.1% accordingly. No difference in continence recovery was found among different preoperative hormonal treatment options (p=0.821). Cox regression showed that membranous urethral length (MUL) was the only independent factor influencing urinary continence recovery either in the univariate analysis (OR=1.13, 95%CI: 1.04-1.22, p=0.002) or in the multivariate analysis (OR=1.12, 95%CI: 1.04-1.20, p=0.002). Different preoperative treatment options were not associated with urinary recovery. More advanced preoperative T stage (OR=0.46, 95%CI: 0.24-0.85, p=0.014) delayed the recovery of immediate continence. MUL was associated with continence restoring at 1 month (OR=1.20, 95%CI: 1.03-1.39, p=0.017), 3 month (OR=1.27, 95%CI: 1.07-1.51, p=0.006), 6 month (OR=1.34, 95%CI: 1.07-1.67, p=0.011) and 12 month (OR=1.36, 95%CI: 1.01-1.84, p=0.044). There is no difference in postoperative continence recovery among ADT, ADT+Docetaxel and ADT+Abiraterone preoperative treatment options. More advanced T stage indicated poor immediate continence recovery. Longer membranous urethral length was a promotional factor for both short-time and long-time continence recovery.

P53 Expression in Luminal Breast Cancer Correlates With TP53 Mutation and Primary Endocrine Resistance

TP53 mutation is associated with primary endocrine resistance in luminal breast cancer (BC). Nuclear accumulation of p53, as determined by immunohistochemistry (IHC), is a surrogate marker for TP53 mutation. The immunohistochemical p53 index that defines a p53-positive status is not well established. This study determined the optimal p53 index cutoff to identify luminal BCs harboring TP53 mutations. In total, 364 luminal BCs from the West German Study Group ADAPT trial (NCT01779206) were analyzed for TP53 mutations by next-generation sequencing and for p53 expression by IHC (DO-7 antibody). P53 indices were determined by automated image analysis. All tumors were from patients treated with short-term preoperative endocrine therapy (pET; tamoxifen or aromatase inhibitor) before tumor resection. IHC evaluation included needle biopsies before therapy (baseline) and resections specimens after therapy (post-pET). Optimal p53 index cutoffs were defined with Youden statistics. TP53 mutations were detected in 16.3% of BC cases. The median p53 indices were significantly higher in TP53-mutated BCs compared to BCs harboring wild-type TP53 (baseline: 47.0% vs 6.4%, P < .001; post-pET: 50.1% vs 1.1%, P < .001). Short-term pET decreased p53 indices in BCs harboring wild-type TP53 (P < .001) but not in TP53-mutated BCs (P = .102). For baseline biopsies, the optimal p53 index cutoff was ≥34.6% (specificity 0.92, sensitivity 0.63, Youden index 0.54, accuracy: 0.87). For post-pET specimens, the optimal cutoff was ≥25.3% (specificity 0.95, sensitivity 0.65, Youden index 0.60, accuracy: 0.90). Using these cutoffs to define the p53 status, p53-positive BCs were >2-fold more common in pET nonresponders compared to pET responders (baseline: 37/162, 22.8% vs 18/162, 11.1%, P = .007; post-pET: 36/179, 20.1% vs 16/179, 8.9%, P = .004). In summary, IHC for p53 identifies TP53-mutated luminal BCs with high specificity and accuracy. Optimal cutoffs are ≥35% and ≥25% for treatment-naïve and endocrine-pretreated patients, respectively.

ERBB2 mutation is associated with sustained tumor cell proliferation after short-term preoperative endocrine therapy in early lobular breast cancer

Invasive lobular breast cancer (ILC) is a special breast cancer (BC) subtype and is mostly hormone receptor (HR)-positive and ERBB2 non-amplified. Endocrine therapy restrains tumor proliferation and is the mainstay of lobular BC treatment. Mutation of ERBB2 has been associated with recurrent ILC. However, it is unknown whether ERBB2 mutation impacts on the otherwise exquisite responsiveness of early ILC to endocrine therapy. We have recently profiled n = 622 HR-positive early BCs from the ADAPT trial for mutations in candidate genes involved in endocrine resistance, including ERBB2. All patients were treated with short-term preoperative endocrine therapy (pET, tamoxifen or aromatase inhibitors) before tumor resection. Tumor proliferation after endocrine therapy (post-pET Ki67 index) was determined prospectively by standardized central pathology assessment supported by computer-assisted image analysis. Sustained or suppressed proliferation were defined as post-pET Ki67 ≥10% or <10%. Here, we report a subgroup analysis pertaining to ILCs in this cohort. ILCs accounted for 179/622 (28.8%) cases. ILCs were enriched in mutations in CDH1 (124/179, 69.3%, P < 0.0001) and ERBB2 (14/179, 7.8%, P < 0.0001), but showed fewer mutations in TP53 (7/179, 3.9%, P = 0.0048) and GATA3 (11/179, 6.1%, P < 0.0001). Considering all BCs irrespective of subtypes, ERBB2 mutation was not associated with proliferation. In ILCs, however, ERBB2 mutations were 3.5-fold more common in cases with sustained post-pET proliferation compared to cases with suppressed post-pET proliferation (10/75, 13.3% versus 4/104, 3.8%, P = 0.0248). Moreover, ERBB2 mutation was associated with high Oncotype DX recurrence scores (P = 0.0087). In summary, our findings support that ERBB2 mutation influences endocrine responsiveness in early lobular BC.

