Tumor-reactive antibodies evolve from non-binding and autoreactive precursors.

The tumor microenvironment hosts antibody-secreting cells (ASCs) associated with a favorable prognosis in several types of cancer. Patient-derived antibodies have diagnostic and therapeutic potential; yet, it remains unclear how antibodies gain autoreactivity and target tumors. Here, we found that somatic hypermutations (SHMs) promote antibody antitumor reactivity against surface autoantigens in high-grade serous ovarian carcinoma (HGSOC). Patient-derived tumor cells were frequently coated with IgGs. Intratumoral ASCs in HGSOC were both mutated and clonally expanded and produced tumor-reactive antibodies that targeted MMP14, which is abundantly expressed on the tumor cell surface. The reversion of monoclonal antibodies to their germline configuration revealed two types of classes: one dependent on SHMs for tumor binding and a second with germline-encoded autoreactivity. Thus, tumor-reactive autoantibodies are either naturally occurring or evolve through an antigen-driven selection process. These findings highlight the origin and potential applicability of autoantibodies directed at surface antigens for tumor targeting in cancer patients.

Rate of breast biopsy referrals in female BRCA mutation carriers aged 50 years or more: a retrospective comparative study and matched analysis.

PURPOSE: To evaluate the total biopsy and positive biopsy rates in women at high risk of breast cancer compared to the general population. METHODS: The study group consisted of 330 women with pathogenic variants (PVs) in BRCA1/2 attending the dedicated multidisciplinary breast cancer clinic of a tertiary medical center in Israel. Clinical, genetic, and biopsy data were retrieved from the central healthcare database and the medical files. Patients aged 50 years or older during follow-up were matched 1:10 to women in the general population referred for routine breast cancer screening at the same age, as recommended by international guidelines. The groups were compared for rate of biopsy studies performed and percentage of positive biopsy results. Matched analysis was performed to correct for confounders. RESULTS: The total biopsy rate per 1000 follow-up years was 61.7 in the study group and 22.7 in the control group (p < 0.001). The corresponding positive biopsy rates per 1000 follow-up years were 26.4 and 2.0 (p < 0.001), and the positive biopsy percentages, 42.9% and 8.7% (p < 0.0001). CONCLUSION: Women aged 50 + years with PVs in BRCA1/2 attending a dedicated clinic have a 2.7 times higher biopsy rate per 1000 follow-up years, a 13.2 times higher positive biopsy rate per 1000 follow-up years, and a 4.9 times higher positive biopsy percentage than same-aged women in the general population.

Taxane versus vinorelbine in combination with trastuzumab and pertuzumab for first-line treatment of metastatic HER2-positive breast cancer: a retrospective two-center study.

BACKGROUND: The combination of a taxane with trastuzumab and pertuzumab is standard of care for first-line treatment of human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer. The combination of vinorelbine with trastuzumab and pertuzumab showed anti-tumor activity in a phase 2 trial. PATIENTS AND METHODS: The databases of two tertiary medical centers were retrospectively searched for patients with HER2-positive metastatic breast cancer who underwent first-line treatment in 2013-2019 with a taxane or vinorelbine in combination with trastuzumab and pertuzumab. Groups were compared for progression-free survival (PFS), overall survival (OS), and toxicity profile. RESULTS: The study included 87 patients in the taxane group and 65 in the vinorelbine group. Overall median PFS was significantly longer in the taxane group [HR 0.56 (0.36-0.88), P = 0.01], but on multivariate analysis the difference was not statistically significant [HR 0.68 (0.4-1.1, P = 0.11)]. PFS was comparable in both groups of patients with recurrent disease [HR 0.94 (0.5-1.79), P = 0.85]. However, in patients with de novo metastatic disease, the difference in favor of the taxane group was pronounced [HR 0.4 (0.2-0.78), P = 0.007] and maintained significance on multivariate analysis [HR 0.46 (0.2-0.97, P = 0.04)]. There was no statistical significant difference in OS in the whole cohort [HR 0.69 (0.39-1.23)] or the subgroups. CONCLUSIONS: Patients with HER2-positive metastatic breast cancer had similar survival with first-line treatment of taxane or vinorelbine combined with trastuzumab and pertuzumab. When the analysis was adjusted for prognostic factors, there was no PFS benefit for taxanes except in the subgroup with de novo disease.

