Development Of Distant Metastatic Disease Research Articles

The impact of obesity on triple negative breast cancer (TNBC) outcomes at a diverse academic cancer center.

e12529 Background: Multiple studies have linked obesity (BMI ≥30 kg/m2) to poor outcomes from triple negative breast cancer (TNBC). To further explore the association between obesity and TNBC, we conducted a retrospective chart review at our institution to examine the association of race and obesity with disease free survival (DFS) and pathologic complete response (pCR) rates. Our institution is a unique setting in which to study this because of its large African-American (AA) pt population relative to other academic medical centers in the United States. Methods: A chart review of 247 early-stage TNBC pts treated from 2004- 2017 was conducted. All cases were retrieved from pathology archival reports. Of these 247 pts, 116 were treated with adjuvant chemotherapy and 131 were treated with neoadjuvant chemotherapy (NAT). Pts were categorized as obese (BMI = / > 30) and non-obese (BMI < 30), AA [n = 151], Caucasian [n = 84], other [n = 11], and missing [n = 1]. The association of race and BMI with pCR following NAT (for the NAT group), and the association of race and BMI with DFS (for all pts) was evaluated. Results: 50.3% of AA pts and 32% of Caucasians were obese. 43% of obese pts had node-positive disease at diagnosis, compared with 31% of non-obese pts. Among the node-positive TNBC pts, non-obese pts had a trend towards a longer DFS than obese pts with a HR 0.80 (95% CI 0.37 – 1.71) and a non-statistically significant p-value of 0.562. We evaluated pCR rates based on race and BMI. Among AA pts, 56.9% did not achieve pCR after NAT, and of these pts 44.4% were obese; 43.1% achieved pCR and of these 58.8% were obese (p = 0.206). Among Caucasian pts, 65% did not achieve pCR, and of these 43.3% were obese; of the 35% of Caucasian pts who achieved pCR, 31.25% were obese (p = 0.424). Among pts who eventually developed distant metastases, there was a strong trend towards shorter DFS in the obese group, with a HR 1.92 (95% CI 0.94-3.95) and a non-statistically significant p-value of 0.075. Conclusions: In this sizable population of TNBC pts at a racially diverse academic medical center, obesity was associated with a higher incidence of nodal involvement at diagnosis, and shorter interval of time to development of distant metastatic disease. Race was not found to impact pCR or DFS in a statistically significant way. This could have been related to small sample size (particularly in the NAT group), or because some socioeconomic variables often tied to poor outcomes among minority pts may have been minimized in this study. The association of obesity with node positivity at diagnosis and with shorter interval times for development of metastases highlights the importance of adopting initiatives to minimize obesity in oncology practices and in the primary care setting. Improving access to healthy food and to safe spaces for exercise will help to prevent obesity, and thus may reduce the risk of developing TNBC and improve breast cancer outcomes among all pts, regardless of race.

A clinical case of a big urethral recurrence after cystectomy in a patient with invasive bladder cancer

The urethral recurrence (UR) of invasive bladder cancer (iBC) after cystectomy is observed in 6% of patients at highest. In this clinical observation of a 38-year old man, a mass (103 38 mm) was found in the proximal urethra by magnetic resonance imaging at 15 months after radical (R0) cystectomy for iBC pT4aN0M0. The clinical picture of UR was characterized by urethrorrhagia and priapism with associated advanced pain syndrome. At 3 months after surgical resection of the UR and subsequent chemotherapy, distant lung, liver and bone metastases were found, which led to the patient's death at 5 months after penectomy. This clinical case indicates that after radical cystectomy, the occurrence of a big-sized urethral recurrence of iBC can cause rapid development of distant metastatic disease.

Histopathological growth distribution of ductal carcinoma in situ: tumor size is not "one size fits all".

Ductal carcinoma in situ (DCIS) is a group of preinvasive breast neoplasms. Studies have shown excellent survival among patients with lumpectomy-amenable disease. Patients requiring mastectomy have been less well characterized. We aim to characterize this cohort and identify whether growth distribution pattern is associated with sentinel lymph node involvement at time of surgery or subsequent development of metastatic disease. Patients were identified using local cancer registry data and were chart reviewed using electronic medical records. Growth pattern was classified as unifocal, multifocal, or diffuse. Chi-squared, Analysis of Variance (ANOVA), and Kaplan-Meier analyses were performed. Two hundred and twenty-six patients were identified with median age at diagnosis 49 and follow up 7.1 years. 42 had unifocal, 51 had multifocal and 20 had diffuse lesions. 3/20 patients with diffuse type lesions developed subsequent distant metastatic disease, while none of the patients with unifocal or multifocal lesions did. 1/20 patients with diffuse and 2/51 with multifocal disease had sentinel lymph node involvement (SLNI) at surgery. Tumor extent was not associated with sentinel lymph node involvement or distant metastatic disease (P=0.2, Kaplan-Meier analysis) but growth pattern was (P=0.01). It was also associated on Kaplan-Meier with development of distant metastatic disease alone (P=0.01). Patients with diffuse growth pattern DCIS were more likely to have SLNI or development of distant metastatic disease. Our findings suggest that patients with diffuse type lesions are at greater risk of metastatic disease and therefore breast cancer death from DCIS. Optimal therapy for these patients will need further elucidation.

