In a trial comparing preoperative chemoradiotherapy and FOLFOX in patients with rectal cancer undergoing sphincter-sparing surgery, 5-year disease-free survival was 80.8% with FOLFOX and 78.6% with ...chemoradiotherapy.
Prognostic and predictive factors are well established in early-stage breast cancer, but less is known about which metastatic sites will be affected.
Patients with early-stage breast cancer diagnosed ...between 1986 and 1992 with archival tissue were included. Subtypes were defined as luminal A, luminal B, luminal/human epidermal growth factor receptor 2 (HER2), HER2 enriched, basal-like, and triple negative (TN) nonbasal. Distant sites were classified as brain, liver, lung, bone, distant nodal, pleural/peritoneal, and other. Cumulative incidence curves were estimated for each site according to competing risks methods. Association between the site of relapse and subtype was assessed in multivariate models using logistic regression.
Median follow-up time among 3,726 eligible patients was 14.8 years. Median durations of survival with distant metastasis were 2.2 (luminal A), 1.6 (luminal B), 1.3 (luminal/HER2), 0.7 (HER2 enriched), and 0.5 years (basal-like; P < .001). Bone was the most common metastatic site in all subtypes except basal-like tumors. In multivariate analysis, compared with luminal A tumors, luminal/HER2 and HER2-enriched tumors were associated with a significantly higher rate of brain, liver, and lung metastases. Basal-like tumors had a higher rate of brain, lung, and distant nodal metastases but a significantly lower rate of liver and bone metastases. TN nonbasal tumors demonstrated a similar pattern but were not associated with fewer liver metastases.
Breast cancer subtypes are associated with distinct patterns of metastatic spread with notable differences in survival after relapse.
The risk of local and regional relapse associated with each breast cancer molecular subtype was determined in a large cohort of patients with breast cancer. Subtype assignment was accomplished using ...a validated six-marker immunohistochemical panel applied to tissue microarrays.
Semiquantitative analysis of estrogen receptor (ER), progesterone receptor (PR), Ki-67, human epidermal growth factor receptor 2 (HER2), epidermal growth factor receptor (EGFR), and cytokeratin (CK) 5/6 was performed on tissue microarrays constructed from 2,985 patients with early invasive breast cancer. Patients were classified into the following categories: luminal A, luminal B, luminal-HER2, HER2 enriched, basal-like, or triple-negative phenotype-nonbasal. Multivariable Cox analysis was used to determine the risk of local or regional relapse associated the intrinsic subtypes, adjusting for standard clinicopathologic factors.
The intrinsic molecular subtype was successfully determined in 2,985 tumors. The median follow-up time was 12 years, and there have been a total of 325 local recurrences and 227 regional lymph node recurrences. Luminal A tumors (ER or PR positive, HER2 negative, Ki-67 < 1%) had the best prognosis and the lowest rate of local or regional relapse. For patients undergoing breast conservation, HER2-enriched and basal subtypes demonstrated an increased risk of regional recurrence, and this was statistically significant on multivariable analysis. After mastectomy, luminal B, luminal-HER2, HER2-enriched, and basal subtypes were all associated with an increased risk of local and regional relapse on multivariable analysis.
Luminal A tumors are associated with a low risk of local or regional recurrence. Molecular subtyping of breast tumors using a six-marker immunohistochemical panel can identify patients at increased risk of local and regional recurrence.
Single-agent immune checkpoint inhibition has not shown activities in advanced refractory colorectal cancer (CRC), other than in those patients who are microsatellite-instability high (MSI-H).
To ...evaluate whether combining programmed death-ligand 1 (PD-L1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibition improved patient survival in metastatic refractory CRC.
A randomized phase 2 study was conducted in 27 cancer centers across Canada between August 2016 and June 2017, and data were analyzed on October 18, 2018. Eligible patients had histologically confirmed adenocarcinoma of the colon or rectum; received all available standard systemic therapies (fluoropyrimidines, oxaliplatin, irinotecan, and bevacizumab if appropriate; cetuximab or panitumumab if RAS wild-type tumors; regorafenib if available); were aged 18 years or older; had adequate organ function; had Eastern Cooperative Oncology Group performance status of 0 or 1, and measurable disease.
We randomly assigned patients to receive either 75 mg of tremelimumab every 28 days for the first 4 cycles plus 1500 mg durvalumab every 28 days, or best supportive care alone (BSC) in a 2:1 ratio.