Preoperative Hormone Therapy in the Treatment of Breast Cancer: What Do We Know So Far?

Breast cancer is the most common malignant disease in the world. One of the methods of treating breast cancer is neoadjuvant chemotherapy. Neoadjuvant chemotherapy (NCT) is now the standard of care for locally advanced breast cancer. Patients with HER2-positive and triple-negative breast cancer subtypes benefi t the most from NCT, with a 50–60 % chance of achieving pCR, while patients with hormone-sensitive, HER2-negative breast cancer subtypes have an average chance of achieving pCR of 10–20 %. For patients with locally advanced, hormone-sensitive Her2neu-negative breast cancer, neoadjuvant hormone therapy contributes to a tumor downstaging and an increasing rate of organ-preserving surgery. However, neoadjuvant hormone therapy is still not used routinely. There are a limited number of clinical guidelines that describe the choice of the optimal drugs, the optimal duration of hormone therapy and the criteria for selecting patients for preoperative hormone therapy. This is the first literature review in Russia that includes a systematization of the evidence regarding the effectiveness of neoadjuvant hormone therapy, a comparison of hormone therapy with neoadjuvant chemotherapy, comparison of hormonal drug groups, optimal duration of hormone therapy, attempts to combine hormone therapy with drugs of the group of selective CDK4/6 cyclin-dependent kinase inhibitors and phosphatidylinositol 3-kinase inhibitors for women with locally advanced hormone-sensitive Her2neu-negative breast cancer. The possibilities of using modern commercial multigene panels to assess the feasibility of identifying the cohort of patients for whom neoadjuvant hormone therapy would be most effective are also considered.

Fall in Ki67 Index After Short-Term Preoperative Letrozole: a Gateway to Assess the Response in Hormone-Positive Early Breast Cancers.

Endocrine treatment for breast cancer acts largely by inhibiting tumor cell proliferation. The study aimed to explore the fall in proliferative marker Ki67 in patients receiving preoperative endocrine therapy and the factors associated with it. A prospective series of hormone receptor-positive postmenopausal women with early N0/N1 breast cancer were enrolled. Patients were requested to take letrozole OD while they await surgery. The fall in Ki67 after the endocrine therapy was defined as the percentage of the difference between the pre-and postoperative Ki67 value with the preoperative Ki67. Sixty cases matched the criteria of which 41 (68.3%) of women showed a good response to preoperative letrozole (fall in Ki67 > 50%; p-value < 0.001). The average mean fall in Ki67 was 57.083 ± 37.97. Postoperative Ki67 after the therapy was less than 10% in 39 (65%) patients. Ten patients (16.6%) had a low Ki67 index at baseline, which continued to remain low after preoperative endocrine therapy. The duration of the therapy did not affect the percentage of Ki67 fall in our study. Short-term changes in the Ki67 index in the neoadjuvant settings may predict outcomes during adjuvant use of the same treatment. Proliferation index on residual tumor holds prognostic importance, and our results reflect that greater attention should be given to the percentage of reduction of Ki67, rather than focusing purely on a fixed value. This could help predict patients who respond well to endocrine therapy, while those who respond poorly may require further adjuvant treatment.

LBA14 Impact of age, recurrence score (RS) and ovarian function suppression (OFS) on endocrine response to short preoperative endocrine therapy (ET): Analysis of ADAPT and ADAPTcycle trials