Adjuvant chemotherapy following chemoradiation as primary treatment for locally advanced cervical cancer compared to chemoradiation alone: The randomized phase III OUTBACK Trial (ANZGOG 0902, RTOG 1174, NRG 0274).

LBA3 Background: Cervical cancer is a common cause of cancer-related death among women worldwide. Standard treatment for locally advanced disease is chemoradiation. However, a significant percentage of women still relapse and die from the development of distant metastatic disease. OUTBACK was designed to determine the effects of giving adjuvant chemotherapy after chemoradiation on survival. Methods: OUTBACK is an international randomized phase III trial of the Gynecologic Cancer InterGroup (GCIG). Participating groups (countries) included ANZGOG (Australia and New Zealand), NRG (USA, Saudi Arabia, Canada, China), and Singapore. Eligible women had locally advanced cervical cancer (FIGO 2008 stage IB1 and node positive, IB2, II, IIIB or IVA) that was suitable for primary treatment with chemo-radiation with curative intent. Women were randomly assigned to either standard cisplatin-based chemo-radiation (control) or standard cisplatin-based chemo-radiation followed by adjuvant chemotherapy (ACT) with 4 cycles of carboplatin and paclitaxel, after stratification for nodal status, participating site, FIGO stage, age, and planned extended-field radiotherapy. The primary end point was overall survival (OS) at 5 years. Secondary endpoints included progression-free survival (PFS); adverse events (AE); and patterns of disease recurrence. The target sample size of 900 provided 80% power with 95% confidence to detect an improvement in OS at 5 years from 72% (control) to 80% (ACT), with some over-accrual to account for non-compliance with ACT and loss to follow-up. Results: 919 of 926 women recruited from April 2011 to June 2017 were eligible and included in the primary analysis: 463 assigned ACT, 456 control. ACT was started in 361 (78%) women assigned to receive it. Median follow-up was 60 months (IQR 45-65). OS at 5 years was similar in those assigned ACT versus control (72% vs 71%, difference <1%, 95% CI -6 to +7; P = 0.91). The hazard ratio for OS was 0·91, (95% CI 0.70 to 1.18). PFS at 5 years was similar in those assigned ACT versus control (63% vs 61%, difference 2%, 95% CI -5 to +9; P = 0.61). The hazard ratio for PFS was 0·87, (95% CI 0.70 to 1.08). AE of grade 3-5 within a year of randomisation occurred in 81% who were assigned and received ACT versus 62% assigned control. There was no evidence of differences between treatment groups in AE beyond 1 year of randomisation. Patterns of disease recurrence were similar in the two treatment groups. Conclusions: Adjuvant chemotherapy given after standard cisplatin-based chemoradiation for women with locally advanced cervical cancer did not improve OS or PFS. Clinical trial information: ACTRN12610000732088.

Prophylactic Central Neck Dissection in Papillary Thyroid Carcinoma: All Risks, No Reward

BackgroundCentral neck dissection (CND) remains a controversial intervention for papillary thyroid carcinoma (PTC) patients with clinically negative nodes (cN0) in the central compartment. Proponents state that CND in cN0 patients prevents locoregional recurrence, while opponents deem that the risks of complications outweigh any potential benefit. Thus, there remains conflicting results amongst studies assessing oncologic and surgical outcomes in cN0 PTC patients who undergo CND. To provide clarity to this controversy, we sought to evaluate the efficacy, safety, and oncologic impact of CND in cN0 PTC patients at our institution. Materials and MethodsSix hundred and ninety-five patients with PTC who underwent thyroidectomy at our institution between 1998 and 2018 were identified using an institutional cancer registry and supplemental electronic medical record queries. Patients were stratified by whether or not they underwent CND; identified as CND(+) or CND(-), respectively. Patients were also stratified by whether or not they received adjuvant radioactive iodine (RAI) therapy. Patient demographics, pathologic results, as well as surgical and oncologic outcomes were reviewed. Standard statistical analyses were performed using ANOVA and/or t-test and chi-squared tests as appropriate. ResultsAmong the 695 patients with PTC, 492 (70.8%) had clinically and radiographically node negative disease (cN0). The mean age was 50 ± 1 years old and 368 (74.8%) were female. Of those with cN0 PTC, 61 patients (12.4%) underwent CND. CND(+) patients were found to have higher preoperative thyroid stimulating hormone (TSH) values, 2.8 ± 0.8 versus 1.5 ± 0.2 mU/L (P = 0.028) compared to CND(-) patients. CND did not significantly decrease disease recurrence, development of distant metastatic disease (P = 0.105) or persistence of disease (P = 0.069) at time of mean follow-up of 38 ± 3 months compared to CND(-) patients. However, surgical morbidity rates were significantly higher in CND(+) patients; including transient hypocalcemia (36.1% versus 14.4%; P < 0.001), transient recurrent laryngeal nerve (RLN) injury (19.7% vers us 7.0%; P < 0.001), and permanent RLN injury (3.3% versus 0.7%; P < 0.001). ConclusionsThe majority of patients at our institution with cN0 PTC did not undergo CND. This data suggests that CND was not associated with improvements in oncologic outcomes during the short-term follow-up period and led to increased postoperative morbidity. Therefore, we conclude that CND should not be routinely performed for patients with cN0 PTC.

