Non-high Grade Research Articles

Risk factors for the failure of first-line PARP inhibitor maintenance therapy in patients with advanced ovarian cancer: Gynecologic Oncology Research Investigators Collaboration Study (GORILLA-3004).

To identify the risk factors for failure of first-line poly (ADP-ribose) polymerase inhibitor (PARPi) maintenance therapy in patients with advanced ovarian cancer. Patients with stage III-IV epithelial ovarian cancer who received first-line PARPi maintenance therapy were retrospectively reviewed. Clinicopathologic factors were compared between two groups-recur/progression of disease (PD) and non-recur/PD. In total, 191 patients were included. Median follow-up was 9.9 months, and recurrence rate was 20.9%. BRCA mutations were found in 63.4% patients. Postoperative residual tumor (60.5% vs. 37.8%), non-high grade serous carcinoma (HGSC) (15.0% vs. 6.0%), neoadjuvant chemotherapy (NAC) (55.0% vs. 35.8%), and pre-PARPi serum CA-125 levels ≥23.5 U/mL (35.9% vs. 15.2%) were more frequently observed in the recur/PD group. Multivariate Cox-regression analysis revealed pre-PARPi serum CA-125 levels ≥23.5 U/mL (HR, 2.17; 95%CI, 1.03-4.57; p = 0.042), non-HGSC (3.28; 1.20-8.97; p = 0.021), NAC (2.11; 1.04-4.26; p = 0.037), and no BRCA mutation (2.23; 1.12-4.44; p = 0.023) as independent risk factors associated with poor progression-free survival (PFS). A subgroup analysis according to BRCA mutation status showed that pre-PARPi serum CA-125 levels ≥26.4 U/mL were the only independent risk factor for poor PFS in women with BRCA mutations (2.75; 1.03-7.39; p = 0.044). Non-HGSC (5.05; 1.80-14.18; p = 0.002) and NAC (3.36; 1.25-9.04; p = 0.016) were independent risk factors in women without BRCA mutations. High pre-PARPi serum CA-125 levels, non-HGSC histology, NAC, and no BRCA mutation might be risk factors for early failure of first-line PARPi maintenance therapy. In women with BRCA mutations, high pre-PARPi serum CA-125 levels, which represent a large tumor burden before PARPi, were the only independent risk factor for poor PFS.

Abstract IA002: DCIS: Pathological heterogeneity and prognosis definition

Abstract Ductal carcinoma in situ represents 15 to 20% of all breast carcinomas and is a non-obligate precursor of invasive carcinomas. Clinically DCIS presents most frequently as microcalcifications detected on screening mammography. DCIS is a proliferation of neoplastic cells confined to the ductulo-lobular tree. Its morphology can recapitulate the diversity of that of invasive carcinomas. DCIS lesions are classified according to the nuclear grade (low, intermediate, high), the presence of necrosis and microinvasion. In resection specimens, the extent of the disease and the quality of the margins are key element for patients management as well as the association of DCIS to the microcalcifications. The reproducibility of the DCIS grading system is relatively poor and promising help emerges from deep learning approaches. The four molecular classes of invasive carcinomas exist but with different proportion in DCIS. Triple negative represent 5-8% of DCIS. Conversely, HER2 overexpression is more frequently observed in particular in high grade DCIS (up to 60% of the cases). The analysis of Estrogens and progesterone receptors is not systematic in clinical practice unless an endocrine therapy may be decided after the patient has completed the loco-regional treatment. At initial diagnosis, it remains very challenging to predict the clinical outcome of the lesion. However, after complete surgical excision followed by whole breast irradiation therapy, the prognosis is excellent with a mortality of 3.7%. The rate of relapse is 7% at 5 years and 16% at 10 years of follow-up. Concerns about overdiagnosis and overtreatment exist worldwide. Retrospective studies identified older age, mammographic detection, small size, non-high grade histology and negative margins at excision associated with favorable outcome. Unfortunately, de-escalation clinical prospective trials based on these criteria, failed to identify the patients presenting DCIS of good prognosis. Biological parameters have been retrospectively associated with a poor prognosis (HER2 amplification, proliferation, RB loss, COX2 expression…). The molecular signature Oncotype DCIS®, has been validated retrospectively in a subgroup of patients from the ECOG E5194, and determined DCIS associated with different risk of relapse. Its prospective validation is on-going in a non randomized trial (DUCHESS). Three on-going trials based in part on clinical criteria, one adding estrogen receptors expression, the other comedonecrosis, propose after a diagnostic biopsy, a simple surveillance. Another trial, leaded by UNITRAD/UNICANCER (France), Romance is a prospective randomized study of omission of whole-breast radiotherapy following breast-conserving surgery in patients with very low risk luminal A ductal carcinoma in situ and enrolment is on. Research efforts is moving into the integration the ecosystem of DCIS (myoepithelial cells, stroma, immune cells and carcinomatous cells) to identify more accurately the DCIS associated with a higher aggressiveness that would allow secure de-escalation clinical trials. Citation Format: Anne Vincent-Salomon. DCIS: Pathological heterogeneity and prognosis definition [abstract]. In: Proceedings of the AACR Special Conference on Rethinking DCIS: An Opportunity for Prevention?; 2022 Sep 8-11; Philadelphia, PA. Philadelphia (PA): AACR; Can Prev Res 2022;15(12 Suppl_1): Abstract nr IA002.

Pre-diagnosis and post-diagnosis dietary patterns and survival in women with ovarian cancer.

