Pancreatic ductal adenocarcinoma (PDAC) is lethal in 88% of patients1, yet harbours mutation-derived T cell neoantigens that are suitable for vaccines 2,3. Here in a phase I trial of adjuvant autogene cevumeran, an individualized neoantigen vaccine based on uridine mRNA–lipoplex nanoparticles, we synthesized mRNA neoantigen vaccines in real time from surgically resected PDAC tumours. After surgery, we sequentially administered atezolizumab (an anti-PD-L1 immunotherapy), autogene cevumeran (a maximum of 20 neoantigens per patient) and a modified version of a four-drug chemotherapy regimen (mFOLFIRINOX, comprising folinic acid, fluorouracil, irinotecan and oxaliplatin). The end points included vaccine-induced neoantigen-specific T cells by high-threshold assays, 18-month recurrence-free survival and oncologic feasibility. We treated 16 patients with atezolizumab and autogene cevumeran, then 15 patients with mFOLFIRINOX. Autogene cevumeran was administered within 3 days of benchmarked times, was tolerable and induced de novo high-magnitude neoantigen-specific T cells in 8 out of 16 patients, with half targeting more than one vaccine neoantigen. Using a new mathematical strategy to track T cell clones (CloneTrack) and functional assays, we found that vaccine-expanded T cells comprised up to 10% of all blood T cells, re-expanded with a vaccine booster and included long-lived polyfunctional neoantigen-specific effector CD8+ T cells. At 18-month median follow-up, patients with vaccine-expanded T cells (responders) had a longer median recurrence-free survival (not reached) compared with patients without vaccine-expanded T cells (non-responders; 13.4 months, P = 0.003). Differences in the immune fitness of the patients did not confound this correlation, as responders and non-responders mounted equivalent immunity to a concurrent unrelated mRNA vaccine against SARS-CoV-2. Thus, adjuvant atezolizumab, autogene cevumeran and mFOLFIRINOX induces substantial T cell activity that may correlate with delayed PDAC recurrence.

Structured abstract Objective Our goal was to investigate, in a large population of women with DCIS and long follow-up, the relationship between margin width and recurrence, controlling for other characteristics. Summary Background Data While DCIS has minimal mortality, recurrence rates after breast-conserving surgery (BCS) are significant, and half are invasive. Positive margins are associated with increased risk of local recurrence, but there is no consensus regarding optimal negative margin width. Methods We retrospectively reviewed a prospective database of DCIS patients undergoing BCS from 1978–2010. Univariate and Cox proportional hazard models were used to investigate the association between margin width and recurrence. Results 2996 cases were identified, of which 363 recurred. Median follow-up for women without recurrence was 75mo (range 0–30years); 732 were followed for ≥10yrs. Controlling for age, family history, presentation, nuclear grade, number of excisions, radiotherapy (RT), endocrine therapy, and year of surgery, margin width was significantly associated with recurrence in the entire population. Larger negative margins were associated with a lower hazard ratio compared to positive margins. An interaction between RT and margin width was significant (p<0.03); the association of recurrence with margin width was significant in those without RT (p<0.0001), but not in those with RT (p=0.95). Conclusions In women not receiving RT, wider margins are significantly associated with a lower rate of LR. Obtaining wider negative margins may be important in reducing the risk of recurrence in women who choose not to undergo RT, and may not be necessary in those that receive RT.

Introduction For women with ductal carcinoma in situ (DCIS) undergoing breast-conserving surgery (BCS), the benefit of magnetic resonance imaging (MRI) remains unknown. Here we examine the relationship of MRI and locoregional recurrence (LRR) and contralateral breast cancer (CBC) for DCIS treated with BCS, with and without radiotherapy (RT). Methods A total of 2,321 women underwent BCS for DCIS from 1997 to 2010. All underwent mammography, and 596 (26 %) also underwent perioperative MRI; 904 women (39 %) did not receive RT, and 1,391 (61 %) did. Median follow-up was 59 months, and 548 women were followed for ≥8 years. The relationship between MRI and LRR was examined using multivariable analysis. Results There were 184 LRR events; 5- and 8-year LRR rates were 8.5 and 14.6 % (MRI), respectively, and 7.2 and 10.2 % (no-MRI), respectively (p = 0.52). LRR was significantly associated with age, menopausal status, margin status, RT, and endocrine therapy. After controlling for these variables and family history, presentation, number of excisions, and time period of surgery, there remained no trend toward association of MRI and lower LRR [hazard ratio (HR) 1.18, 95 % confidence interval (CI) 0.79–1.78, p = 0.42]. Restriction of analysis to the no-RT subgroup showed no association ofMRI with lower LRR rates (HR 1.36, 95 % CI 0.78–2.39, p = 0.28). No difference in 5- or 8-year rates of CBC was seen between the MRI (3.5 and 3.5 %) and no-MRI (3.5 and 5.1 %) groups (p = 0.86). Conclusions We observed no association between perioperative MRI and lower LRR or CBC rates in patients with DCIS, with or without RT. In the absence of evidence that MRI improves outcomes, the routine perioperative use of MRI for DCIS should be questioned.