Predicting distant metastatic disease in differentiated thyroid cancer: a matched case-control study.

The occurrence of distant metastasis (DM) is the most important prognostic factor influencing survival outcomes in differentiated thyroid cancer (DTC). Identifying patients who are likely to develop DM and offering these cases more aggressive surgical approaches and I-131 therapy, is paramount to achieving the best possible outcomes. DM on presentation in DTC are uncommon, with an incidence of 1-9%. However, the incidence of DTC is rising and the disease affects a relatively young cohort of patients. The aims of this study were to investigate predictive factors in the development of DM by comparing a homogenous group of DTC patients with and without DM, and to illustrate the overall and disease-specific survival (DSS) rates of DTC patients presenting with DM. A matched case-control study of patients with DTC and DM was undertaken. The study group comprised a consecutive series of cases with DM treated in the period 1968-2014. Patients with DM at initial presentation were identified (DTC-DM group). A control group of patients without DM were matched based on age, gender, tumour size and histological subtype. The primary outcome measures were overall and disease-free survival. Secondary outcome measures were lymph node involvement (LNI), extra-thyroidal extension (ETE) of tumour and presence of BRAFV600E mutation identified on immunohistochemistry. A total of 2547 patients with DTC were reviewed and of these 83 (3.26%) had DM at initial presentation. At 5 and 10 years, the overall survival rates for DTC-DM patients were 89.6% and 64%, respectively. The 5 and 10 year DSS rates for DTC-DM cases were 90.2% and 67.3%, respectively. When compared to the DTC group, the DTC-DM group had significantly higher rates of ETE (63% vs. 29.5%, P < 0.0001) and LNI (32.5% vs. 18.8%, P = 0.044). Among patients with papillary thyroid cancer (PTC), the presence of BRAFV600E mutation was significantly associated with DM (62.2% vs. 36.8%, P = 0.028). ETE, LNI and BRAFV600E mutation in PTC are significant predictors for the development of distant metastatic disease.

Abstract 4455: Combination of bempegaldesleukin and anti-CTLA-4 prevents metastatic dissemination after primary surgery or radiation therapy in a preclinical model of non-small cell lung cancer

Abstract Purpose: Surgical resection or stereotactic ablative radiation therapy (SBRT) in early stage non-small cell lung cancer (NSCLC) have local control rates of 90% or higher. Current treatment paradigms effectively control primary tumor sites, but distant relapse remains a challenge with metastatic failure in more than 30% of patients with primary tumors larger than 5 cm. We hypothesized that adjuvant immune checkpoint blockade with anti-CTLA4 (C4) and /or bempegaldesleukin (NKTR-214), a CD122-preferential pegylated-interleukin-2 (IL2) pathway agonist,in combination with primary tumor ablative radiation or surgical resection would reduce metastases in a spontaneously metastatic syngeneic Lewis Lung Carcinoma (LLC) model. Methods: LLC flank tumors were established in C57BL/6 mice (n=6 per replicate, 12 total). When tumors were ~100 mm3 they were randomized to receive: vehicle only (VO); NKTR-214 (16 μg on Days 6, 15, 24) + C4 (200 μg IP on Days 4, 7, 10); RT (8Gy x 3 on Days 1, 2, 3); RT + C4, RT + NKTR-214; RT + C4 + NKTR-214; Primary surgery (Day 16), or Surgery + NKTR-214 + C4. Primary tumor size, survival, and a binary assessment of metastatic disease was made for each mouse. Flow cytometry studies examined tumor immune cell infiltrates on Day 21 in mice treated with VO, RT, RT + C4, C4 + NKTR-214, or RT + C4 + NKTR-214. Results: NKTR + C4 prevented development of spontaneous metastasis (p &amp;lt; 0.01) but did not control primary disease compared to VO treatment. RT alone significantly reduced primary tumor size compared to VO control (p &amp;lt; 0.01), but these mice all developed metastases. Adjuvant NKTR-214 + C4 after RT reduced development of spontaneous metastasis in mice treated by this regimen by 91% and 73% compared to RT alone and RT + C4 respectively. RT + C4 + NKTR-214 also significantly improved survival compared to both RT + C4 and RT + NKTR-214 (p = 0.02, p = 0.003). 58% of mice treated with RT + C4 + NKTR-214 cleared their primary tumors compared to 16% with RT + C4 and 0% in RT + NKTR-214 at day 30 (p = 0.03, p &amp;lt; 0.01). All mice clearing primary tumors rejected LCC rechallenge. Flow cytometric immuneprofiling of the primary tumors demonstrated increased CD8+T cells, NK cells (NK1.1+CD3−), and NKT cells (NK1.1+CD3+) with NKTR-214 + C4 w/wo RT treatment compared to VO controls. NKTR-214 + C4 prior to surgical resection also reduced the development of spontaneous lung metastases compared to surgery alone (p &amp;lt; 0.01). Conclusions: Addition of systemic NKTR-214 + C4 treatment to RT or primary surgical resection reduces development of distant metastatic disease in a preclinical NSCLC model. Moreover, treatment with NKTR-214 + C4 increases infiltration of innate and adaptive immune effector cells in the primary tumor. This treatment strategy has important translational potential to prevent distant relapse in patients undergoing definitive local therapies for early stage NSCLC. Citation Format: Ryan J. Brown, Luke Zangl, Ian Arthur, Alex Pieper, Peter M. Carlson, Juliana Castillo, Paul M. Sondel, Alexander Rakhmilevich, Zach S. Morris, Ravi B. Patel. Combination of bempegaldesleukin and anti-CTLA-4 prevents metastatic dissemination after primary surgery or radiation therapy in a preclinical model of non-small cell lung cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4455.