Evidence is limited on inflammation-related dietary patterns and mortality in ovarian cancer survivors. We examined the associations between pre- and post-diagnosis dietary patterns, including change in diet from before to after diagnosis, and mortality among 1003 ovarian cancer survivors in two prospective cohort studies. Dietary pattern scores for empirical dietary inflammatory pattern (EDIP) and Alternative Healthy Eating Index (AHEI) were calculated based on food frequency questionnaires. We used Cox proportional hazard models to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for ovarian cancer-specific and all-cause mortality. Pre-diagnosis EDIP score and AHEI were not associated with mortality. Among non-high grade serous cases, a higher post-diagnosis EDIP score was associated with increased risk of all-cause mortality (HR5th vs 1st quintile = 1.95, 95% CI = 1.04-3.67, p-trend = 0.06). Compared to survivors consuming a low EDIP score diet before and after diagnosis, high post-diagnosis EDIP was associated with increased risk of ovarian cancer specific mortality (pre-to-post diagnosis low/high, HR = 1.38, 95% CI = 0.99-1.92; high/high HR = 1.58, 95% CI = 1.09-2.30) and all-cause mortality (low/high HR = 1.44, 95% CI = 1.06-1.95; high/high HR = 1.55, 95% CI = 1.10-2.19). Consuming a more inflammatory dietary pattern post-diagnosis was associated with increased mortality in ovarian cancer survivors, suggesting limiting the inflammatory potential of diet post-diagnosis could lead to enhanced survivorship.

Abstract 1300: Identification of efficacious treatment for glioblastoma (GBM) by applying computational drug sensitivity imputation to novel GBM avatars and GBM clinical datasets

Abstract Glioblastoma (GBM) is a debilitating disease associated with poor prognosis and a limited response to therapies. At present, patients receive chemotherapy with temozolomide, following radiation therapy and surgery; however, none of the treatments are curative, and clinical trials are recommended as the preferred option for eligible patients. Regrettably, only 3-5% of GBM patients survive 3 years or more. Therefore, it is imperative to develop efficacious therapies. To achieve this goal, we have developed a computation method that allows us to impute drug sensitivity when transcriptome data is available. We have applied this imputation method to several publicly available normal brain tissue, low grade glioma (LGG), and GBM patient datasets to identify compounds of interest. We also compared the leads from these patient/in vivo data analyses with those generated from previous imputations made using a novel GBM avatar model; this model was created by introducing different genetic driver mutations using CRISPR-Cas9 into human induced pluripotent stem cells, followed by differentiation to GBM-associated mutations containing neural progenitor cells (NPC) and animal engraftment to develop human adult GBM models. We applied the drug imputation to over 1200 human normal brain, LGG and GBM samples as well as 18 NPC, tumor sphere and engrafted GBM tumor avatar samples. For each sample, we imputed over 700 drug sensitivity scores. Our model was trained independently using one of two separate high throughput in vitro drug screening datasets (GDSC and CTRP). To identify drugs showing higher sensitivity in GBM than in normal tissues, we compared the imputed drug sensitivity for each compound between samples belonging to the precancerous or the non-high grade glioma state (represented by the normal tissue and LGG data) and samples representing the cancerous or high grade glioma state (GBM). We identified a number of compounds showing higher imputed sensitivity in samples belonging to the cancerous state when compared to those in the precancerous or LGG state. We were also able to cross check compounds of interest with our avatar data. Among them, some agents have been used in the clinic to treat GBM, supporting the validity of integration of our computational tool with novel ex vivo GBM avatars and GBM clinical data in the development of new therapeutic strategy for GBM. More importantly, we have identified other compounds with various mechanism of action that show higher efficacy in GBM and will be further evaluated with the goal to quickly translate into clinic. Therefore, we can successfully integrate ovel experimental and computational models to speed up drug discovery with the goal of finding new therapeutics for GBM. Citation Format: Danielle Maeser, Robert Gruener, Robert Galvin, Tomoyuki Koga, Frank B. Furnari, David Largaespada, Clark C. Chen, Stephanie R. Huang. Identification of efficacious treatment for glioblastoma (GBM) by applying computational drug sensitivity imputation to novel GBM avatars and GBM clinical datasets [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1300.

TIME‐TO‐RESPONSE FOR PATIENTS WITH RELAPSED/REFRACTORY AGGRESSIVE B CELL NON‐HODGKIN LYMPHOMA TREATED WITH POLATUZUMAB‐BASED THERAPY

