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Highlights • A prospective pilot phase I/II study on metformin given concurrently with neoadjuvant chemoradiation (CRT) in non-diabetic rectal cancer patients. • Three patients had a clinical complete response (cCR) and did not have surgical resection. • Of the 12 patients who underwent surgery, there were two pCRs. For the combined pCR/cCR rate of 33% (95% CI 19–47%), a total of 85 patients will be required to yield a 95% CI with a 10% margin of error. • These pilot results are encouraging, and will serve to refine the design and conduct of a future phase 2 trial to determine whether adding metformin to CRT improves pCR/cCR rates., Purpose Neoadjuvant radiotherapy with or without chemotherapy decreases the risk of local recurrence after surgery for rectal cancer. Emerging data suggest that diabetic patients on metformin may have improved cancer outcome after radiotherapy. A single institutional pilot study was performed to determine if metformin given concurrently with long course chemoradiation (CRT) may improve pathologic complete response (pCR) in non-diabetic rectal cancer patients. The study was designed to construct a confidence interval (CI) for the pCR rate to determine the sample size for a phase 2 trial. Methods Non-diabetic patients with biopsy confirmed rectal cancer deemed candidates for long course neoadjuvant CRT were invited to participate. Radiation consisted of 50.4 Gy in 28 daily fractions with concurrent daily capecitabine (825 mg/m2 twice daily). Participants self-administered metformin (500 mg of twice daily) 2 weeks prior to, during and for 4 weeks after CRT. Results A total of 16 patients were accrued. One patient withdrew from the study. Only grade 1 or 2 adverse events were observed. Three patients had a clinical complete response (cCR) and did not undergo surgery. Of the 12 patients who underwent surgery, there were two pCRs. For the combined pCR/cCR rate of 33% (95% CI 19–47%), a total of 85 patients will be required to yield a 95% CI with a 10% margin of error. Conclusions Adding metformin to neoadjuvant CRT for rectal cancer does not appear to enhance toxicities. These results will be used to refine the design and conduct of a future phase 2 trial to determine whether adding metformin to CRT improves pCR/cCR rates.

Highlights • The 3-year disease-free survival of locally-advanced anal carcinoma is about 60%. • Anal carcinoma is considered an immunogenic tumor due to its association with HPV. • The PD-L1 inhibitor durvalumab may synergize with radiochemotherapy. • The RADIANCE trial will test durvalumab with radiochemotherapy in anal carcinoma., Purpose Anal squamous cell carcinomas (ASCC) are increasing in frequency across the developed world. The 3-year disease-free survival (DFS) in patients with locally-advanced disease is approximately 60% after primary radiochemotherapy (RCT). There is a strong rationale for combining immunotherapy with RCT in patients with ASCC due to its association with human papilloma virus (HPV) infection. Methods/design RADIANCE is an investigator initiated, prospective, multicenter, randomized phase II trial testing the addition of Durvalumab, a PD-L1 immune checkpoint inhibitor, to standard RCT in 178 patients with locally advanced ASCC (T2 ≥ 4 cm Nany, cT3-4 and/or cN+). In the control arm, patients will be treated with standard mitomycin C (MMC)/5-fluorouracil (5-FU)-based RCT. Intensity-modulated radiotherapy (IMRT) will be applied as follows: PTV_A (primary tumor) T1-T2

Treatment of locally advanced rectal cancer includes chemotherapy, radiation, and surgery but patient responses to neoadjuvant treatment are variable. We have shown that rectal tumors are comprised of multiple genetically distinct sub-clones. Unique sub-clones within tumors may harbor mutations which contribute to inter-patient variation in response to neoadjuvant chemoradiotherapy (nCRT). Analysis of the influence of nCRT on the extent and nature of intra-tumoral genetic heterogeneity in rectal cancer may provide insights into mechanisms of resistance. Locally advanced rectal cancer patients underwent pre-treatment biopsies. At the time of surgery, tissue from the treated tumor was obtained and analyzed. Pre- and post-treatment specimens were subjected to whole exome and confirmatory deep sequencing for somatic mutations. Copy number variation was assessed using OncoScan SNP arrays. Genomic data were analyzed using PyClone to identify sub-clonal tumor population following nCRT. Alterations that persisted or were enriched in the post-treatment tumor specimen following nCRT were defined for each patient. Thirty-two samples were obtained from ten patients. PyClone identified 2 to 10 genetic sub-clones per tumor. Substantial changes in the proportions of individual sub-clones in pre- versus post-treatment tumor material were found in all patients. Resistant sub-clones recurrently contained mutations in TP53, APC, ABCA13, MUC16, and THSD4. Recurrent copy number variation was observed across multiple chromosome regions after nCRT. Pathway analysis including variant alleles and copy number changes associated with resistant sub-clones revealed significantly altered pathways, especially those linked to the APC and TP53 genes, which were the two most frequently mutated genes. Intra-tumoral heterogeneity is evident in pre-treatment rectal cancer. Following treatment, sub-clonal populations are selectively modified and enrichment of a subset of pre-treatment sub-clones is seen. Further studies are needed to define recurrent alterations at diagnosis that may contribute to resistance to nCRT.