Abstract 3384: Characterization of the tumor microenvironment and liquid biopsy in head and neck and non-small cell lung cancer

Abstract Metastasis in cancer patients is reflected by measurable levels of circulating tumor cells (CTCs) in the blood of cancer patients. CTCs represent cancer cells from the primary and metastatic sites, thereby providing a comprehensive representation of the tumor burden of an individual patient. Recent advancements have shown that PD-1/PD-L1 immune checkpoint therapies have durable responses in a number of solid tumor types. Our study was designed to use multiple CTC enrichment platforms for the capture of CTCs and novel culture formulations for the ex vivo expansion of CTCs. Head and Neck cancer (n=350) and lung cancer (n=150) patients were recruited to investigate the prognostic role of CTCs. In parallel, a subset of HNC tumors were profiled using the NanoString GeoMx Digital Spatial Profiling (DSP) technology using a 44-plex antibody cocktail. We evaluated multiple CTC isolation technologies (CellSearch, filtration, CD45 depletion, Spiral, Straight and novel microfluidic chip technology) using matched patient samples which showed that epitope-independent CTC isolation captured a greater proportion of CTCs. Molecular alterations present in the primary tissue were confirmed in the CTCs by 3D-DNA FISH (EGFR-amplification, ALK-translocations). In HNC, the presence of CTC clusters associated with the development of distant metastatic disease (P=0.0313). HNC CTC-positive patients had shorter progression free survival (Hazard ratio [HR]: 4.946; 95% [CI]:1.571-15.57; P=0.0063) and PD-L1-positive CTCs were found to be significantly associated with worse outcome ([HR]:5.159; 95% [CI]:1.011-26.33; P=0.0485). In a proof of principle study, we were able to demonstrate for the first time, short-term patient derived CTC cultures outside the patient's body and exome sequencing of CTCs cultures confirmed the presence of mutational signatures consistent with The Cancer Genome Atlas (TCGA). Spatial characterization of the tumor microenvironment revealed immune subsets predictive of outcome to immunotherapy. Comprehensive characterization of the tumor microenvironment and liquid biopsy allows for the recapitulation of the molecular diversity present within the tumor, understanding of the disease progression and testing of therapies. Citation Format: Arutha Kulasinghe, Joanna Kapeleris, Liz Kenny, Brett Hughes, Majid Warkiani, Ian Vela, Jean-Paul Thiery, Ken O'Byrne, Chamindie Punyadeera. Characterization of the tumor microenvironment and liquid biopsy in head and neck and non-small cell lung cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3384.

Abstract A03: Isolation, characterization, and expansion of circulating tumor cells in head and neck cancers