The primary end point was overall survival (OS) and a 2-sided P<.10 was considered statistically significant. Circulating cell-free DNA from baseline plasma was used to determine microsatellite instability (MSI) and tumor mutation burden (TMB).
Of 180 patients enrolled (121 men 67.2% and 59 women 32.8%; median range age, 65 36-87 years), 179 were treated. With a median follow-up of 15.2 months, the median OS was 6.6 months for durvalumab and tremelimumab and 4.1 months for BSC (hazard ratio HR, 0.72; 90% CI, 0.54-0.97; P = .07). Progression-free survival was 1.8 months and 1.9 months respectively (HR, 1.01; 90% CI, 0.76-1.34). Grade 3 or 4 adverse events were significantly more frequent with immunotherapy (75 64% patients in the treatment group had at least 1 grade 3 or higher adverse event vs 12 20% in the BSC group). Circulating cell-free DNA analysis was successful in 168 of 169 patients with available samples. In patients who were microsatellite stable (MSS), OS was significantly improved with durvalumab and tremelimumab (HR, 0.66; 90% CI, 0.49-0.89; P = .02). Patients who were MSS with plasma TMB of 28 variants per megabase or more (21% of MSS patients) had the greatest OS benefit (HR, 0.34; 90% CI, 0.18-0.63; P = .004).
This phase 2 study suggests that combined immune checkpoint inhibition with durvalumab plus tremelimumab may be associated with prolonged OS in patients with advanced refractory CRC. Elevated plasma TMB may select patients most likely to benefit from durvalumab and tremelimumab. Further confirmation studies are warranted.
ClinicalTrials.gov Identifier: NCT02870920.
The optimal management of locally advanced rectal cancer is rapidly evolving. The National Cancer Institute Rectal-Anal Task Force convened an expert panel to develop consensus on the design of ...future clinical trials of patients with rectal cancer. A series of 82 questions and subquestions, which addressed radiation and neoadjuvant therapy, patient perceptions, rectal cancer populations of special interest, and unique design elements, were subject to iterative review using a Delphi analytical approach to define areas of consensus and those in which consensus is not established. The task force achieved consensus on several areas, including the following: 1) the use of total neoadjuvant therapy with long-course radiation therapy either before or after chemotherapy, as well as short-course radiation therapy followed by chemotherapy, as the control arm of clinical trials; 2) the need for greater emphasis on patient involvement in treatment choices within the context of trial design; 3) efforts to identify those patients likely, or unlikely, to benefit from nonoperative management or minimally invasive surgery; 4) investigation of the utility of circulating tumor DNA measurements for tailoring treatment and surveillance; and 5) the need for identification of appropriate end points and recognition of challenges of data management for patients who enter nonoperative management trial arms. Substantial agreement was reached on priorities affecting the design of future clinical trials in patients with locally advanced rectal cancer.
Anti-epidermal growth factor receptor (EGFR) antibodies are effective treatments for metastatic colorectal cancer. Improved understanding of acquired resistance mechanisms may facilitate circulating ...tumor DNA (ctDNA) monitoring, anti-EGFR rechallenge, and combinatorial strategies to delay resistance.
Patients with treatment-refractory metastatic colorectal cancer (n = 169) enrolled on the CO.26 trial had pre-anti-EGFR tissue whole-exome sequencing (WES) compared with baseline and week 8 ctDNA assessments with the GuardantOMNI assay. Acquired alterations were compared between patients with prior anti-EGFR therapy (n = 66) and those without. Anti-EGFR therapy occurred a median of 111 days before ctDNA assessment.
ctDNA identified 12 genes with increased mutation frequency after anti-EGFR therapy, including
(
= .0007),
(
= .0017),
(
= .0046),
(
= .0086),
(
= .018),
(
= .018),
(
= .048), and
(
= .048). Acquired mutations appeared as multiple concurrent subclonal alterations, with most showing decay over time. Significant increases in copy-gain frequency were noted in 29 genes after anti-EGFR exposure, with notable alterations including
(
< .0001),
(
< .0001),
(
< .0001),
(
= .0002),
(
= .0002),
(
= .0006),
(
= .004), and
(
= .006). Copy gains appeared stable without decay 8 weeks later. There were 13 gene fusions noted among 11 patients, all but one of which was associated with prior anti-EGFR therapy. Polyclonal resistance was common with acquisition of ≥ 10 resistance related alterations noted in 21% of patients with previous anti-EGFR therapy compared with 5% in those without (
= .010). Although tumor mutation burden (TMB) did not differ pretreatment (
= .63), anti-EGFR exposure increased TMB (
= .028), whereas lack of anti-EGFR exposure resulted in declining TMB (
= .014).