Introduction: Knowledge of time-to-response after initiation of therapy (TTR) may influence treatment recommendations made to patients (pts) with relapsed/refractory (R/R) aggressive B cell non-Hodgkin lymphoma (aBNHL) given the potential for rapid disease growth. If reported in clinical trials, TTR is dependent upon the timing of protocol-specified imaging response assessments (IRA) and does not account for clinical response to therapy (Rc), which may precede radiographic response (Rr). Here we report TTR and other response-related outcomes in pts with R/R aBNHL treated with polatuzumab (pola). Methods: Pts analyzed were those with non-Burkitt R/R aBNHL diagnosed on most recent tissue biopsy and first treated with pola at the University of Pennsylvania from 7/2019 to 12/2020. Rc was defined as reduction in lymph node size on examination, resolution of disease-related symptoms, normalization of lactate dehydrogenase (LDH) previously >2x upper limit of normal or disease response on imaging performed for indication other than IRA. Rr was assessed per Revised Response Criteria for Malignant Lymphoma. Timing of clinical/laboratory assessments and IRA were at the discretion of the treating clinician. Data were censored on 3/1/2021. Results: Fifty pts were included in this analysis. Baseline clinicopathologic and treatment characteristics at time of pola initiation are listed in Table 1. Nineteen pts (38%) were treated with the intent to bridge to cellular therapies (CT). Median number of cycles of pola received was 3. Rc was achieved by 18 pts (36%), Rr by 16 pts (32%) and the composite outcome of Rc or Rr (overall response, [Ro]) by 24 pts (48%). IRA was not performed for 9 pts: 7 due to proceeding to planned CT (5 with Rc) and 2 due to death not attributed to aBNHL with ongoing Rc. The median TTRc, TTRr and earliest of TTRc or TTRr (TTRe) were 21 d (range 7-41 d), 64 d (range 17-137 d) and 22 d (7-67 d), respectively. Of 12 pts who achieved Rc and had subsequent IRA performed, 8 achieved Rr. Twelve pts stopped tx in remission: 7 pts due to proceeding to planned CT, 3 due to toxicity (gastrointestinal in 2 pts and neuropathy in 1 pt) and 2 pts due to choice. Excluding the 7 pts proceeding to planned CT in remission, the estimated proportion of pts with ongoing Rc and Rr at 180 d were 53% and 51%, respectively. Of characteristics listed in Table 1, non-high grade B cell histology and receipt of prior CD19-directed chimeric antigen receptor-modified T cell therapy were significantly associated with achievement of Ro; additionally, age ≤60 years, largest tumor diameter ≤7.5 cm and disease refractory to most recent prior therapy were significantly associated with shorter TTRe. Conclusions: For R/R aBHL pts treated with pola at our institution, frequently with the intention to bridge to CT, 48% achieved Rc or Rr with median TTR of 22 d. These findings may further inform use of pola in the standard-of-care and investigational settings. Keywords: Aggressive B-cell non-Hodgkin lymphoma Conflicts of interests pertinent to the abstract M. E Hughes Consultant or advisory role: AstraZeneca, Genzyme, Janssen, AbbVie, Karyopharm Research funding: Acerta S. D Nasta Consultant or advisory role: Morphosys, Merck Research funding: Roche/Genentech, Millennium/Takeda, Pharmacyclics, ATARA, Forty Seven J. N Gerson Consultant or advisory role: Pharmacyclics, Genentech, AbbVie Research funding: Loxo J. Svoboda Consultant or advisory role: Seattle Genetics, Bristol-Myers Squibb, Pharmacyclics, Imbrium Therapeutics, Genmab, Adaptive Biotechnologies, ADC Therapeutics, Atara Biotherapeutics Research funding: Celgene, Seattle Genetics, Pharmacyclics, Merck, Bristol-Myers Squibb, Incyte Educational grants: Imbrium Therapeutics E. A Chong Consultant or advisory role: Novartis, Tessa Therapeutics, Bristol-Myers Squibb, Kite/Gilead S. J Schuster Consultant or advisory role: Celgene, Nordic Nanovector, Novartis, AbbVie, Acerta, Alimera Sciences, BeiGene, Juno Therapeutics, Loxo Oncology, Tessa Therapeutics, Genetech/Roche, Research funding: Novartis, Pharmacyclics, Adaptive Biotechnologies, Merck, Genetech/Roche, Celgene, Juno Therapeutics, AbbVie, Incyte, TG Therapeutics, DTRM, S. K Barta Consultant or advisory role: Monsanto Honoraria: Atara, Seattle Genetics, Janssen, Pfizer, Acrotech Research funding: Seattle Genetics, D. J Landsburg Consultant or advisory role: Morphosys, Karyoparhm, Celgene Research funding: Takeda, Curis, Triphase Other remuneration: Karyopharm

Anthropometric risk factors for ovarian cancer in the NIH-AARP Diet and Health Study

ObjectiveIdentifying potentially modifiable risk factors for ovarian cancer is essential for prevention because this cancer is predominantly detected at a late stage. Here, we estimated the relations of general adiposity and measures reflecting body fat distribution to the risk of epithelial ovarian cancer.MethodsWe ascertained 683 ovarian epithelial cancers (343 high-grade serous, 141 non-high grade serous) among 145,575 women, aged 50–72 years (median follow-up 12.6 years), from the National Institutes of Health—American Association of Retired Persons (NIH-AARP) Diet and Health Study. Using Cox models, we estimated confounder-adjusted hazard ratios (HRs) and 95% confidence intervals (CI) for associations of overall ovarian cancer, high-grade serous and non-high-grade serous carcinoma with body mass index, waist circumference, hip circumference, waist–hip ratio, waist–height ratio, body adiposity index, body shape index, and abdominal volume index.ResultsAnthropometric measures were unrelated to overall ovarian cancer, high-grade serous cancer, and non-high-grade serous cancer. For example, the HR for overall ovarian cancer per standard deviation increment of body mass index at baseline was 0.98 (95% CI 0.88–1.10). Similar associations were observed with measurements of body fat distribution.ConclusionThese results do not indicate that adult adiposity is associated with ovarian cancer risk in post-menopausal women.