Abstract Metastasis in head and neck cancer (HNC) patients is reflected by measurable levels of circulating tumor cells (CTCs) in the blood of patients. CTCs represent cancer cells from the primary and metastatic sites, thereby providing a comprehensive representation of the tumor burden of an individual patient. Recent advancements have shown that PD-1/PD-L1 immune checkpoint therapies have durable responses in HNC. Our study was designed to use multiple CTC enrichment platforms for the capture of CTCs and novel culture formulations for the ex vivo expansion of CTCs. n=300 head and neck cancer patients were recruited to investigate the prognostic role of CTCs. We evaluated multiple CTC isolation technologies (CellSearch, filtration, CD45 depletion, inertial microfluidics) using matched patient samples, which showed that epitope-independent CTC isolation captured a greater proportion of CTCs. Molecular alterations present in the primary tissue were confirmed in the CTCs by 3D-DNA FISH (EGFR-amplification). The presence of CTC clusters was associated with the development of distant metastatic disease (P=0.0313). HNC CTC-positive patients had shorter progression-free survival (PFS) (Hazard ratio [HR]: 4.946; 95% confidence interval [CI]:1.571-15.57; P=0.0063) and PD-L1-positive CTCs were found to be significantly associated with worse outcome ([HR]:5.159; 95% [CI]:1.011-26.33; P=0.0485). In a proof-of-principle study, we were able to demonstrate for the first time short-term patient-derived CTC cultures outside the patient’s body from 7/18 HNC samples (4/7 HPV-positive). Recently, we have preliminary data that suggest that PD-L1 is frequently expressed on CTCs in HNC and an immunoscore may be able to identify patients likely to benefit from immunotherapy—a current unmet clinical need. Expanding CTCs outside the patient’s body allows for the recapitulation of the molecular diversity present within the tumor, understanding of the disease progression, and testing of therapies. Citation Format: Arutha Kulasinghe, Joanna Kapeleris, Liz Kenny, Majid Warkiani, Ian Vela, Jean Paul Thiery, Ken O’Byrne, Chamindie Punyadeera. Isolation, characterization, and expansion of circulating tumor cells in head and neck cancers [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research; 2019 Apr 29-30; Austin, TX. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(12_Suppl_2):Abstract nr A03.

162P - Circulating tumour cells in head and neck and non-small cell lung cancer

BackgroundMetastasis in cancer patients is reflected by measurable levels of circulating tumour cells (CTCs) in the blood of cancer patients. CTCs represent cancer cells from the primary and metastatic sites, thereby providing a comprehensive representation of the tumour burden of an individual patient. MethodsOur study was designed to use microfluidic devices for the capture of CTCs and novel culture formulations for the ex vivo expansion of CTCs. Head and Neck cancer (HNC) and non-small cell lung cancer (NSCLC) patients were recruited to investigate the prognostic role of CTCs (n=400). ResultsWe demonstrated a higher CTC capture efficiency using microfluidic CTC platforms. Molecular alterations present in the primary tissue were confirmed in the CTCs by DNA FISH (EGFR-amplification, ALK-translocations). The presence of CTC clusters was associated with the development of distant metastatic disease (P=0.0313). In a proof of principle study, we were able to demonstrate for the first time, short-term patient derived CTC cultures outside the patient’s body from 7/18 HNC samples (4/7 HPV-positive). Likewise CTC cultures were established from 6/40 NSCLC samples. Exome sequencing of CTC and white blood cells (as germline control) confirmed the presence of somatic mutations in the CTC culture with mutational signatures consistent with NSCLC. Additionally our preliminary data indicate that PD-L1 is frequently expressed on CTCs in HNC and lung cancer and an immunoscore may be able to identify patients likely to benefit from immunotherapy. ConclusionsExpanding CTCs outside the patient’s body allows for the recapitulation of the molecular diversity present within the tumour, understanding of the disease progression and testing of therapies. Legal entity responsible for the studyThe author. FundingHas not received any funding. DisclosureThe author has declared no conflicts of interest.

Adjuvant Breast Radiotherapy Using a Simultaneous Integrated Boost for Early-Stage Breast Cancer: Results from a Phase II Trial

The purpose of the study was to report outcome analysis of a prospective institutional phase 2 trial of patients undergoing postoperative whole breast irradiation with inversely intensity modulated radiotherapy (IMRT) and a simultaneous integrated boost following breast-conserving surgery (BCS). This prospective cohort study (NCT01394575) included 532 patients treated with RT for invasive breast cancer (T1-2, N1-2M0) or carcinoma in situ after BCS. Patients received whole-breast radiation therapy to 45 Gy in 25 weekly fractions with a simultaneous integrated boost to the tumor bed of 60Gy in 25 fractions. The primary endpoint was ipsilateral breast tumor recurrence, development of distant metastatic disease, and overall survival. Patients were also evaluated for acute toxicity (Common Terminology Criteria for Adverse Events version 3.0). Between 2010 and 2014, 532 eligible patients (65 DCIS and 467 invasive breast cancer) underwent whole breast irradiation with intensity modulated radiotherapy and simultaneously integrated boost (IMRT-SIB) following BCS. The median age was 46 years old (range, 22-74 years), and the median follow-up period was 5.06 years. The most common grade 1 or 2 acute toxicities were breast pain, radiation dermatitis, and fatigue. There was only one patient presenting a grade 3 event (0.18%). Ipsilateral breast tumor recurrence developed in a total of two patients (0.3%), one in conjunction with widespread metastatic disease. Distant metastatic disease developed in eight patients (1.5%), and the five-year disease-free survival and overall survival rates were 98.1% and 99.2%, respectively. Five-year disease-specific outcomes for adjuvant breast radiotherapy using a simultaneous integrated boost are favorable in early-stage breast cancer.