Benefit of chemotherapy (CT) addition to ET remains controversial in premenopausal (pre) patients (pts) with 0-3 positive LNs (N0-1) and RS ≤25. In ADAPT, excellent outcome was observed in young N0-1 pts and ET response after short-term preoperative ET and RS 12-25 with ET alone. Here, we investigate impact of age, RS, and OFS on ET response, in ADAPT and its validation in the first part of ongoing phase III ADAPTcycle trial. In ADAPT, pts with clinical high-risk HR+/HER2- EBC received 3w of induction standard ET prior to surgery or core biopsy, and then ET-alone if N0-1 and RS 0-11 or 12-25 ± post-endocrine Ki67post≤10%, or CT if Ki67post>10%. In ADAPTcycle (n=5000 to screen), N0-1 pts with RS>25 and Ki67post≤10% and N2-3 pts with RS≤25 and ET-response are randomized to (neo)adjuvant CT or AI+ribociclib. 5938 pts included (ADAPT, n=3666; Acycle, n=2272): 1975 pts ≤50y/pre, 424 pts ≤40y. ET in ≤50y/pre pts included tamoxifen (98% ADAPT, 70.4% Acycle), TAM+OFS (15.2% Acycle) and AI+OFS (14.4% Acycle); >80% of >50y or post pts had AI. Baseline ER did not differ significantly between age groups ≤40, >40-50- and >50 ys. Mean baseline RS scores were higher in pts ≤40ys, but comparable between pts aged >40-50 and >50. ET-response rates varied substantially by type of ET, age, and RS in particular if no OFS in premenopausal pts. In ADAPT, ET-response was associated with improved iDFS in all age cohorts, independent of baseline Ki67.Table: LBA14Age subgroupRS 0-25 (ADAPT/A-Cycle) Endocrine Response Ki67post<= 10% (%)RS>25 (ADAPT/A-cycle) Endocrine Response Ki67post<= 10% (%)TamTAM+ OFS*AI+ OFS*AITAMTAM+ OFS*AI+ OFS*AI≤50 years and premenopausal45.1/ 37.6%65.0%76.5%14.3/ 19.5%48.0%77.8%≤40 years37.7/ 41.7%72.2%84.6%3.9/ 14.3%44.4%69.2%41-50 years46.8/ 36.8%61.9%74.617.8/ 21.8%52.2%82.6%>50 years old or postmenopausal61.7/ 49.7%****88.6/ 85.8%21.5/ 15.2%****44.6/ 64.7%* OFS data in ADAPTCycle only, in ADAPT, only 2% AI+OFS in pts ≤50 ys ** only few pts treated by OFS in >50 ys, pre group Open table in a new tab * OFS data in ADAPTCycle only, in ADAPT, only 2% AI+OFS in pts ≤50 ys ** only few pts treated by OFS in >50 ys, pre group ET-response after TAM or AI according to RS groups was similar in both trials, but adding OFS to TAM or AI substantially improves ET-response in pre pts ≤ 50y, rendering similar results as in AI-treated post pts. ET-response assessment provides clinically relevant information for CT-decision making in pre ≤50y N0-1 pts in addition to gene expression testing.

Association of serum reproductive hormones changes after neoadjuvant chemotherapy with hormone receptors expression alterations and survival outcomes in breast cancer.

PurposeThis study aimed to determine the effect of neoadjuvant chemotherapy (NAC) on circulating levels of reproductive hormones and evaluate the correlation of hormone changes after NAC with hormone receptors expression alterations and relapse-free survival (RFS) outcomes in breast cancer.MethodsInformation from 181 breast cancer patients who received NAC was retrospectively analyzed. For hormones parameters, the median and interquartile range (IQR) were provided at baseline and the end of NAC then was compared by Wilcoxon signed-rank test. Categorical variables were represented as numbers and percentages and were compared via two-sided chi-square and Fisher's tests. The RFS outcomes were compared between patients according to hormone changes using the log-rank test. Univariate and multivariate survival analyses with hazard ratios (HR) and 95% confidence intervals (95% CI) were carried out using Cox regression.ResultsSex steroids including estradiol, progesterone, testosterone, and dehydroepiandrosterone sulfate (DHEAS) levels decreased significantly after NAC among both premenopausal and postmenopausal patients (all P < 0.05). Decreased estradiol levels were associated with reduced progesterone receptor (PR) expression (P = 0.030). In multivariate survival analysis, the non-decreased progesterone level was strongly associated with worse RFS (non-decreased vs. decreased, HR = 7.178, 95% CI 2.340–22.019, P = 0.001). Patients with decreased progesterone levels exhibited better 3-year RFS compared with those with non-decreased (87.6% vs. 58.3%, log-rank, P = 0.001).ConclusionMultiple reproductive hormone levels were influenced by NAC. The change in estradiol level had a positive connection with PR expression alteration. Furthermore, an inverse association between the change in progesterone level and RFS outcomes was found. These findings may provide a theoretical basis for pre-operative endocrine therapy combined with NAC in breast cancer patients.

Gene Expression Profiling between Patient Groups with High and Low Ki67 Levels after Short-term Preoperative Aromatase Inhibitor Treatment for Breast Cancer.

According to a recent report, a low Ki67 level after short-term preoperative hormone therapy (post-Ki67) might suggest a more favorable prognosis compared with a high post-Ki67 level in patients with hormone receptorpositive/human epidermal growth factor 2-negative (HR+/HER2-) breast cancer with high levels of Ki67. This study aimed to evaluate the pre-treatment genetic differences between these two patient groups. Forty-five luminal B-like patients were stratified into two groups, namely, a group with high (H→H) and one with low (H→L) Ki67 levels after short-term preoperative aromatase inhibitor (AI) treatment. We compared pre-treatment gene expression profiles between the two groups. In gene level analysis, there was no significant difference between the two groups by the class comparison test. In pathway analysis, five metabolism-related gene sets were significantly upregulated in the H→L group (p≤0.05). In the search for novel targets, five genes (PARP, BRCA2, FLT4, CDK6, and PDCD1LG2) showed significantly higher expression in the H→H group (p≤0.05). Several metabolism-related pathways were associated with sensitivity to AI. In the future, it will be necessary to seek out new therapeutic strategies for the poor prognostic group with high post-Ki67.

Defining the role of pre-operative hormonal therapy in hypospadias.