1659P AI-based grading approach identifies FNCLCC grade 3 soft tissue sarcomas

Morphologic grading is an established prognostic parameter in soft tissue sarcomas. Three-tiered FNCLCC grading is highly correlated with overall survival of sarcoma patients and is therefore widely used for deciding on perioperative chemo- and radiotherapy. Clinical routine, however, faces two major limitations of conventional FNCLCC grading: a) Grading correctness is hampered by intratumoral heterogeneity, especially in small biopsies; b) G2 sarcomas represent a clinically equivocal subgroup but account for the majority of patients. We selected H&E-stained sections of 52 soft tissue sarcomas. At least 13 mm2 of viable tumor regions were annotated (necroses were excluded) per case. After scanning the resulting 240 slides at 20 × resolution, we extracted approximately 1.3 million image tiles (112.6×112.6 μm) of the tumor regions. We trained a convolutional neural network (customized pre-trained EfficientNetB0) to classify tiles in high grade (FNCLCC G3; 24 cases) and non-high grade (G1 or G2; 28 cases) by predicting the respective class probabilities. For training, we used 41 cases (incl. 11 for validation), balancing the numbers of tiles per case, and withheld 11 test cases for independent evaluation. Finally, we optimized the cut-off values of a) the class probability for classifying tiles and b) the proportion of high-grade tiles required for classifying a case as high-grade. For default cut-off values of 0.5, we obtained accuracies of 68% (slide-based) and 64% (case-based) for the test cases. Optimizing the cut-off values, accuracies increased to 77% (slide-based) and 73% (case-based). G3 tumors were correctly classified as high grade (3/4), except for one pleomorphic liposarcoma, probably misclassified due to specific tumor morphology. G2 tumors were classified either as low grade (4/6) or high grade (2/6), one G1 tumor was classified correctly. Our data indicate that computerized grading is feasible for sarcomas and AI-based analysis can recognize G3 sarcomas correctly, without being predicted on heterogeneous parameters, e.g., mitotic count and extent of necroses. Possibly observable patterns in the tile-wise classification of G2 sarcomas require further investigation and correlation with clinical outcome data.

Ipsilateral invasive cancer risk after diagnosis with ductal carcinoma in situ (DCIS): Comparison of patients with and without index surgery.

519 Background: Most women diagnosed with ductal carcinoma in situ (DCIS) undergo surgical resection, potentially leading to overtreatment of patients who would not develop clinically significant breast cancer in the absence of locoregional treatment. We compared the risk of ipsilateral invasive breast cancer (iIBC) between DCIS patients who received breast conserving surgery (BCS) for their index diagnosis of DCIS (BCS group) and patients who did not receive any locoregional treatment within 6 months of diagnosis (surveillance [SV] group). Methods: A treatment-stratified random sample of patients diagnosed with screen-detected and biopsy-confirmed DCIS in 2008-14 was selected from 1,330 Commission on Cancer-accredited facilities (20/site). Excluding patients who received a mastectomy ≤6 months, the final analytic cohort contained 14,245 (88.2%) BCS and 1,914 (11.8%) SV patients. Subsequent breast events were abstracted up to 10 years after diagnosis. Primary outcome was the 8-year absolute difference in iIBC risk between BCS and SV; a subgroup analysis was performed for grade I/II patients. A propensity score (PS) model for treatment was fitted with sampling design (SD) weighting and random effects for patients within facilities. Absolute risk differences were estimated using PS-SD-weighted Kaplan Meier estimators. Results: Overall, median age at diagnosis was 61 years (IQR: 52-69) and median follow-up was 5.8 years (95% CI 5.7-6.1). The majority of patients were Caucasian (81.9%), with estrogen receptor-positive (80.6%), and nuclear grade I/II (54.5%) DCIS. The fraction of patients with a Charlson comorbidity score of ≥2 was higher in SV (14.2%) compared to BCS (6.4%, p < 0.001). The 8-year risk of iIBC was 3.0% (95% CI: 2.4%-3.6%) for BCS and 7.7% (95% CI: 4.9%-10.5%) for SV, with an absolute risk difference of 4.7% (95% CI: 4.5%-4.9%; log-rank p < 0.001). Among patients with grade I/II tumors, the 8-year risk of iIBC was 3.1% (95% CI: 2.3%-4.0%) for BCS and 6.1% (95% CI: 2.5%-9.8%) for SV; difference: 3.0% (95% CI: 2.7%-3.2%; p = 0.005). Conclusions: Despite an increased risk of iIBC in SV patients compared to BCS patients, the 8-year risk did not exceed 10% in either group. The risk of recurrence in BCS patients was comparable to previously reported estimates. These data demonstrate a considerable degree of overtreatment among patients with non-high grade DCIS. Prospective clinical trials will help determine the tradeoffs between universally directed as opposed to selectively applied surgery for low risk DCIS.

Abstract PD6-7: Pathological features and lessons learned from screen detected ductal carcinoma in situ (DCIS) - Results from 11 337 cases in the UK Sloane project