Abstract 1333: Isolation, characterization and expansion of circulating tumor cells in solid cancers

Abstract Metastasis in cancer patients is reflected by measurable levels of circulating tumor cells (CTCs) in the blood of cancer patients. CTCs represent cancer cells from the primary and metastatic sites, thereby providing a comprehensive representation of the tumor burden of an individual patient. Recent advancements have shown that PD-1/PD-L1 immune checkpoint therapies have durable responses in a number of solid tumor types. Our study was designed to use multiple CTC enrichment platforms for the capture of CTCs and novel culture formulations for the ex vivo expansion of CTCs. Head and Neck cancer (n=300) and lung cancer (n=80) patients were recruited to investigate the prognostic role of CTCs. We evaluated multiple CTC isolation technologies (CellSearch, filtration, CD45 depletion, inertial microfluidics) using matched patient samples which showed that epitope-independent CTC isolation captured a greater proportion of CTCs. Molecular alterations present in the primary tissue were confirmed in the CTCs by 3D-DNA FISH (EGFR-amplification, ALK-translocations). In HNC, the presence of CTC clusters associated with the development of distant metastatic disease (P=0.0313). HNC CTC-positive patients had shorter progression free survival (PFS) (Hazard ratio [HR]: 4.946; 95% confidence internal [CI]:1.571-15.57; P=0.0063) and PD-L1-positive CTCs were found to be significantly associated with worse outcome ([HR]:5.159; 95% [CI]:1.011-26.33; P=0.0485). In a proof of principle study, we were able to demonstrate for the first time, short-term patient derived CTC cultures outside the patient’s body from 7/18 HNC samples (4/7 HPV-positive). Recently, we have preliminary data that suggests that PD-L1 is frequently expressed on CTCs in HNC and lung cancer and an immunoscore may be able to identify patients likely to benefit from immunotherapy-a current unmet clinical need. Expanding CTCs outside the patient’s body allows for the recapitulation of the molecular diversity present within the tumor, understanding of the disease progression and testing of therapies. Citation Format: Arutha Kulasinghe, Joanna Kapeleris, Liz Kenny, Majid Warkiani, Ian Vela, Jean-Paul Thiery, Ken O'Byrne, Chamindie Punyadeera. Isolation, characterization and expansion of circulating tumor cells in solid cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1333.

A postpartum diagnosis increases risk for and determines an altered profile of metastasis in young women's breast cancer

A diagnosis of breast cancer in a woman in the early years after a childbirth has been shown to increase risk for metastasis and death, however, limited data exists on how many years postpartum does this risk prevail, what known clinically prognostic factors are associated with this risk, and what are the pattern of metastasis in these women. This study was conducted to determine how many years after the most recent childbirth that a postpartum breast cancer diagnosis is associated with the increased development of distant metastatic disease. Also, to evaluate known clinical prognostic factors, including tumor proliferation status on influencing the increased risk for metastasis for postpartum breast cancer. This cohort study enrolled 802 cases as a sub study of the larger Colorado Young Women’s Breast Cancer Cohort (>9000 cases), with cases collected from 1991-2014. This is a multicenter study involving a tertiary care, academic hospital-based breast center and its regional affiliate. Included subjects are women diagnosed with stage I-III invasive breast cancer age 45 and under for whom parity data on timing of last childbirth was available, had undergone treatment with curative intent, and had known metastatic disease specific data. The studies primary objective is metastasis-free survival, based on first clinical documentation of metastasis by radiologic or physical exam findings, or date of pathologic confirmation. The primary exposure was prior childbirth or no prior childbirth and the time between the most recent childbirth and diagnosis of breast cancer. The results demonstrate that a diagnosis of breast cancer up to ten years postpartum increases the risk for metastasis. This increased risk is most associated with stage I/II diagnosis and is present in both ER+ and ER- cases. ER+ cases show a prolonged timeline of risk up to 15 years post diagnosis, highlighting an under-recognized risk for young mothers with luminal cancer. Postpartum breast cancer is also associated with an increase in lymph node involvement and lymphovascular invasion, which aligns with the known mechanism of increased lymphangiogenesis in preclinical models. Lastly, increased liver metastasis occurs in postpartum breast cancer at time of first metastasis in comparison to nulliparous controls, highlighting the increased risk for mortality from a postpartum diagnosis.

A Collective Route to Head and Neck Cancer Metastasis

Distant metastasis (DM) from head and neck cancers (HNC) portends a poor patient prognosis. Despite its important biological role, little is known about the cells which seed these DM. Circulating tumour cells (CTCs) represent a transient cancer cell population, which circulate in HNC patients’ peripheral blood and seed at distant sites. Capture and analysis of CTCs offers insights into tumour metastasis and can facilitate treatment strategies. Whilst the data on singular CTCs have shown clinical significance, the role of CTC clusters in metastasis remains limited. In this pilot study, we assessed 60 treatment naïve HNC patients for CTCs with disease ranging from early to advanced stages, for CTC clusters utilizing spiral CTC enrichment technology. Single CTCs were isolated in 18/60–30% (Ranging from Stage I-IV), CTC clusters in 15/60–25% (exclusively Stage IV) with 3/15–20% of CTC clusters also containing leukocytes. The presence of CTC clusters associated with the development of distant metastatic disease(P = 0.0313). This study demonstrates that CTC clusters are found in locally advanced patients, and this may be an important prognostic marker. In vivo and in vitro studies are warranted to determine the role of these CTC clusters, in particular, whether leukocyte involvement in CTC clusters has clinical relevance.