In hypospadias surgery, pre‐operative hormonal therapy (PHT) is primarily used to increase penile dimensions and the vascularity of tissues available for reconstruction, but its use is non‐uniform in clinical practice, with no consensus on application or utility. This review aims to summarise: (i) the penile tissue response to hormone therapy, (ii) its impact on hypospadias surgery outcomes, and (iii) the endocrinological considerations and sequelae. PHT is more often indicated for complex cases such as proximal hypospadias, hypospadias with microphallus and hypospadias reoperations. While PHT has clear effects on penile morphometry, and more recent controlled trials suggest improved surgical outcomes, the lack of consistent outcome definitions and generally inadequate follow‐up periods continue to consign many of the potential long‐term effects of PHT to the unknown. There is currently insufficient robust evidence to allow a clinical guideline to be constructed. The need for a well‐powered multi‐centre prospective randomised trial to address this question is evident but awaits a unified consensus on issues surrounding the understanding of aetiology, classification of hypospadias morphology, definition of important prognostic variables and uniform application of outcome measures. The effects of PHT may be utilised to improve outcomes in cases of proximal and severe hypospadias, which under the current paradigm represent a significant surgical challenge.

CO70 Change in KI-67 Index in Patients Receiving Preoperative Endocrine Therapy Among Hormone Positive Breast Cancer Patients: A Systematic Review and Meta-Analysis

Effectiveness of pre-operative endocrine therapy (PoET) in hormone-positive early-stage breast cancer (BC) patients for additional benefits (reduced cell proliferation and risk of recurrence) is being debated. Hence, we aimed to conduct this systematic review and meta-analysis to provide overview and comprehensive data on the effectiveness of PoET in reducing cancer cell proliferation among hormone positive breast cancer patients.

Short-term preoperative endocrine therapy allows to estimate and revert patient prognosis with further treatment plan correction in HR+ HER2- early breast cancer patients.

e12628 Background: The anomaly function of ER/PR-dependent molecular cascade is a key driver of ER-positive HER2-negative breast cancer (HR+ HER2- BC) progression. Ki67&gt;10% and/or grade 3 (G3) determine the initial poor patient (pts) prognosis in this group. The short-term pre-operative endocrine therapy (P-ET) simply allows to look ahead to properly the further adjuvant therapy (AT) and to estimate the endocrine therapy (ET) sensibility of each pts in the routine clinical practice. The existing diagnostic methods weaknesses for the baseline lymph nodes invasion, high BC heterogeneity do not allow to accurately estimate the disease stage and tumor phenotype, respectively, with 100% accuracy before surgery. In addition to pre-ET the post-operative IHC is a base method for further pts treatment plan especially for high heterogenicity breast tumors. Our study is focused on pts proportion estimation with P-ET benefit or tumor phenotype reversion in patients with early HR+ HER2- BC. Methods: HR+ HER2- BC pts stages I-II any level of Ki67 independent from grade have received P-ET (letrozole (L)/anastrozole (A)/tamoxifen (TAM)) no less than 2 weeks until surgery in MCSC named after A.S. Loginov. Enrollment period runs from Jun’21 and will end with 1,000 pts. The primary goal of the study was pts’s proportion evaluation with baseline Ki67&gt;10% who experienced suppression of the proliferation marker to 10% or less and/or phenotype change during P-ET followed by AT strategy amendment. Results: At the data cut-off (Jan’22) 832 pts (5 pts were men) with HR+ HER2- BC were enrolled (IIT population) with median age 61 (range:26-85) and ECOG 0-2. 736 (89%) pts have baseline Ki67&gt;10% of whom 100 (14%) pts - with G3, 291 (35%) pts - with baseline Ki67≥30%. Tumors of the 398 (54%) pts suppressed proliferation marker Ki67≤ 10% and 352 (88%) pts among them avoid planned adjuvant chemotherapy followed by ET prolongation independent of ET type (L/A/TAM). The median time of P-ET amounted to 39,5 days (range: 14-90) in focused group. Post-operative evaluation of specimens in 20 (2,4%) pts have resulted in the identification of phenotype change to HER2+ BC and TNBC with subsequent modification of AT decisions (including anti-HER2-based and/or dose dense regimens). Conclusions: In HR+ HER2- early BC pts short-term P-ET simply allows to estimate pts prognosis and further AT strategy proper planning: to identify the pts population of whom CT can be avoided while maintaining treatment efficacy with a better quality of life (42% pts of IIT) (1), to radically change the planned AT to achieve optimal treatment results (2,4% pts of IIT) (2).

Concordance and clinical impact of ER, PR, HER2 expression by local and central immunohistochemistry versus RT-PCR in HR+/HER2- early breast cancer (EBC): Results from the ADAPT trial.