Abstract Background: The UK Sloane project aims to improve knowledge of the pathology, radiology and management of DCIS through a UK national prospective audit of in situ carcinoma and atypias. Methods: Phase one included collection of multidisciplinary data on screen detected DCIS, lobular in situ neoplasia (LISN) and atypical ductal hyperplasia (ADH) between 2003-12 through collation of prospective proformas on imaging, pathology, management and subsequent outcome data. Results: A total of 11337 cases of DCIS from 82 UK screening units have been recorded; 54% of cases <20mm (n=6067), 26% <10mm (n=2881), 28% (10-19.9mm, n=3186). 1979 (18%) were 20 -29.9mm, 1071 (10%) 30 - 39.9mm and 1989 (18%) > 40mm and 131 (1%, unknown). There has been a slight but steady increase in DCIS size, from mean of 21.4mm in 2003/04 to 24.1mm in 2011/12. This was largely due to an increase in lesions measuring 30 mm or more. 7213 DCIS cases (63%) were of high nuclear grade, 27% (3121) intermediate and 9% were of low grade (34 unknown grade). A small gradual increase in the proportion of high grade DCIS was noted from 59% in 2004 to 65% in 2012, coupled with a slight decrease in the proportion of low grade DCIS, from 10% to 6% from 2004 to 2012. Comedo necrosis was reported in 61%, more commonly in high grade DCIS (78%) compared with low/intermediate grade lesions (31%). Solid DCIS was the predominant architectural pattern, seen in 61% of cases; 72% of high grade DCIS was of solid pattern, compared with 42% of non-high grade DCIS. Only 3% (233) of patients with breast conserving surgery had margin clearance described as 0mm, with another 3% having disease <1mm from the margin. The most common margin width was 10mm or over (35%; 2814 patients) with 8% (614), 20% (1559) and 25% (2015) having margin widths of 1-1.9mm, 2-4.9mm and 5-9.9mm, respectively. Atypical ductal hyperplasia (ADH) alone was reported in association with DCIS in 611 patients, of whom 39% had high grade DCIS, 37% intermediate grade DCIS and 24% had low grade disease. In a further 111 patients, ADH and lobular in situ neoplasia were associated with the DCIS, more commonly intermediate (36%) or low grade DCIS (34%) than high grade disease (29%). Lobular neoplasia alone was seen most commonly in patients with high grade DCIS (294 cases, 53%), rather than in patients with low grade DCIS (64, 12%) or intermediate grade disease (190, 34%). ADH and LISN were associated in 6% and 3.6% of cases respectively. Ipsilateral recurrences were almost equally distributed between in situ (n=212) and invasive (n=243) disease (unknown disease in 9 cases). Of the 243 patient who developed ipsilateral invasive disease, 148, 76 and 17 had high, intermediate and low grade disease respectively at presentation (2 original grade unknown). Of the 243 invasive lesions, 148 had a primary diagnosis of high grade DCIS; 66 of these 148 recurrences were also of histological grade 3, 60 were grade 2 and only 10 were of histological grade 1 (12 invasive grade not known). Contralateral lesions were more commonly invasive than DCIS (207 invasive carcinomas and 74 DCIS; 1 unknown). 52 of the invasive carcinomas were of grade 3, 106 grade 2 and 42 grade 1. High grade DCIS was the most common primary disease recorded (174) with 90 intermediate and 18 low grade DCIS. 120 of contralateral invasive cancers had had previous primary high grade DCIS, 72 intermediate and only 15 had had low grade DCIS. Conclusion: The study provides a unique opportunity to understand the histological characteristics and behaviour of screen detected DCIS and the change in the pathological features and management over time. An increase in DCIS size and proportion of high grade lesions is noted. Both ipsilateral and contralateral carcinoma are more common, in the short term, in patients with high grade DCIS but longer follow-up will provide more information. Citation Format: Abeer M Shaaban, Elena Provenzano, Bridget Hilton, Karen Clements, Shan Cheung, Alastair Thompson, Sarah Pinder, on behalf of the Sloane Project Steering Committee. Pathological features and lessons learned from screen detected ductal carcinoma in situ (DCIS) - Results from 11 337 cases in the UK Sloane project [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr PD6-7.

Low Utility in Colposcopy-directed Biopsies for Non-high Grade Cytological Abnormalities on PAP Smear

Background: Clinicians commonly perform colposcopy directed biopsies on patients with low grade squamous intraepithelial lesion (LSIL) on PAP cytology even when not consistent with clinical guidelines. Objective: We study the association of PAP cytology screening results with cervical intra-epithelia neoplasia (CIN) 2-3 high-grade dysplasia, as confirmed by colposcopy-directed biopsy. Methods: A retrospective study of 263 women with an abnormality on the PAP smear. Multinomial logistic regression was performed with predictors of PAP cytology screening results with the outcome variable of colposcopy-directed biopsy. Results: High grade squamous intraepithelial lesion (HSIL) had significantly increased relative risk for CIN 2-3 (RR: 9.85, 95% CI: 1.84, 52.79, p=0.008). LSIL was not significantly associated with CIN 2-3. In the comparisons of negative with CIN-1, both HSIL and LSIL were not significantly associated with a negative biopsy. Conclusion: HSIL is associated with cervical dysplasia of CIN 2-3 while LSIL is not associated with cervical dysplasia of CIN 2-3. We do not recommend routine biopsies in patients with LSIL cytologic abnormalities unless additional compelling factors exist.