Central nervous system metastases in breast cancer: the impact of age on patterns of development and outcome.

PURPOSE: The purpose of this study is to explore differences in the pattern and outcome of central nervous system (CNS) involvement in breast cancer by age at diagnosis. METHODS: A retrospective database of a tertiary cancer center yielded 174 consecutive patients with breast cancer who were diagnosed with CNS metastases in 2006-2019. Data on histopathology, characteristics of CNS involvement, treatments, and survival (at three time points during the disease course) were compared between patients aged ≤ 45 and > 45 years. Pearson Chi-square or Fisher exact test and Kaplan-Meier survival curves with log-rank test were used for statistical analyses. RESULTS: Study population was divided according to age at diagnosis of breast cancer. 65 patients were ≤ 45 years old and 109 patients > 45 years old. The younger group was characterized by longer median overall survival (117.1 months vs 88 months, p = 0.017) and longer interval between breast cancer diagnosis to development of CNS metastases (97.4 months vs 75.9 months, p = 0.026). Median survival after development of CNS disease was not significantly different (18.7 months vs 11.1 months, p = 0.341), although it was significantly longer in younger patients within the subgroup of patients with triple-negative disease (22.5 vs 7.9 months, p = 0.033). There were no between-group differences in number, location, and clinical presentation of CNS metastases or in systemic and CNS-directed treatment approaches. CONCLUSION: While the presentation of CNS involvement was similar between the different age groups, younger patients had significantly longer CNS-free interval and longer overall survival, and for the subgroups of triple-negative patients, younger age at breast cancer diagnosis was associated with longer survival after diagnosis of CNS disease.

The Impact of Exogenous Estrogen Exposure on the Characteristics and Outcome of Estrogen Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Early-Stage Breast Cancer.

INTRODUCTION: The impact of exogenous estrogen exposure on breast cancer characteristics and outcomes is not well described. We aimed to investigate the effect of prior treatment with oral contraceptives (OCT), hormone replacement therapy (HRT), and fertility treatments on early-stage, estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer. METHODS: This is a single-center retrospective cohort study comprising all women with ER-positive, HER2-negative, early breast cancer whose tumors were sent to Oncotype DX analysis between 2005 and 2012. Data on prior exposures to OCT, HRT, and fertility treatments were collected. The impact of these exposures on prespecified histopathological features was assessed including tumor size, nodal status, intensity of the hormonal receptors, grade, Oncotype recurrence score, Ki67, and lymphovascular and perineural invasion. The impact of these exposures on disease-free survival (DFS) and overall survival (OS) was also evaluated. RESULTS: A total of 620 women were included, of which 19% had prior exposure to OCT, 30% to HRT, and 11% to fertility treatments. OCT use was associated with smaller (≤1 cm) tumors (p = 0.023) and were less likely to have grade 3 disease (p = 0.049). No other associations were found between exogenous estrogen exposure and tumor characteristics. Median follow-up was 10.4 years. Ten-year DFS was 85.7%, and it was not influenced by exogenous exposure. Ten-year OS was 90.2%, and OCT was associated with improved OS in univariate analysis (HR = 0.31, 95% CI: 0.11-0.85), but this difference did not remain significant in multivariate analysis (p = 0.275). CONCLUSION: The impact of exogenous estrogen exposure on ER-positive, HER2-negative early breast cancer characteristics is limited. In the long term, none of the evaluated exposures had negative effect on DFS and OS.

3,3-Diindolylmethane (DIM): a nutritional intervention and its impact on breast density in healthy BRCA carriers. A prospective clinical trial.