536 Background: We evaluated concordance of ER, PR and HER2 status between local, central, and RT-PCR/mRNA assessments and its clinical impact in the ADAPT trial collective in HR+ HER2- EBC (NCT01779206). Particularly, validity of borderline ER-positivity (expression level 1-10%) has great clinical relevance as treatment concepts between luminal-like and triple negative (TNBC) EBC differ substantially. Methods: Patients (pts) with clinically high-risk HR+/HER2- EBC (ER and/or PR &gt;1%) were initially treated by 3 (+/-1) weeks of endocrine therapy (ET) before surgery or sequential core biopsy (CB) and then allocated to an ET-alone or chemotherapy (ET) trial, depending on risk and endocrine response. OncotypeDX (incl. RT-PCR for ER, PR, HER2) and central IHC for ER, PR, HER2 were performed on the initial 1.CB. ER-low cohort was defined as 1-10% expression by local OR central lab (ASCO-CAP). Cox models were used to estimate hazard ratios. Results: In ADAPT, 5149 pts from 81 centers in Germany with locally ER and/or PR positive (known quantitative levels) EBC were screened 2012-2018. Median follow-up was 59 months. For ER (positive vs. negative), overall concordance measured as agreement (κ) was high between all three assessments: Local vs. central IHC: 99.3% (κ = 0.45), RT-PCR vs. central IHC: 99% (κ = 0.48). Concordance was lower for PR: RT-PCR vs. central IHC: 90.5% (κ = 0.58), local vs. central IHC: 93.1% (κ = 0.56). 3% were centrally found as HER2+ in 1.CB (73% of them were negative by RT-PCR) and/or 2. Sample. Regarding HER2-low status (1+ or 2+ but ISH negative), concordance between local and central IHC was only 53.8% (κ = 0.09). Of all pts, only 2% (n=109; n=85 with both measurements available) had low ER expression (1-10%) by either local or central pathology. Only 9 of them were concordantly identified as ER-low (11%); 8/58 (14%) ER-low by local lab had TNBC by central lab. 17/47 ER-low cases (36.2%) with known post-endocrine Ki67post had Ki67post &lt;10% vs. 59.7% in ER&gt;10%. 41.8% of ER-low cases had RS&lt;25 vs. 76.7% in ER&gt;10%. All cases with ER &lt;10% by both assessments and those with Ki-67≥40% had RS &gt;25. We observed worse iDFS (HR 1.91, p=0.034) in the ER-low group vs. ER&gt;10%. Conclusions: Although we have confirmed high agreement between local and central IHC and RT-PCR for ER, PR, HER2 assessment in locally HR+/HER2- EBC, there are still a few clinically relevant discordances. Regarding HER2-low status, standardization and quality assurance are needed if this becomes clinically relevant. Treatment of the heterogeneous ER-low group as TNBC appears reasonable only if “ER-low” is confirmed by a second assessment and in cases with Ki-67&gt;40%. Preoperative ET response assessment may be helpful if an endocrine-based therapy concept is intended. Clinical trial information: NCT01779206.

Endocrine Therapy Response and 21-Gene Expression Assay for Therapy Guidance in HR+/HER2- Early Breast Cancer.

To our knowledge, WSG-ADAPT-HR+/HER2- (ClinicalTrials.gov identifier: NCT01779206; n = 5,625 registered) is the first trial combining the 21-gene expression assay (recurrence score [RS]) and response to 3-week preoperative endocrine therapy (ET) to guide systemic therapy in early breast cancer. Baseline and postendocrine Ki67 (Ki67post) were evaluated centrally. In the endocrine trial, all patients received exclusively ET: patients with pathologic regional lymph node status (pN) 0-1 (ie, 0-3 involved lymph nodes) entered control arm if RS ≤ 11 and experimental arm if RS12-25 with ET response (Ki67post ≤ 10%). All other patients (including N0-1 RS12-25 without ET response) received dose-dense chemotherapy (CT) followed by ET in the CT trial. Primary end point of the endocrine trial was noninferiority of 5-year invasive disease-free survival (5y-iDFS) in experimental (v control) arm; secondary end points included distant DFS, overall survival, and translational research. Intention-to-treat population comprised 2,290 patients (n = 1,422 experimental v n = 868 control): 26.3% versus 34.6% premenopausal and 27.4% versus 24.0% pN1. One-sided 95% lower confidence limit of the 5y-iDFS difference was -3.3%, establishing prespecified noninferiority (P = .05). 5y-iDFS was 92.6% (95% CI, 90.8 to 94.0) in experimental versus 93.9% (95% CI, 91.8 to 95.4) in control arm; 5-year distant DFS was 95.6% versus 96.3%, and 5-year overall survival 97.3% versus 98.0%, respectively. Differences were similar in age and nodal subgroups. In N0-1 RS12-25, outcome of ET responders (ET alone) was comparable with that of ET nonresponders (CT) for age > 50 years and superior for age ≤ 50 years. ET response was more likely with aromatase inhibitors (mostly postmenopausal) than with tamoxifen (mostly premenopausal): 78.1% versus 41.1% (P < .001). ET response was 78.8% in RS0-11, 62.2% in RS12-25, and 32.7% in RS > 25 (n = 4,203, P < .001). WSG-ADAPT-HR+/HER2- demonstrates that guiding systemic treatment by both RS and ET response is feasible in clinical routine and spares CT in pre- and postmenopausal patients with ≤ 3 involved lymph nodes.

Pre-treatment circulating reproductive hormones levels predict pathological and survival outcomes in breast cancer submitted to neoadjuvant chemotherapy.