Synchronous and metachronous bilateral breast cancer: clinicopathologic characteristics and prognostic outcomes

The incidence of bilateral breast cancer (BBC) reportedly ranges from 1.4 to 11.8%. Women with a first primary breast cancer are at a 2- to 6-fold increased risk of developing contralateral BC. However, there have been limited studies analyzing the clinicopathologic features of BBC and conflicting data exist on the prognostic significance of BBC. In this study, we sought to analyze the incidence of BBC in the era of modern medicine and assess the clinicopathologic characteristics and prognostic outcomes compared to unilateral BC (UBC). Of the 5941 patients with stage I-III BC diagnosed between 1998 and 2013 at our institution, 110 developed BBC, including 58 synchronous BBC (SBBC, interval between the first and the contralateral BC ≤3 months) and 52 metachronous BBC (MBBC, interval >3 months). The median time to the second tumor was 67.9 months among patients with MBBC. BBC was associated with a significantly lower rate of having a ductal type, high grade, HER2-positive or node-positive disease when compared to UBC, while no difference was found for age, race, ER/PR status, or pathologic tumor stage. When compared to MBBC, SBBC was strongly associated with a lobular phenotype, non-high grade, and ER/PR-positive disease; and further demonstrated a significantly higher concordant rate for ER, PR, and HER2 status. Patients with BBC had a significantly worse distant relapse-free survival (RFS) but a similar disease-specific survival (DSS) when compared to those with UBC. Being African American, having a high histologic grade and higher pathologic tumor or node stage was significantly associated with a worse prognosis, while SBBC was associated with a favorable RFS by multivariate analysis. Nodal status was the only independent prognosticator for DSS in patients with BBC. Further investigation into the complex biologic and clinical behavior of BBC may provide novel insights into the therapeutic strategies in the pursuit of precision medicine in this unique subset of patients.

Outcomes of non-high grade serous carcinoma after neoadjuvant chemotherapy for advanced-stage ovarian cancer: a Korean gynecologic oncology group study (OV 1708)

BackgroundOutcomes of patients with ovarian high-grade serous carcinoma (HGSC) treated with neoadjuvant chemotherapy (NAC) have been widely studied, but there is limited information on the outcomes of patients with non-HGSC. This study aimed to evaluate the outcomes of NAC in non-HGSC patients with advanced-stage ovarian cancer.MethodsWe conducted a retrospective cohort study of patients who underwent NAC for advanced stage non-HGSC between 2002 and 2017 in 17 institutions. Demographics, surgical outcomes, and survival rates were evaluated according to histological subtypes.ResultsA total of 154 patients were included in this study, comprising 20 cases (13.0%) of mucinous adenocarcinoma, 31 cases (20.1%) of endometrioid adenocarcinoma, 28 (18.2%) cases of clear cell carcinoma, 29 (18.8%) cases of low-grade serous carcinoma and 12 cases (7.8%) of carcinosarcoma. Complete remission/partial remission after the third cycle of NAC was achieved in 100 (64.9%) patients and optimal debulking surgery (residual disease ≤1 cm) at interval debulking surgery was achieved in 103 (66.9%) patients. The most common reason for performing NAC was high tumor burden (n = 106, 68.8%). The median progression-free survival (PFS) was 14.3 months and median overall survival (OS) was 52.9 months. In multivariate analyses, mucinous and clear cell carcinoma were negative prognostic factors for both PFS (p = 0.007 and p = 0.017, respectively) and OS (p = 0.002 and p = 0.013, respectively).ConclusionsIn this study, poor survival outcomes were observed in patients with mucinous and clear cell carcinoma undergoing NAC. Different treatment strategies are urgently required to improve survival outcomes for this disease subset.

109P - PARP inhibitor (PARPi) monotherapy treatment in non-BRCA and/or non-serous gynaecological cancers

Background: The vast majority of PARPi clinical trial experience in gynaecological cancer is for patients with platinum sensitive high grade serous ovarian carcinoma (HGSOC) and deleterious BRCA1/2 mutations. It is known that other homologous recombination deficiency (HRD) associated mutations exist eg RAD51, BRIP1 that can potentially sensitise to PARPi. Extremely limited clinical data exists on the use of PARPi in HGSOC with HRD mutations other than BRCA1/2; or in BRCA-mutated gynaecological cancers excluding HGSOC. We investigated the role of PARPi in a cohort of patients with non-BRCA and/or non-high grade serous (HGS) gynaecological cancer. Methods: Retrospective case series from two tertiary referral centres. Results: Ten cases were identified. Non-HGS cohort included large cell neuroendocrine carcinoma (LCNEC) of the cervix, small cell ovarian cancer, low grade ovarian cancer (LGSOC) and endometrial carcinoma. Non-BRCA patients were affected by alterations of RAD51, ATM and EMSY. Median number of cycles of PARPi received was 2 (range 1-16). CA125 response was seen in 75% (6 of 8 cases with minimum three CA125 results) with a median reduction of 53.3%. Overall radiological response rate 28.6% (2 of 7 cases with minimum one restaging scan). Progression free survival (PFS) was greater for non-HGS BRCA mutant patients (median PFS 10.5m, range 2-15m), than for HGSOC non-BRCA patients (median PFS 1.2m, range 1-2m). Legend: Abbreviations as in text, germline (g), somatic (s). Conclusions: In this series, deleterious BRCA mutation or variant of unknown significance (VUS) remains the single strongest predictor for response to PARPi irrespective of histology. It may be difficult to classify a BRCA mutation as deleterious or VUS in rarer gynaecological cancer populations. Non-BRCA mutations in HRD related genes eg RAD51/ATM may also sensitise to treatment with PARPi. Four patients remain on treatment and updated results will be presented. Legal entity responsible for the study: Dr R Kristeleit. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.Table: 109PSiteBRCA 1/2Other mutsNumber cyclesCA125 ResponseRadiological ResponsePFSEndometrialBRCA1 mut (g)16yesyes15.5LCNEC cervixBRCA2 VUS (s)8yesN10.7LGSOCBRCA2 VUS (g)13yes (<50%)yes (on treatment)7.9Small cell ovarianBRCA2 VUS (g)2no dataN2.2HGSOCWTEMSY (s)4yes (<50%)N2.7HGSOCWTATM (s)2NN1.2HGSOCWTRAD51L3 (s)2NN1.0HGSOCWTRAD51C (g)2Nno data (on treatment)NAPP (as HGSOC)WTRAD51D (g)1yes (<50%)no data (on treatment)NAHGSOCWTRAD51C (g)2yesno data (on treatment)NA Open table in a new tab

Do clinical and radiologic features help predict malignancy of B3 breast lesions without epithelial atypia (B3a)?

