Mutation profile differences in younger and older patients with advanced breast cancer using circulating tumor DNA (ctDNA).

PURPOSE: Little is known regarding the mutation profiles of ctDNA in the older adult breast cancer population. The objective of this study is to assess differences in mutation profiles in the older adult breast cancer population using a ctDNA assay as well as assess utilization of testing results. METHODS: Patients with advanced breast cancer underwent molecular profiling using a plasma-based ctDNA NGS assay (Guardant360) between 5/2015 and 10/2019 at Siteman Cancer Center. The profiling results of a multi-institutional database of patients with advanced breast cancer who had undergone molecular profiling were obtained. Associations between mutations and age group (≥ 65 vs. < 65) were examined using a Fisher's exact test. RESULTS: In the single-institutional cohort, 148 patients (69.2%) were < 65 years old and 66 patients (30.8%) ≥ 65 years old. ATM, BRAF, and PIK3CA mutations were found more frequently in older patients with ER + HER2- breast cancers (p < 0.01). In the multi-institutional cohort, 5367 (61.1%) were < 65 years old and 3417 (38.9%) ≥ 65 years old. ATM, PIK3CA, and TP53 mutations were more common in the older cohort (p < 0.0001) and MYC and GATA3 mutations were less common in the older cohort (p < 0.0001). CtDNA testing influenced next-line treatment management in 40 (19.8%) patients in the single-institutional cohort. CONCLUSION: When controlling for subtype, results from a single institution were similar to the multi-institutional cohort showing that ATM and PIK3CA were more common in older adults. These data suggest there may be additional molecular differences in older adults with advanced breast cancers.

Immunogenomic profiling and pathological response results from a clinical trial of docetaxel and carboplatin in triple-negative breast cancer.

PURPOSE: Patients with triple-negative breast cancer (TNBC) who do not achieve pathological complete response (pCR) following neoadjuvant chemotherapy have a high risk of recurrence and death. Molecular characterization may identify patients unlikely to achieve pCR. This neoadjuvant trial was conducted to determine the pCR rate with docetaxel and carboplatin and to identify molecular alterations and/or immune gene signatures predicting pCR. EXPERIMENTAL DESIGN: Patients with clinical stages II/III TNBC received 6 cycles of docetaxel and carboplatin. The primary objective was to determine if neoadjuvant docetaxel and carboplatin would increase the pCR rate in TNBC compared to historical expectations. We performed whole-exome sequencing (WES) and immune profiling on pre-treatment tumor samples to identify alterations that may predict pCR. Thirteen matching on-treatment samples were also analyzed to assess changes in molecular profiles. RESULTS: Fifty-eight of 127 (45.7%) patients achieved pCR. There was a non-significant trend toward higher mutation burden for patients with residual cancer burden (RCB) 0/I versus RCB II/III (median 80 versus 68 variants, p 0.88). TP53 was the most frequently mutated gene, observed in 85.7% of tumors. EGFR, RB1, RAD51AP2, SDK2, L1CAM, KPRP, PCDHA1, CACNA1S, CFAP58, COL22A1, and COL4A5 mutations were observed almost exclusively in pre-treatment samples from patients who achieved pCR. Seven mutations in PCDHA1 were observed in pre-treatment samples from patients who did not achieve pCR. Several immune gene signatures including IDO1, PD-L1, interferon gamma signaling, CTLA4, cytotoxicity, tumor inflammation signature, inflammatory chemokines, cytotoxic cells, lymphoid, PD-L2, exhausted CD8, Tregs, and immunoproteasome were upregulated in pre-treatment samples from patients who achieved pCR. CONCLUSION: Neoadjuvant docetaxel and carboplatin resulted in a pCR of 45.7%. WES and immune profiling differentiated patients with and without pCR. TRIAL REGISTRATION: Clinical trial information: NCT02124902, Registered 24 April 2014 & NCT02547987, Registered 10 September 2015.

Isolated Kaposi sarcoma of the upper aerodigestive tract in immunocompetent individuals, an underrecognized entity with favorable prognosis.

Kaposi sarcoma (KS) is a rare vascular neoplasm that most commonly arises in the setting of immunosuppression, in areas with high prevalence of Human Herpesvirus-8 infection, and when both situations coexist. Most cases affect the skin, isolated involvement of the upper respiratory tract without skin involvement is extremely rare with only a few cases reported in the literature. We present a case of isolated nasopharyngeal KS in an immunocompetent patient who achieved remission after multimodality therapy. Recent advances in KS-therapy are discussed.

A phase II trial of an alternative schedule of palbociclib and embedded serum TK1 analysis.