Paired tissue and ctDNA sequencing identified multiple novel mutations, copy gains, and fusions associated with anti-EGFR therapy that frequently co-occur as subclonal alterations in the same patient.
Background
Somatostatin analog functional imaging with gallium‐68 (Ga‐68) dotatate positron emission tomography/computed tomography (PET/CT) has demonstrated superiority in lesion detection in ...patients with neuroendocrine tumors (NETs). The clinical impact of this imaging modality on US surgical and medical oncology practices has not been established.
Methods
Consecutive patients with NET at our institution who received an initial Ga‐68 dotatate PET/CT between July 2017 and September 2018 were included. Ga‐68 dotatate PET/CT was compared with prior imaging.
Results
Among 101 eligible patients, 51 of 50 were female/male, site of origin was gastroenteropancreatic (75%), unknown primary (13%), lung (8%), thymus (2%), and other (2%). All NETs were histologically well/moderately differentiated. Ga‐68 dotatate imaging findings altered management in 36 (35.6%) patients: documentation of progression led to the initiation of systemic therapy in 14 patients, obviated the need for biopsy in four patients, and altered surgical plans in 7 of 14 (50%) patients referred for surgery. In 11 patients, decisions regarding peptide receptor radionucleotide therapy and somatostatin analogs were altered.
Conclusions
In this series, Ga‐68 dotatate PET/CT altered diagnosis and management in one‐third of patients and changed operative plans in half of the patients who were referred for surgical evaluation. These results support the routine use of this imaging in the care of patients with early‐stage and advanced NETs.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Deficient mismatch repair (dMMR)/microsatellite instability-high (MSIH) colorectal cancer is resistant to conventional chemotherapy but responds to immune checkpoint inhibition (ICI). We review the ...standard of care in locally advanced dMMR rectal cancer with a focus on ICI. We also present a case report to highlight the treatment complexities and unique challenges of this novel treatment approach. ICI can lead to immune related adverse events (irAEs), resulting in early treatment discontinuation as well as new challenges to surveillance and surgical management. Overall, neoadjuvant ICI can lead to robust treatment responses, but its impact on durable response and organ preservation requires further study.
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Available for:
IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK, VSZLJ
Background
Goblet cell carcinoids (GCCs) of the appendix are rare mucinous neoplasms, for which optimal therapy is poorly described. We examined prognostic clinical and treatment factors in a ...population-based cohort.
Methods
Patients diagnosed with GCC from 1984 to 2014 were identified from the British Columbia Cancer Agency and the Vancouver Lower Mainland Pathology Archive.
Results
Of 88 cases with confirmed appendiceal GCCs, clinical data were available in 86 cases (annual population incidence: 0.66/1,000,000). Median age was 54 years (range 25–91) and 42 patients (49%) were male. Metastasis at presentation was the strongest predictor of overall survival (OS), with median OS not reached for stage I–III patients, and measuring 16.2 months 95% confidence interval (CI) 9.1–29 for stage IV patients. In 67 stage I–III patients, 51 (76%) underwent completion hemicolectomy and 9 (17%) received adjuvant 5-fluorouracil-based chemotherapy. No appendicitis at initial presentation and Tang B histology were the only prognostic factors, with inferior 5-year recurrence-free survival (53 vs. 83% with appendicitis,
p
= 0.02; 45% Tang B vs. 89% Tang A,
p
< 0.01). Of 19 stage IV patients, 10 (62.5%) received 5-fluorouracil-based chemotherapy and 11 (61%) underwent multiorgan resection (MOR) ± hyperthermic intraperitoneal chemotherapy (HIPEC). Low mitotic rate and MOR ± HIPEC were associated with improved 2-year OS, but only MOR ± HIPEC remained significant on multivariate analysis (hazard ratio 5.4, 95% CI 1.4–20.9;
p
= 0.015).
Conclusions
In this population-based cohort, we demonstrate excellent survival outcomes in stage I–III appendiceal GCCs and clinical appendicitis. Hemicolectomy remains the standard treatment. In metastatic disease, outcomes remain poor, although MOR ± HIPEC may improve survival.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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