First Results of a Phase 2 Trial of Once-Weekly Hypofractionated Breast Irradiation (WHBI) for Early-Stage Breast Cancer

To report early outcome analysis of a prospective institutional phase 2 trial of weekly hypofractionated breast irradiation (WHBI) for patients undergoing breast-conserving surgery (BCS). Patients who underwent BCS for American Joint Committee on Cancer stage 0, I, or II breast cancer with negative surgical margins received whole-breast radiation therapy to 30 or 28.5Gy in 5 weekly fractions with or without an additional boost.The eligibility criteria were the same as for NSABP (National Surgical Adjuvant Breast and Bowel Project) B39/RTOG (Radiation Therapy Oncology Group) 0413, and there were no restrictions on age, breast size, tumor grade, receptor status, or the use of cytotoxic chemotherapy for otherwise eligible patients.The primary endpoint was ipsilateral breast tumor recurrence. Patients were also evaluated for acute toxicity (Common Terminology Criteria for Adverse Events version 3.0), cosmesis (Harvard Scale), development of distant metastatic disease, and overall survival. Between January 2011 and October 2015, 158 eligible patients underwent WHBI immediately following BCS. The median age was 60years (range, 30-84years), and the median follow-up period was 3years. Ipsilateral breast tumor recurrence developed in a total of 2 patients (1.3%), 1 in conjunction with widespread metastatic disease. Distant metastatic disease developed in 4 patients (2.5%), and the 3-year disease-free survival and overall survival rates were 97.5% and 96.2%, respectively.The most common grade 1 or 2 acute toxicities were breast pain, radiation dermatitis, and fatigue. There were 2 grade 3 events (1.3%): pain requiring narcotic analgesics (1) and posttreatment infection requiring hospitalization (1). The rate of excellent or good cosmesis versus fair or poor cosmesis was 82.3% versus 17.7%. The rate of significant cosmetic change from baseline to last follow-up (dropping from excellent or good to fair or poor) was 11.6%. Early outcomes after WHBI are favorable and parallel those seen with daily hypofractionated whole-breast irradiation. With broader entry criteria than all previous reports of WHBI, this study will facilitate comparison to the results of NSABP B39/RTOG 0413. With continued follow-up, future reports will assess cosmetic stability and disease-specific outcomes.

Risk Factors for Subsequent Development of Distant Metastatic Disease in a Cohort of Patients Treated With Reirradiation for Recurrent Head and Neck Cancer

Patients treated with re-irradiation typically have had limited lifespans characterized by in-field re-recurrences. As radiation techniques have improved, higher and more definitive doses of re-irradiation have been possible. The clinician is faced with the quandary of which patients may benefit from more protracted courses of definitive retreatment, which may increase local control but entail longer treatment periods in a group of patients who are also at high risk of developing distant metastases (DM). We examined 73 consecutive patients treated from 2010 to 2015 with definitive-intent re-irradiation for head and neck cancer, with a fraction size of 2-2.5Gy/fraction. Only areas of gross disease were typically included in the re-irradiation fields. Potential risk factors including immunosuppression, smoking, nodal levels 1-6 involvement, number of involved nodes, tumor volume, and tumor dose coverage were examined with respect to the risk of the development of subsequent DM. 30% of patients experienced DM. On univariate analysis, risk of subsequent DM was associated with recurrent disease in level 2 (52% vs 21%, P = 0.012) and the presence of indeterminate lung nodules on staging of patients with recurrent disease (42% vs 19%, P = 0.04). Both level 2 involvement (OR = 4.1, 95% CI [1.4, 12.1]) and indeterminate lung nodules (OR = 3.2, 95% CI [1.1, 9.2]) on initial staging were significant on multivariable logistic regression analysis. At second recurrence, out-of-field regional failure was strongly associated with DM (65% vs 20%, P = 0.001), while in-field and primary site second recurrence was not. Concurrent regional second recurrence outweighed the impact of initial level 2 recurrence or initial indeterminate lung nodules as a risk factor for DM on multivariable regression analysis. In our cohort of patients treated with definitive-intent re-irradiation, there is a significant risk of subsequent distant metastases (30%). We find that patients with level 2 recurrence or indeterminate lung nodules at diagnosis are at higher risk of DM. The significant association of second regional recurrence with DM at the time of second failure suggests that improved methods of diagnosing subclinical regional involvement at initial recurrence may be important to obtain improved distant control outcomes in the future.

A systematic review of primary active surveillance management of low-risk papillary carcinoma.