To evaluate excision histology outcome of B3a lesions diagnosed at imaging-guided core biopsy and assess whether clinical and radiologic features may predict upgrade to malignancy. A total of 153 B3a lesions (74 papillomas, 51 radial scars and 28 fibro-epithelial lesions) that underwent surgical excision were assessed. PPV for malignancy in all B3a lesions and specific for each sub-category was evaluated. Multivariate analysis was conducted to identify association between clinical (age, family or personal history of breast cancer, symptoms), diagnostic findings (imaging modality, lesion size, final BI-RADS category) and final excision outcome. Eleven (7%) of 153 B3a lesions were upgraded to malignancy. All carcinomas diagnosed on excision were non-high grade DCIS. Following features were significantly associated with malignancy: lesions identified only on mammography (3/21; 14%), both mammography and ultrasound (7/44; 16%), lesion size > 10mm (10/74; 13.5%) and BI-RADS category 4-5 (8/29; 27.6%). The absence of residual microcalcification after biopsy was associated with decreased risk for malignancy (15/16[93.7%]; p = 0.0297). Lesion size > 10mm (OR = 9.3832; 95%; p = 0.0398) and BI-RADS category 4-5 (OR = 12.6004; 95%; p = 0.0006) were found to be independent predictors of upgrade to malignancy. B3a lesions are associated with low risk of malignancy at excision. Lesion size > 10mm and BI-RADS 4-5 category may represent useful predictors of upgrade to malignancy.

Risk factors for the development of invasive cancer in unresected ductal carcinoma in situ

BackgroundThe natural history of ductal carcinoma in situ (DCIS) remains uncertain. The risk factors for the development of invasive cancer in unresected DCIS are unclear. MethodsWomen diagnosed with DCIS on needle biopsy after 1997 who did not undergo surgical resection for ≥1 year after diagnosis were identified by breast centres and the cancer registry and outcomes were reviewed. ResultsEighty-nine women with DCIS diagnosed 1998–2010 were identified. The median age at diagnosis was 75 (range 44–94) years with median follow-up (diagnosis to death, invasive disease or last review) of 59 (12–180) months. Twenty-nine women (33%) developed invasive breast cancer after a median interval of 45 (12–144) months. 14/29 (48%) with high grade, 10/31 (32%) with intermediate grade and 3/17 (18%) with low grade DCIS developed invasive cancer after median intervals of 38, 60 and 51 months. The cumulative incidence of invasion was significantly higher in high grade DCIS than other grades (p = .0016, log-rank test). Invasion was more frequent in lesions with calcification as the predominant feature (23/50 v. 5/25; p = .042) and in younger women (p = .0002). Endocrine therapy was associated with a lower rate of invasive breast cancer (p = .048). ConclusionsHigh cytonuclear grade, mammographic microcalcification, young age and lack of endocrine therapy were risk factors for DCIS progression to invasive cancer. Surgical excision of high grade DCIS remains the treatment of choice. Given the uncertain long-term natural history of non-high grade DCIS, the option of active surveillance of women with this condition should be offered within a clinical trial.

The Prevalence and Associated Factors of Microsatellite Instability in Ovarian Epithelial Cancers Detected by Molecular Genetic Studies in a Sample of Iranian Women

Background: Microsatellite instability, the main genetic element in HNPCC syndrome, is associated with a number of cancers, including ovarian epithelial carcinomas. These cancers have distinct characteristics compared to non-MSI related ones. Objectives: The present study aims at determining the prevalence of microsatellite instability in ovarian carcinomas and their associated factors in Iranian patients. Methods: Paraffin-embedded blocks, belonging to 37 patients with definite diagnosis of ovarian epithelial cancers, were retrieved from the archives. After DNA extraction from tumor tissue and PCR reaction, the results were assessed in accordance with melting curve analysis. Subsequently, the relationship among microsatellite status and tumor histology, grade, stage, and size were investigated statistically. Results: The predominant histological type was serous histology. Four out of 37 carcinomas were microsatellite unstable (10.8%) and only 1 was MSI-high type (2.1%). The MSI was more frequent among younger patients with unilateral, non-serous histology, non-high grade, and stage I tumors without omental involvement. After statistical analysis, the only significant relationship was found between histological type (non-serous) and microsatellite status. Conclusions: Microsatellite stable and unstable ovarian cancers may have different associations with various factors in a sample of Iranian women. The identification of these characteristics may help narrow down indications to test this prognostic and predictive genetic error.

Abstract P1-11-03: Rates of ipsilateral breast tumor recurrence (IBTR) following breast concerving surgery (BCS) and hypofractionated radiotherapy for ductal carcinoma in situ (DCIS)

Abstract P1-11-03: Rates of ipsilateral breast tumor recurrence (IBTR) following breast concerving surgery (BCS) and hypofractionated radiotherapy for ductal carcinoma in situ (DCIS)

Adult body mass index and risk of ovarian cancer by subtype: a Mendelian randomization study.