Highlights • The rate of pathological complete response (pCR) following NACRT was 14.7 %. • Combination of morphology and DWI patterns was 89–96 % accurate in predicting pCR. • Radiologists of varying experience agreed best with combined approach. • Radiologists were more confident of their response using the combined approach., Purpose To assess the diagnostic performance, interobserver agreement and confidence level for determining response to neoadjuvant chemoradiotherapy (NACRT) using morphology based MR-tumour regression grade (MR TRG), diffusion weighted imaging (DWI) patterns and their combination in patients with locally advanced rectal cancer. Methods This was a retrospective study including patients with locally advanced rectal cancer treated with NACRT and subsequent surgery. Two independent radiologists blinded to the histopathology reviewed staging and restaging MRI. Diagnostic performance of morphology based MR-TRG, DWI patterns and their combination for determining complete (CR) and incomplete (IR) response was assessed with pathological response as the reference. Likert’s scale was used to assess the radiologist’s level of confidence. Interobserver agreement was determined using Kappa statistics. Results The study included 251 patients (mean age of 47.9+/-14 (range 19–86) years, M:F = 164:87). Rate of pathological CR was 14.7 % (n = 37). Pattern based interpretation of DWI and combined approach (DWI + T2-HR) had superior diagnostic performance than morphology based assessment alone with area under curve (AUC) for T2HR, DWI and their combination being 0.531, 0.887, 0.874 respectively for observer 1 and 0.558, 0.653, 0.678 respectively for observer 2, p < 0.001. Interobserver agreement was substantial (k = 0.688) for combined approach, moderate (k = 0.402) for DWI patterns and fair (k = 0.265) for T2 HR MRI with both observers exhibiting highest level of confidence for determining response with the combined approach. Conclusion Complete response to neoadjuvant chemoradiotherapy can be determined with excellent accuracy, substantial interobserver agreement and high level of confidence by combined interpretation of DWI and T2 high resolution MRI.

Highlights • There is no standard therapy for locally advanced TNBC showing disease progression during NAC. • We presented a case of locally advanced TNBC showing pCR to weekly paclitaxel with bevacizumab treatment showing PD during standard NAC. • This report suggests the potential of bevacizumab in response-guided sequential therapy and this finding should be confirmed in clinical trial., Introduction Neoadjuvant chemotherapy (NAC) is the standard of care for locally advanced triple negative breast cancer, however, approximately 5% of cases show disease progression during NAC. Although downstaging is essential to create an opportunity for curative surgery and to improve the local control outcome in such a case, no additional line of chemotherapy has been established. Case presentation A 60-year-old woman was referred to our hospital for an axillary mass presenting three weeks ago and was diagnosed as having right locally advanced (T2N2M0, stage IIIA) triple negative breast cancer. After two courses of epirubicine and cyclophosphamide as NAC, disease progression was recognized and curative resection was considered impossible due to enlarged axillary lymph nodes showing invasion to surrounding tissue. As second-line chemotherapy, weekly paclitaxel with bevacizumab treatment was initiated and significant shrinkage was immediately obtained. A clinically complete response was diagnosed after four courses of weekly paclitaxel with bevacizumab and she underwent a right breast mastectomy with axillary lymph node dissection without major complications. Histopathological examination of surgical specimens showed no residual invasive or noninvasive disease and she was diagnosed as having a pathological complete response. Conclusions Although the addition of bevacizumab to standard adjuvant chemotherapy is not recommended in unselected triple negative breast cancer, the potent effect on tumor shrinkage should be considered in the treatment of locally advanced triple negative breast cancer showing disease progression during standard NAC.

Highlights • Breast cancers that are positive for human epidermal growth factor receptor 2 (HER2) are aggressive and typically associated with a poor prognosis. • Novel anti-HER2 therapies have recently improved the outcomes in these cases. • We report a case series in which women were treated for metastatic HER2-positive breast cancer using trastuzumab and various chemotherapies. • These patients ultimately achieved clinical complete response, and subsequently terminated their systemic therapy after maintenance therapy. • Our findings indicate that select patients may be suitable for treatment termination if they have achieved a prolonged period of complete response., Background Human epidermal growth factor receptor 2 (HER2) -positive breast cancers tend to be more aggressive and more likely to recur than HER2-negative breast cancers. However, novel anti-HER2 therapies have dramatically improved the prognosis of patients with HER2-positive breast cancer. Case report We review the cases of 4 women with metastatic breast cancer who achieved clinical complete response (cCR) and terminated their systemic therapy. Two patients had de novo metastatic disease and two patients experienced relapse after adjuvant therapy. All patients achieved cCR using multidisciplinary therapy, experienced prolonged complete remission, and subsequently terminated their systemic therapy without experiencing secondary recurrence. Conclusion There is no evidence that systemic therapy can be safely terminated after a specific time period, although adverse events (e.g., cardiotoxicity) and unnecessary treatment should be avoided. Thus, it is possible that select patients may be suitable for termination of systemic therapy after they have achieved a prolonged period of cCR.