Active surveillance is close follow-up of neoplasms, with predetermined intervention triggers. We systematically reviewed the published English language literature on primary active surveillance of low-risk papillary thyroid cancer (PTC). We searched seven electronic databases (1980-2015), supplemented with a hand search. Two reviewers independently screened 1715 citations and reviewed 32 full-text papers, ultimately including two papers. Data were independently abstracted. There were two Japanese single-center, single-arm studies reporting on 1235 and 322 patients with PTC microcarcinoma (primary ≤1 cm in diameter) confined to the thyroid. Mean study follow-up was of 5.0 and 6.5 years, respectively. Disease triggers for thyroidectomy included progression of the primary tumor or incident metastatic disease. The rates of thyroidectomy were 15.5% (191/1235) and 8.7% (28/322) in respective studies. The incidence of primary tumor enlargement ≥3 mm in maximal diameter was 4.6% (58/1235) and 5.0% (16/322). The incidence of nodal metastases was 1.5% (19/1235) and 0.9% (3/322). There were neither reports of PTC-related death nor development of distant metastatic disease. Quality of life, psychosocial health, and economic outcomes were not reported. In two Japanese single-arm studies, active surveillance of PTC microcarcinoma was relatively well tolerated; however, more long-term outcome research is needed.

Chemotherapy for Stage II Colon Cancer.

The adjuvant treatment of patients with stage II colon cancer is an area of controversy in medical oncology. Adjuvant chemotherapy aims to eradicate micrometastatic disease present at the time of surgery, preventing the development of distant metastatic disease and thereby curing those patients of their cancer. National and international guidelines for the adjuvant treatment of stage II colon cancer recommend a range of treatment options from observation to chemotherapy with single-agent or combination regimens, depending on the presence or absence of high-risk features (poorly differentiated histology, presence of lymphovascular invasion, presence of perineural invasion, report of < 12 lymph nodes, bowel obstruction, localized perforation, or positive margins). In the one prospective study designed to address the role of adjuvant chemotherapy in stage II colon cancer, a small but statistically significant benefit in overall survival was seen for those patients who received adjuvant chemotherapy; however, multiple meta-analyses and retrospective subgroup analyses have called these findings into question. Though there may be a role for adjuvant chemotherapy in the treatment of patients with stage II colon cancer, its incremental benefit is small, at best, and comes with the risks of real and rarely fatal complications of chemotherapy.

HPV‐related oropharyngeal cancer: Risk factors for treatment failure in patients managed with primary transoral robotic surgery

The purpose of this study was to determine clinical factors that predict locoregional recurrence or distant metastasis in patients with human papillomavirus (HPV)-positive oropharyngeal cancer treated with surgery and guideline-indicated adjuvant therapy. We identified all presumed HPV-positive patients with oropharyngeal cancer in our health system from January 2010 to August 2012 treated with surgery and guideline-indicated adjuvant therapy. Statistical analysis was performed to identify clinical predictors associated with treatment failure. One hundred fourteen p16+ oropharyngeal cancers managed with initial surgical resection were identified. Median follow-up was 17 months. Two-year locoregional failure was 3.3% and distant failure was 8.4%. Statistical analysis found that conventional poor prognostic features did not predict treatment failure. Locoregional recurrence and development of distant metastatic disease are uncommon in patients who are appropriately selected for surgical management of p16+ oropharyngeal cancer regardless of the presence or absence of conventional poor prognostic features.

Efficacy of Repeat Sentinel Lymph Node Biopsy in Patients Who Develop Recurrent Melanoma

Even after negative sentinel lymph node biopsy (SLNB) for primary melanoma, patients who develop in-transit (IT) melanoma or local recurrences (LR) can have subclinical regional lymph node involvement. A prospective database identified 33 patients with IT melanoma/LR who underwent technetium 99m sulfur colloid lymphoscintigraphy alone (n = 15) or in conjunction with lymphazurin dye (n = 18) administered only if the IT melanoma/LR was concurrently excised. Seventy-nine percent (26 of 33) of patients undergoing SLNB in this study had earlier removal of lymph nodes in the same lymph node basin as the expected drainage of the IT melanoma or LR at the time of diagnosis of their primary melanoma. Lymphoscintography at time of presentation with IT melanoma/LR was successful in 94% (31 of 33) cases, and at least 1 sentinel lymph node was found intraoperatively in 97% (30 of 31) cases. The SLNB was positive in 33% (10 of 30) of these cases. Completion lymph node dissection was performed in 90% (9 of 10) of patients. Nine patients with negative SLNB and IT melanoma underwent regional chemotherapy. Patients in this study with a positive sentinel lymph node at the time the IT/LR was mapped had a considerably shorter time to development of distant metastatic disease compared with those with negative sentinel lymph nodes. In this study, we demonstrate the technical feasibility and clinical use of repeat SLNB for recurrent melanoma. Performing SLNB cannot only optimize local, regional, and systemic treatment strategies for patients with LR or IT melanoma, but also appears to provide important prognostic information.