This study aimed to evaluate the correlation of pre-treatment circulating reproductive hormones levels with pathological and survival outcomes in breast cancer patients received neoadjuvant chemotherapy (NAC). Information from 196 premenopausal and 137 postmenopausal breast cancer patients who received NAC were retrospectively analyzed. Treatment response to NAC, with odds ratios (OR) and 95% confidence intervals (95% CI) was estimated using logistic regression adjusted for key confounders. Survival outcomes with hazard ratios (HR) and 95% CI were estimated using Cox regression adjusted for key confounders. The Kaplan-Meier method was applied in the survival analysis. Premenopausal patients with lower testosterone levels (OR = 0.996, 95% CI 0.992-0.999, P = 0.026), and postmenopausal patients with higher follicle-stimulating hormone (FSH) levels (OR = 1.045, 95% CI 1.014-1.077, P = 0.005) were likely to achieve pathological complete response (pCR). In multivariate survival analysis, the lowest tertile (T) progesterone was associated with worse overall survival (OS) in premenopausal patients (T2 vs T1, HR = 0.113, 95% CI 0.013-0.953, P = 0.045; T3 vs T1, HR = 0.109, 95% CI 0.013-0.916, P = 0.041). Premenopausal patients with the lowest tertile progesterone exhibited worse 3-year OS compared with those with higher tertiles (72.9% vs 97.4%, log-rank, P = 0.007). Pre-treatment testosterone and FSH are significant independent predictors for pCR to NAC in premenopausal and postmenopausal patients, respectively. Low progesterone levels are correlated with worse OS in premenopausal patients. These findings may provide a theoretical basis for pre-operative endocrine therapy combined with NAC in breast cancer.

Abstract P5-14-03: National claims data analysis of breast cancer diagnosis and treatment before versus during the COVID-19 pandemic

Abstract Background: The COVID-19 pandemic imposed great burden on the healthcare system and required patients and their physicians to make unprecedented choices about cancer care. Hospital-based retrospective reviews suggested changes in breast cancer management during 2020 compared to previous years, including greater use of preoperative therapy. We used insurance claims data to understand the impact of the pandemic on breast cancer diagnosis and treatment at a national level. Methods: We identified new diagnoses of breast cancer from 2017-2020 in the Optum data set, consisting of claims records linked to electronic health records. The overall population (enrolled in Optum for at least 6 months with at least one diagnosis of any condition and no prior breast cancer diagnosis) included an average of 8 million adult Americans per year. A breast cancer diagnosis was defined as a first-ever ICD code for breast cancer with a breast diagnostic biopsy procedure code (considered the cancer diagnosis date) within 6 months before to 3 months after that ICD code. Each year’s cohort of breast cancer cases was limited to those diagnosed between February 1 and May 30, with follow-up through June 30 of the diagnosis year. First treatment after diagnosis was classified as either endocrine therapy, chemotherapy, or surgery. Geographic area was defined by the 9 Census Bureau regions. We used a Poisson regression to compare the rate of breast cancer diagnosis in 2020 versus 2017-2019 and a Chi-squared test to compare the distributions of first treatment. To investigate differences in the impact of the pandemic on rate of diagnosis (Poisson regression) or use of preoperative therapy (logistic regression) by race/ethnicity, income, or geographic area, we included each of these covariates as well as its interaction with year (2020 vs 2017-2019) in separate models. Results: There were 2,841 breast cancer diagnoses February-May 2020 (0.037% of overall population), compared to 3,880 in 2019 (0.045%), 3,509 in 2018 (0.043%), and 2,999 in 2017 (0.041%). In 2020 compared to 2017-2019, new breast cancer diagnoses decreased by 12.3% (95% CI 8.6%-15.9%; p &amp;lt; 0.0001). No significant differences were observed in this reduction in diagnoses by race/ethnicity, income level, or geographic area. Median date of diagnosis was earlier in 2020 (March 11) compared to 2017-2019 (March 29-April 1), a result of the diagnosis rate dropping more in later months. Among patients who received treatment during follow-up (83.1% in 2017-2019 vs 86.2% in 2020, a difference likely reflecting this shift in diagnosis date), there was a marked reduction in surgery as first treatment in 2020 compared to previous years (88.7% in 2017-2019 vs 69.3% in 2020), while both preoperative chemotherapy (6.1% in 2017-2019 vs 10.7% in 2020) and preoperative endocrine therapy (5.2% in 2017-2019 vs 20.1% in 2020) increased (p &amp;lt; 0.0001). There were no differences in the shift toward preoperative therapy by race/ethnicity or income, but there was a significant difference by geographic area (p=0.0003): the Mountain region had the least change in use of preoperative therapy (odds ratio 2.46 [95% CI 1.75-3.47] of preoperative therapy during vs before the pandemic) while the Middle Atlantic region had the greatest (odds ratio 5.64 [95% CI 3.79-8.38]). Conclusions: Among insured U.S. patients, new breast cancer diagnoses decreased by 12.3% during February-May 2020 compared to the same period in the previous three years, and use of preoperative therapy, largely endocrine, increased by 2.7-fold. The impact of the pandemic on choice of first treatment differed by geographic area, but not by race/ethnicity or income in this insured population. We will monitor with continued follow-up of claims data to assess the longer-term impact of these pandemic-related changes on treatment patterns, cost, and patient outcomes. Citation Format: Jennifer L Caswell-Jin, Maryam N Shafaee, Lan Xiao, Mina Liu, Natasha Purington, Esther M John, Melissa L Bondy, Allison W Kurian. National claims data analysis of breast cancer diagnosis and treatment before versus during the COVID-19 pandemic [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 P5-14-03.