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<0.0001). Controlling for age, family history, presentation, nuclear grade, necrosis, number of excisions, margin status, 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, association of recurrence with treatment period persisted in those treated without radiation (HR 0.62, p=0.003). 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 persists in 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.

BACKGROUND:The current study was conducted to examine the association between ipsilateral breast tumor recurrence (IBTR) and the timing of radiotherapy (RT) in women with ductal carcinoma in situ (DCIS) undergoing breast-conserving surgery (BCS). METH-ODS: Women with DCIS who were treated with BCS and RT from 1980 through 2010 were identified from a prospectively maintained database. IBTR rates, measured from the time of RT completion, were compared between those who initiated RT 8 weeks, >8 to 12 weeks, and >12 weeks after the completion of surgery. The association between RT timing and IBTR was evaluated by Kaplan-Meier and log-rank analyses; Cox modeling was used for multivariable analysis. RESULTS: A total of 1323 women met the inclusion criteria. The median follow-up was 6.6 years, with 311 patients followed for 10 years. A total of 126 IBTR events occurred. Patients were categorized by RT timing: 806 patients (61%) with timing of 8 weeks, 386 patients (29%) with timing of >8 to 12 weeks, and 131 patients (10%) with timing >12 weeks. The 5-year and 10-year IBTR rates were 5.8% and 13.0%, respectively, for RT starting 8 weeks after surgery; 3.8% and 7.6%, respectively, for RT starting >8 to 12 weeks after surgery; and 8.8% and 23.0%, respectively, for an RT delay >12 weeks after surgery (P 5 .004). On multivariable analysis, menopause (hazard ratio [HR], 0.54; P 5 .0009) and endocrine therapy (HR, 0.45; P 5 .002) were found to be protective against IBTR, whereas a delay in RT >12 weeks compared with 8 weeks was associated with a higher risk of IBTR (HR, 1.92; P 5 .014). There was no difference in IBTR noted between RT initiation at 8 weeks and initiation at >8 to 12 weeks after BCS (P 5 .3). CONCLUSIONS: A delay in RT >12 weeks is associated with a significantly higher risk of IBTR in women undergoing BCS for DCIS. Efforts should be made to avoid delays in starting RT to minimize the risk of disease recurrence. Cancer 2018;124:46-54. V C 2017 American Cancer Society.KEYWORDS: breast cancer, ductal carcinoma in situ, radiotherapy, recurrence. INTRODUCTIONDuctal carcinoma in situ (DCIS), or stage 0 breast cancer, is a noninvasive breast lesion that comprises approximately 20% of all breast cancer diagnoses. In 2017, it is estimated that nearly 53,000 women will be diagnosed with DCIS in the United States. 1,2 The majority of these women (60%-77%) will undergo breast-conserving surgery (BCS), with or without adjuvant therapy. [3][4][5][6] Survival is excellent after BCS for DCIS, with 10-year breast cancer-specific mortality rates of 1% to 4%. 7-10 However, rates of ipsilateral breast tumor recurrence (IBTR) are not insignificant, with the risk of IBTR reported to be 1% to 3% per year, 5,8 with long-term recurrence rates reported to range from 25% to 35% after BCS alone in 4 large, prospective, randomized controlled trials. 9,[11][12][13] A marked decrease in the risk of IBTR in patients with DCIS has been observed with the use of adjuvant radiotherapy (RT) after BCS. The Early Breast Cancer Trialists' Collabor...