Women who carry the BRCA mutation are at high lifetime risk of breast cancer, but there is no consensus regarding an effective and safe chemoprevention strategy. A large body of evidence suggests that 3,3-diindolylmethane (DIM), a dimer of indole-3-carbinol found in cruciferous vegetables, can potentially prevent carcinogenesis and tumor development. The primary aim of this prospective single-arm study was to investigate the effect of DIM supplementation on breast density, a recognized predictive factor of breast cancer risk. Participants were 23 healthy female BRCA carriers (median age 47 years; 78% postmenopausal) who were treated with oral DIM 100 mg × 1/day for 1 year. The amount of fibroglandular tissue (FGT) and background parenchymal enhancement (BPE) on magnetic resonance imaging (MRI) performed before and after the intervention was scored by two independent expert radiologists using the Breast Imaging and Reporting Data System. The results showed a decrease in the average score for FGT amount from 2.8 ± 0.8 at the onset to 2.65 ± 0.84 after 1 year (P = 0.031), with no significant change in BPE (P = 0.429). A group of DIM-untreated age- and menopausal-status-matched women from the BRCA clinic did not show a significant change in FGT amount (P = 0.33) or BPE (P = 0.814) in a parallel year. Mean estradiol level decreased from 159 to 102 pmol/l (P = 0.01), and mean testosterone level decreased from 0.42 to 0.31 pmol/l (P = 0.007). Side effects were grade 1. In conclusion, 1 year's supplementation with DIM 100 mg × 1/day in BRCA carriers was associated with a significant decline in FGT amount on MRI. Larger randomized studies are warranted to corroborate these findings.

Neoadjuvant Chemotherapy for Elderly Patients with Advanced Stage Ovarian Carcinoma.

BACKGROUND: The treatment of elderly patients with advanced stage ovarian carcinoma is challenging due to a high morbidity. OBJECTIVES: To evaluate the clinical course and outcome of elderly patients with advanced stage ovarian carcinoma receiving neoadjuvant chemotherapy (NACT). METHODS: A retrospective study of all patients with stage IIIC and IV ovarian carcinoma receiving NACT in one medical center (between 2005 and 2017). The study group criteria age was above 70 years. The control group criteria was younger than 70 years old at diagnosis. Demographics and treatment outcomes were compared between groups. Primary outcomes were progression-free survival (PFS) and overall survival (OS). RESULTS: Overall, 105 patients met the inclusion criteria, 71 patients (67.6%) were younger than 70 years and 34 patients (32.4%) older. Rates of interval cytoreduction were significantly higher in younger patients (76.1% vs. 50.0%, P = 0.01). Of those who underwent interval cytoreduction, no difference was found in rates of optimal debulking between groups (83.35% vs. 100%, P = 0.10). Using a Kaplan-Meier survival analysis, no significant differences were observed between groups in PFS or OS, P > 0.05. Among the elderly group alone, patients who underwent interval cytoreduction had significantly longer PFS than those without surgical intervention (0.4 ± 1.7 vs. 19.3 ± 19.4 months, P = 0.001). CONCLUSIONS: Elderly patients with ovarian carcinoma who received NACT undergo less interval cytoreduction than younger patients, with no difference in PFS and OS. However, among the elderly, interval cytoreduction is associated with significantly higher PFS.

Malignant Ascites: Validation of a Novel Ascites Symptom Mini-Scale for Use in Patients With Ovarian Cancer.

BACKGROUND: Ascites is a common finding in patients with ovarian cancer. Paracentesis is a relatively simple, safe, and effective procedure for draining fluid from the peritoneum, but valid quality-of-life tools are needed to determine its subjective value for alleviating symptoms and improving patient quality of life. The objective of this study was to prospectively evaluate the performance of a novel Ascites Symptom Mini-Scale (ASmS) and compare it with a previously available questionnaire. METHODS: Patients with ovarian cancer-related ascites presenting for paracentesis were asked to complete the newly devised ASmS before the procedure and 1 and 24 hours after. Patients also completed a pain assessment scale and a previously validated ascites questionnaire at the same time points. RESULTS: The cohort included 28 patients of median age 68 years (range, 51-86 years), 13 (46.4%) with primary ovarian cancer and 15 with recurrent disease. A median of 3300 mL of ascites was drained. The median score on the ASmS decreased significantly from 21.5 before paracentesis to 11.0 at 1 hour after paracentesis (P < 0.001) and remained low at 24 hours. No demographic factor predicted greater benefit from the procedure. Patients with both mild and severe symptoms reported significant relief. CONCLUSIONS: The ASmS is a robust quality-of-life tool for the specific assessment of symptoms of ovarian cancer-related malignant ascites. It can be used in the clinical trial setting assessing interventions aimed at treating ascites and in the clinic to identify those patients with mild symptoms, who may benefit from paracentesis.