Abstract P5-14-01: National claims data analysis of breast cancer diagnosis and treatment before versus during the COVID-19 pandemic

Abstract Background: The COVID-19 pandemic imposed great burden on the healthcare system and has required patients and their physicians to make unprecedented choices about cancer care. Hospital-based retrospective reviews have suggested changes in breast cancer management during 2020 compared to previous years, including greater use of preoperative therapy. We used insurance claims data to understand the impact of the pandemic on breast cancer diagnosis and treatment at a national level. Methods: We identified new diagnoses of breast cancer from 2017-2020 in the Optum Clinformatics claims data set, consisting of claims records linked to electronic health records. The overall population (enrolled in Optum for at least 6 months with at least one diagnosis of any condition and no prior breast cancer diagnosis) included an average of 8 million adult Americans per year. A new breast cancer diagnosis was defined as a first-ever ICD code for breast cancer with a breast diagnostic biopsy procedure code (considered the cancer diagnosis date) within 6 months before to 3 months after that ICD code. Each year’s cohort of breast cancer cases was limited to those diagnosed between February 1 and May 30, with follow-up through June 30 of the diagnosis year. First treatment after diagnosis was classified as either endocrine therapy, chemotherapy, or surgery. Geographic area was defined by the 9 Census Bureau regions. We used a Poisson regression to compare the rate of breast cancer diagnosis in 2020 compared to 2017-2019 and a Chi-squared test to compare the distribution of first treatment in 2020 compared to 2017-2019. To investigate differences in the impact of the pandemic on rate of diagnosis (Poisson regression) or use of preoperative therapy (logistic regression) by race/ethnicity, income, or geographic area, we included each of these covariates as well as its interaction with year (2020 vs 2017-2019) in separate models. Results: There were 2,841 breast cancer diagnoses February-May 2020 (0.037% of overall population), compared to 3,880 in 2019 (0.045%), 3,509 in 2018 (0.043%), and 2,999 in 2017 (0.041%). In 2020 compared to 2017-2019, new breast cancer diagnoses decreased by 12.3% (95% CI 8.6%-15.9%; p &amp;lt; 0.0001). No significant differences were observed in this reduction in diagnoses by race/ethnicity, income level, or geographic area. Median date of diagnosis was earlier in 2020 (March 11) compared to 2017-2019 (March 29, April 1, and April 1 respectively), a result of a larger drop in diagnoses later in the time interval in 2020. Among patients who received treatment during follow-up (83.1% in 2017-2019 vs 86.2% in 2020, a difference likely reflecting this shift in diagnosis date), there was a marked reduction in surgery as first treatment in 2020 compared to previous years (88.7% in 2017-2019 vs 69.3% in 2020), while both preoperative chemotherapy (6.1% in 2017-2019 vs 10.7% in 2020) and preoperative endocrine therapy (5.2% in 2017-2019 vs 20.1% in 2020) increased (p &amp;lt; 0.0001). There were no differences in the shift toward preoperative therapy by race/ethnicity or income, but there was a significant difference by geographic area (p=0.0003): the Mountain region had least change in use of preoperative therapy (odds ratio 2.46 [95% CI 1.75-3.47] of preoperative therapy during vs before the pandmic) while the Middle Atlantic region had the greatest (odds ratio 5.64 [95% CI 3.79-8.38]). Conclusions: Among insured U.S. patients, new breast cancer diagnoses decreased by 12.3% during February-May 2020 compared to the same period in the previous three years, and use of preoperative therapy, largely endocrine, increased by 2.7-fold. The impact of the pandemic on choice of first treatment differed by geographic area, but not by race/ethnicity or income in this insured population. We will monitor with continued follow-up of claims data to assess the longer-term impact of these pandemic-related changes on treatment patterns, cost, and patient outcomes. Citation Format: Jennifer L Caswell-Jin, Maryam N Shafaee, Lan Xiao, Mina Liu, Natasha Purington, Esther M John, Melissa L Bondy, Allison W Kurian. National claims data analysis of breast cancer diagnosis and treatment before versus during the COVID-19 pandemic [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 P5-14-01.

Abstract P1-02-12: Genomic testing on breast cancer core biopsy material is feasible and provides useful treatment information