Observational studies have reported a positive association between body mass index (BMI) and ovarian cancer risk. However, questions remain as to whether this represents a causal effect, or holds for all histological subtypes. The lack of association observed for serous cancers may, for instance, be due to disease-associated weight loss. Mendelian randomization (MR) uses genetic markers as proxies for risk factors to overcome limitations of observational studies. We used MR to elucidate the relationship between BMI and ovarian cancer, hypothesizing that genetically predicted BMI would be associated with increased risk of non-high grade serous ovarian cancers (non-HGSC) but not HGSC. We pooled data from 39 studies (14 047 cases, 23 003 controls) in the Ovarian Cancer Association Consortium. We constructed a weighted genetic risk score (GRS, partial F-statistic = 172), summing alleles at 87 single nucleotide polymorphisms previously associated with BMI, weighting by their published strength of association with BMI. Applying two-stage predictor-substitution MR, we used logistic regression to estimate study-specific odds ratios (OR) and 95% confidence intervals (CI) for the association between genetically predicted BMI and risk, and pooled these using random-effects meta-analysis. Higher genetically predicted BMI was associated with increased risk of non-HGSC (pooled OR = 1.29, 95% CI 1.03-1.61 per 5 units BMI) but not HGSC (pooled OR = 1.06, 95% CI 0.88-1.27). Secondary analyses stratified by behaviour/subtype suggested that, consistent with observational data, the association was strongest for low-grade/borderline serous cancers (OR = 1.93, 95% CI 1.33-2.81). Our data suggest that higher BMI increases risk of non-HGSC, but not the more common and aggressive HGSC subtype, confirming the observational evidence.

Diffuse invasive breast carcinoma of no special type.

Diffuse invasive breast carcinomas are rare tumors associated with unfavorable prognostic parameters. This growth pattern is often related to invasive lobular cancer (ILC). Diffuse ductal breast carcinoma of no special type (NST) is largely under-recognized in the literature. We identified 70 diffuse invasive breast carcinomas in a consecutive series of 1249 invasive tumors. Based on morphology and E-cadherin expression, 15/70 were NST and 55/70 were ILC. Subgroups differed in mammographic appearance, as more NST tumors than ILCs formed stellate masses (53 vs. 18 %, p = 0.000436) while ILCs displayed more architectural distortion. NST tumors were significantly more often radiologically extensive than ILCs (80 vs. 38 %, p = 0.0042987). Subgroups did not differ significantly in disease extent on histology, lymph node status, progesterone receptor status, and molecular phenotype, with a difference of borderline statistical significance in estrogen receptor status (87 vs. 100 %, p = 0.0434783). Significantly more NST tumors were HER2 positive (27 vs. 4 %, p = 0.0050463) and showed high Ki67 proliferation index (60 vs. 25 %, p = 0.0121808). The most striking differences occurred in the histology grade of the in situ (high grade in 53 vs. 4 %) and invasive (high grade in 27 vs. 2 %) tumor components and in the distribution of the in situ component (diffuse in 73 vs. 11 %). We conclude that diffuse invasive breast carcinomas of NST comprise a small subgroup of breast carcinomas. Most of these cancers are non-high grade and of luminal phenotype, but extensive and lymph node positive with worse prognostic parameters than diffuse ILC.

Recurrence rates for ductal carcinoma in situ: Analysis of 2,996 patients treated with breast-conserving surgery over 30 years.

32 Background: Randomized trials of radiation after breast-conserving surgery (BCS) for DCIS found substantial rates of recurrence, with half of recurrences invasive. Decreasing local recurrence rates for invasive breast carcinoma have been observed, and are largely attributed to systemic therapy improvements. Here we examine recurrence rates after BCS for DCIS over 3 decades at one institution. Methods: We retrospectively reviewed a prospectively maintained database of DCIS patients undergoing BCS from 1978–2010. Cox proportional hazard models were used to investigate the association between treatment period and recurrence, controlling for other variables. Results: 363 (12%) recurrences among 2996 cases were observed. Median follow-up for patients without recurrence was 75 months (range 0–30 years); 732 were followed for ≥ 10 years. The 5-year recurrence rate for 1978–1998 was 13.6% versus 6.6% for 1999–2010 (hazard ratio [HR] 0.62, p &lt; 0.0001). After controlling for age, family history, presentation (radiologic vs clinical), nuclear grade (non-high vs. high grade), necrosis, number of excisions ( ≤ 2 vs ≥ 3), margin status (positive/close vs negative), radiation, and endocrine therapy, treatment period remained significantly associated with recurrence, with later years associated with a lower HR (0.74, p = 0.02) compared to earlier. After stratification by radiation use, and adjustment for 7 other factors, the decrease in recurrence rates was limited to those without radiation (HR 0.62, p = 0.003); there was no decline in recurrence rates among those receiving radiation (HR 1.13, p = 0.6). Conclusions: Recurrence rates for DCIS have fallen over time. Increases in screen-detection, negative margins, and use of adjuvant therapies only partially explain the decrease. The unexplained decline is limited to women not receiving radiation, suggesting it is not due to changes in radiation efficacy, but may be due to improvements in radiologic detection and pathologic assessment. The lower recurrence risk observed for DCIS patients treated in more recent years is important for patient education, especially in view of the widely reported recent increase in use of mastectomy.