Phase II study of oral ridaforolimus in women with recurrent or metastatic endometrial cancer.

OBJECTIVE: The phosphatidylinositol-3 kinase/serine-threonine kinase PI3K/AKT pathway is postulated to be central to cancer cell development. Activation of this pathway is believed to promote angiogenesis, protein translation and cell cycle progression. A large percentage of endometrial carcinomas have demonstrated mutations within this regulation pathway which result in constitutional activation. The downstream effector protein mammalian target of rapamycin (mTOR) acts as a critical checkpoint in cancer cell cycling and is a logical target for drug development. The efficacy and tolerability of the oral mTOR inhibitor ridaforolimus were evaluated in this study. METHODS: This phase II study evaluated the single agent tolerability and activity of oral ridaforolimus administered at a dose of 40mg for 5 consecutive days followed by a 2day break, in women with recurrent or metastatic endometrial carcinoma who had received no chemotherapy in the metastatic setting. RESULTS: 31 of 34 patients were evaluable. Three partial responses (8.8%) were observed with response duration ranging between 7.9 and 26.5months. An additional 18 patients showed disease stabilization (52.9%) for a median duration of 6.6months. Response rates were not affected by previous chemotherapy exposure. No correlation was found between response and mutation status. CONCLUSION: Oral ridaforolimus was reasonably tolerated and demonstrated modest activity in women with recurrent or metastatic endometrial cancers. Potential synergy between mTOR inhibition, angiogenesis and hormonal pathways warrants ongoing evaluation.

Olaparib plus Durvalumab, with or without Bevacizumab, as Treatment in PARP Inhibitor-Naïve Platinum-Sensitive Relapsed Ovarian Cancer: A Phase II Multi-Cohort Study.

PURPOSE: Early results from the phase II MEDIOLA study (NCT02734004) in germline BRCA1- and/or BRCA2-mutated (gBRCAm) platinum-sensitive relapsed ovarian cancer (PSROC) showed promising efficacy and safety with olaparib plus durvalumab. We report efficacy and safety of olaparib plus durvalumab in an expansion cohort of women with gBRCAm PSROC (gBRCAm expansion doublet cohort) and two cohorts with non-gBRCAm PSROC, one of which also received bevacizumab (non-gBRCAm doublet and triplet cohorts). PATIENTS AND METHODS: In this open-label, multicenter study, PARP inhibitor-naïve patients received olaparib plus durvalumab treatment until disease progression; the non-gBRCAm triplet cohort also received bevacizumab. Primary endpoints were objective response rate (ORR; gBRCAm expansion doublet cohort), disease control rate (DCR) at 24 weeks (non-gBRCAm cohorts), and safety (all cohorts). RESULTS: The full analysis and safety analysis sets comprised 51, 32, and 31 patients in the gBRCAm expansion doublet, non-gBRCAm doublet, and non-gBRCAm triplet cohorts, respectively. ORR was 92.2% [95% confidence interval (CI), 81.1-97.8] in the gBRCAm expansion doublet cohort (primary endpoint); DCR at 24 weeks was 28.1% (90% CI, 15.5-43.9) in the non-gBRCAm doublet cohort (primary endpoint) and 74.2% (90% CI, 58.2-86.5) in the non-gBRCAm triplet cohort (primary endpoint). Grade ≥ 3 adverse events were reported in 47.1%, 65.6%, and 61.3% of patients in the gBRCAm expansion doublet, non-gBRCAm doublet, and non-gBRCAm triplet cohorts, respectively, most commonly anemia. CONCLUSIONS: Olaparib plus durvalumab continued to show notable clinical activity in women with gBRCAm PSROC. Olaparib plus durvalumab with bevacizumab demonstrated encouraging clinical activity in women with non-gBRCAm PSROC. No new safety signals were identified.