Abstract Background: Genomic profiling assays for invasive breast cancer provide useful predictive and prognostic information and are performed most commonly on surgical resection specimens. Obtaining the molecular profile at the time of initial core needle biopsy is ideal because it could provide information that could significantly alter preoperative decision-making and avoid unnecessary treatments. In January 2020, the breast center began a 3 month pilot program that would reflexively send core biopsy material on all newly diagnosed patients for genomic testing using the MammaPrint (MPT) and BluePrint (BPT) assays regardless of receptor status. The goals were to determine feasibility and examine the impact to patient care. Methods: Breast core biopsy tissue was triaged by an attending pathologist as soon as slides were available. If invasive carcinoma with at least 3 mm in linear extent of tumor with 20% cellularity was identified, materials were immediately sent to Agendia for MPT/BPT testing even before ER/PR/HER2 testing was available to the pathologist. Clinicopathologic information, turn-around time (TAT) and adequacy data were tracked. The impact was discussed regularly at breast tumor board to determine if the results led to altered decision-making that could reduce unnecessary interventions and time to initial treatment. Results: 445 core biopsy specimens were sent for genomic testing. Of those 442, (97%) yielded genomic results with an average TAT from biopsy to genomic result of 11 calendar days. MPT identified 233 (53%) cases that were low risk and 209 (47%) cases that were high risk. BPT showed that 60 (14%) cases were Basal, 18 (4%) cases were HER2, and 364 (82%) cases were Luminal. Further analysis of the Luminal subgroup demonstrated that 154 (42%) were Luminal A low risk, 78 (21%) were Luminal A Ultralow risk and 132 (36%) were Luminal B High Risk. Analysis by race demonstrated a significantly higher percentage of high risk tumors in African-American women including a higher percentage of basal cancers (26%) as compared to Caucasian women (10%). Of note, 51 patients in the pilot study had additional OncotypeDX (ODX) testing on subsequent surgical resection. There was fair correlation between the assays with the majority of the low risk MPT having low risk ODX scores (&amp;lt;=25) and the high risk MPT having high risk ODX scores (&amp;gt;25), though MPT identified more patients as being high risk. The COVID-19 pandemic altered plans to assess time to treat and treatment interventions as initially intended. However, the knowledge of genomic result enhanced the ability to triage patients, allowing those patients with low risk tumors to begin endocrine therapy and delay surgery. Use of preoperative hormone therapy was considered more often in place of neoadjuvant chemotherapy in patients with low genomic risk ER+/HER2- patients. Because of the continued feedback indicating positive impact, the pilot ultimately was extended to 11 months to allow time for formal implementation. Conclusions: Genomic testing using the MPT/BPT assay on core biopsy samples with at least 3 mm yields results 97% of the time with an average TAT of 11 days from biopsy date to result. The genomic information at the time of initial diagnosis impacted patient care most notably in the ER+ setting. The results led to the immediate implementation of direct reflex testing of all newly diagnosed ER+ and HER2- or IHC 2+ cancers by pathology after the initial pilot phase. Citation Format: Hannah Gilmore, Philip Bomeisl, Alberto Montero. Genomic testing on breast cancer core biopsy material is feasible and provides useful treatment information [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 P1-02-12.

PROSTATE-SPECIFIC ANTIGEN LEVEL AT 6 MONTHS AFTER RADICAL PROSTATECTOMY ENABLES STRATIFICATION OF FOLLOW-UP PERIODS IN THE CANCER REGIONAL ALLIANCES CRITICAL PATH

(Objectives)Factors related to prostate-specific antigen (PSA) recurrence, including PSA at 6 months after radical prostatectomy, were evaluated to determine if the postoperative follow-up period in the cancer regional alliances critical path could be individualized using a coordinated path. (Patients and methods)Among 352 patients who underwent laparoscopic radical prostatectomy at our hospital from May 2009 to June 2015, 331 who did not undergo preoperative hormone therapy were examined retrospectively. Cases with PSA < 0.01 ng/mL at 6 months after surgery (group A, n=209) were compared with those with PSA > 0.01 ng/mL at the same time point (group B, n=122). (Results)PSA recurrence was significantly higher in group B (n=21 (10.0%) vs. n=70 (57.4%), p< 0.001) and the time to recurrence was significantly shorter (44 vs.12.5 months, p< 0.001). In multivariate analysis within group A, the Gleason Grade Group (GGG) and extraprostatic extension in surgical specimens were predictors of PSA recurrence. In group A, all cases (n=30) of GGG1 in surgical specimens had no extraprostatic extension and no PSA recurrence. There were 90 cases of surgical specimens with GGG2 and no extracapsular infiltration, and only 4 of these cases had recurrence (4.4%). (Conclusion)The results of the study indicate that follow-up interval stratification is possible using the PSA level at 6 months after radical prostatectomy, GGG and extraprostatic extension in the surgical specimen.

Clinical validity and clinical utility of Ki67 in early breast cancer.

Ki67 represents an immunohistochemical nuclear localized marker that is widely used in surgical pathology. Nuclear immunoreactivity for Ki67 indicates that cells are cycling and are in G1- to S-phase. The percentage of Ki67-positive tumor cells (Ki67 index) therefore provides an estimate of the growth fraction in tumor specimens. In breast cancer (BC), tumor cell proliferation rate is one of the most relevant prognostic markers and Ki67 is consequently helpful in prognostication similar to histological grading and mRNA profiling-based BC risk stratification. In BCs treated with short-term preoperative endocrine therapy, Ki67 dynamics enable distinguishing between endocrine sensitive and resistant tumors. Despite its nearly universal use in pathology laboratories worldwide, no internationally accepted consensus has yet been achieved for some methodological details related to Ki67 immunohistochemistry (IHC). Controversial issues refer to choice of IHC antibody clones, scoring methods, inter-laboratory reproducibility, and the potential value of computer-assisted imaging analysis and/or artificial intelligence for Ki67 assessment. Prospective clinical trials focusing on BC treatment have proven that Ki67, as determined by standardized central pathology assessment, is of clinical validity. Clinical utility has been demonstrated in huge observational studies.