Recent advances in systemic therapy for advanced endometrial cancer.

PURPOSE OF REVIEW: Endometrial cancer is the most common gynaecologic cancer in the western world. Systemic treatments for advanced disease have traditionally included hormonal therapy and chemotherapy. Responses to treatment are short-lived and advanced-stage disease remains incurable. Recent research has focused on optimizing chemotherapy regimens, the development of alternative hormonal therapy strategies and the introduction of targeted therapies. The most recent developments in these areas will be reviewed here. RECENT FINDINGS: Phase III trials continue to focus on the optimization of combination chemotherapy regimens. The elucidation of a hormonal pathway central to the control of oestrogen-stimulated cancer growth has led to the development of a new class of hormonal agents currently undergoing evaluation in the clinical trial setting. Increasing understanding of the molecular basis for malignant transformation continues to provide rationale for the development of many targeted therapies. Mammalian target of rapamycin inhibition, in particular, offers further encouraging results in this context. SUMMARY: The development of new hormone treatments and effective targeted therapies will provide new opportunities to improve therapy for women with advanced endometrial cancer. Optimization of therapy will require an approach to personalized therapy in order to guide choice and sequence of therapy and improve survival and quality of life.

Comparison of Poly (ADP-ribose) Polymerase Inhibitors (PARPis) as Maintenance Therapy for Platinum-Sensitive Ovarian Cancer: Systematic Review and Network Meta-Analysis.

BACKGROUND: Three PARPis (olaparib, niraparib and rucaparib) are currently FDA-approved as maintenance therapy in newly diagnosed and recurrent ovarian cancer. However, thus far, no trial has compared the three approved PARPis in the overall population, in patients with BRCA mutations, or in those with wild-type BRCA. METHODS: A frequentist network meta-analysis was used for indirect comparisons between the different PARPis with respect to progression free survival (PFS), overall survival (OS), and adverse events. RESULTS: Overall, six randomized clinical trials involving 2,770 patients, were included in the analysis. Results from the indirect comparisons revealed no statistically significant differences between the three PARPis with respect to PFS or OS in the entire population and in patients with mutated and wild-type BRCA, separately. Niraparib showed a statistically significant increased risk for grade 3 and 4 thrombocytopenia (risk-difference [RD] from placebo: 0.3; 95% confidence interval [CI], 0.27‒0.34) and any grade neutropenia (RD from placebo: 0.22; 95% CI, 0.18‒0.25) as compared with the other PARPis. CONCLUSION: No statistically significant difference was found between the three PARPis with respect to PFS or OS (overall and in subpopulations by BRCA status). There is, however, a statistical difference in toxicity as niraparib is associated with a greater risk for thrombocytopenia and neutropenia.

Neoadjuvant Chemotherapy Treatment Modifications in Ovarian Carcinoma: The Impact on Surgical Outcome and Progression-free Survival.

OBJECTIVE: Little is known on the impact of neoadjuvant chemotherapy (NACT) treatment modifications on surgical outcome and progression-free survival (PFS) in patients with ovarian carcinoma. We aimed to report the changes we made during NACT and to evaluate its impact on patient outcome. METHODS: A retrospective cohort study of all women with advanced stage ovarian carcinoma treated with NACT followed by interval cytoreduction in one university-affiliated medical center (January 2005 to June 2017). We excluded those who were treated with NACT without any surgical intervention. NACT modifications included delay in treatment, change in chemotherapy, and dose reduction. Demographics, tumor characteristics, surgical outcome, and PFS were compared between patients exposed to NACT treatment modifications and those who received standard treatment. RESULTS: Seventy-nine patients met inclusion criteria of whom, 59 patients received standard, nonmodified treatment and 20 patients modified NACT. There were no intergroup differences with respect to age at diagnosis (59.5±11.6 vs. 64.70±8.09, P=0.09) and stage of disease (P=0.13). Radiologic complete response rates (25.0% vs. 32.2%, P=0.545) and optimal cytoreduction rates (75.0% vs. 86.4%, P=0.23) were similar in both treatment groups. Mean PFS (in months) was comparable between patients receiving standard treatment and those who required NACT modifications (18.5 vs. 12.2, P=0.125). CONCLUSIONS: NACT treatment modifications did not affect surgical outcome and PFS. We conclude that when clinically indicated, dose alteration and scheduling can be implemented without apparent detriment to outcome.

Association of Ipilimumab With Safety and Antitumor Activity in Women With Metastatic or Recurrent Human Papillomavirus-Related Cervical Carcinoma.

Importance: Based on evidence of human papillomavirus (HPV)-induced immune evasion, immunotherapy may be an attractive strategy in cervical cancer. Ipilimumab is a fully humanized monoclonal antibody that blocks cytotoxic T-lymphocyte antigen-4 (CTLA-4), which acts to downregulate the T-cell immune response. Objective: To assess the safety and antitumor activity of ipilimumab in recurrent cervical cancer. Design, Setting, and Participants: A multicenter trial was designed for patients with metastatic cervical cancer (squamous cell carcinoma or adenocarcinoma) with measurable disease and progression after at least 1 line of platinum chemotherapy. A run-in safety cohort using ipilimumab, 3 mg/kg, every 21 days for 4 cycles in 6 patients was followed by a phase II cohort of ipilimumab, 10 mg/kg, every 21 days for 4 cycles and then 4 cycles of maintenance therapy every 12 weeks for patients demonstrating radiologic response or stabilization. Immune correlative studies were performed on peripheral blood before and after therapy on archival tissue and fresh tumor obtained prior to registration and 7 days after cycle 2. The study was conducted from December 3, 2012, to September 15, 2014. The data were analyzed from April 2016 to June 2016 and in July 2017. Main Outcomes and Measures: The primary end points were safety and objective response rate. Immune analyses were performed on blood and tumor tissue. Results: A total of 42 women (median age, 49 years; range, 23-78 years) were enrolled (29 [69%] squamous cell cervical cancer and 13 [31%] adenocarcinoma; 37 [93%] of 40 patients with tissue available for analysis had HPV-positive confirmation; there was no archival tissue for 2 women). Grade 3 toxic effects included diarrhea in 4 patients, 3 of whom had colitis. Of 34 patients evaluated for best response (Response Evaluation Criteria in Solid Tumors, version 1.1), 1 patient had partial response and 10 had stable disease. The median progression-free survival and overall survival were 2.5 months (95% CI, 2.1-3.2 months) and 8.5 months (95% CI, 3.6-not reached; 1 patient was still alive), respectively. Intratumoral pretreatment CD3, CD4, CD8, FoxP3, indoleamine 2,3-dioxygenase, and programmed cell death ligand 1 (PD-L1) expression was not predictive of benefit and did not significantly change with treatment. Multicolor flow cytometry on peripheral lymphocytes revealed a treatment-dependent increase of inducible T-cell costimulator, human leukocyte antigen-antigen D related, and PD-1 during initial treatment, which returned to baseline during maintenance. Conclusions and Relevance: Ipilimumab was tolerable in this population but did not show significant single-agent activity. Immune changes were induced by anti-CTLA-4 therapy but did not correlate with clinical activity. Changes in these markers may guide further treatment strategies.

Axillary lymph node metastasis in ovarian carcinoma: Two case reports and review of literature.

•Extra-peritoneal metastasis is uncommon in epithelial ovarian carcinoma.•Metastasis of epithelial ovarian carcinoma to axillary lymph node is rare.•Lymphatic drainage system can explain the rout of this distant metastasis.•Tissue diagnosis is the mainstay in identifying the origin of axillary metastasis.