Palbociclib 3-weeks-on/1-week-off, combined with hormonal therapy, is approved for hormone receptor positive (HR+)/HER2-negative (HER2-) advanced/metastatic breast cancer (MBC). Neutropenia is the most frequent adverse event (AE). We aim to determine whether an alternative 5-days-on/2-days-off weekly schedule reduces grade 3 and above neutropenia (G3 + ANC) incidence. In this single-arm phase II trial, patients with HR+/HER2- MBC received palbociclib 125 mg, 5-days-on/2-days-off, plus letrozole or fulvestrant per physician, on a 28-day cycle (C), as their first- or second-line treatment. The primary endpoint was G3 + ANC in the first 29 days (C1). Secondary endpoints included AEs, efficacy, and serum thymidine kinase 1 (sTK1) activity. At data-cutoff, fifty-four patients received a median of 13 cycles (range 2.6-43.5). The rate of G3 + ANC was 21.3% (95% CI: 11.2-36.1%) without G4 in C1, and 40.7% (95% CI: 27.9-54.9%), including 38.9% G3 and 1.8% G4, in all cycles. The clinical benefit rate was 80.4% (95% CI: 66.5-89.7%). The median progression-free survival (mPFS) (95% CI) was 19.75 (12.11-34.89), 33.5 (17.25-not reached [NR]), and 11.96 (10.43-NR) months, in the overall, endocrine sensitive or resistant population, respectively. High sTK1 at baseline, C1 day 15 (C1D15), and C2D1 were independently prognostic for shorter PFS (p = 9.91 × 10-4, 0.001, 0.007, respectively). sTK1 decreased on C1D15 (p = 4.03 × 10-7), indicating target inhibition. Rise in sTK1 predicted progression, with the median lead time of 59.5 (inter-quartile range: -206.25-0) days. Palbociclib, 5-days-on/2-days-off weekly, met its primary endpoint with reduced G3 + ANC, without compromising efficacy. sTK1 is prognostic and shows promise in monitoring the palbociclib response. ClinicalTrials.gov#: NCT3007979.

Management of Salivary Gland Malignancy: ASCO Guideline.

PURPOSE: To provide evidence-based recommendations for practicing physicians and other healthcare providers on the management of salivary gland malignancy. METHODS: ASCO convened an Expert Panel of medical oncology, surgical oncology, radiation oncology, neuroradiology, pathology, and patient advocacy experts to conduct a literature search, which included systematic reviews, meta-analyses, randomized controlled trials, and prospective and retrospective comparative observational studies published from 2000 through 2020. Outcomes of interest included survival, diagnostic accuracy, disease recurrence, and quality of life. Expert Panel members used available evidence and informal consensus to develop evidence-based guideline recommendations. RESULTS: The literature search identified 293 relevant studies to inform the evidence base for this guideline. Six main clinical questions were addressed, which included subquestions on preoperative evaluations, surgical diagnostic and therapeutic procedures, appropriate radiotherapy techniques, the role of systemic therapy, and follow-up evaluations. RECOMMENDATIONS: When possible, evidence-based recommendations were developed to address the diagnosis and appropriate preoperative evaluations for patients with a salivary gland malignancy, therapeutic procedures, and appropriate treatment options in various salivary gland histologies.Additional information is available at www.asco.org/head-neck-cancer-guidelines.

Management of Male Breast Cancer: ASCO Guideline.

PURPOSE: To develop recommendations concerning the management of male breast cancer. METHODS: ASCO convened an Expert Panel to develop recommendations based on a systematic review and a formal consensus process. RESULTS: Twenty-six descriptive reports or observational studies met eligibility criteria and formed the evidentiary basis for the recommendations. RECOMMENDATIONS: Many of the management approaches used for men with breast cancer are like those used for women. Men with hormone receptor-positive breast cancer who are candidates for adjuvant endocrine therapy should be offered tamoxifen for an initial duration of five years; those with a contraindication to tamoxifen may be offered a gonadotropin-releasing hormone agonist/antagonist plus aromatase inhibitor. Men who have completed five years of tamoxifen, have tolerated therapy, and still have a high risk of recurrence may be offered an additional five years of therapy. Men with early-stage disease should not be treated with bone-modifying agents to prevent recurrence, but could still receive these agents to prevent or treat osteoporosis. Men with advanced or metastatic disease should be offered endocrine therapy as first-line therapy, except in cases of visceral crisis or rapidly progressive disease. Targeted systemic therapy may be used to treat advanced or metastatic cancer using the same indications and combinations offered to women. Ipsilateral annual mammogram should be offered to men with a history of breast cancer treated with lumpectomy regardless of genetic predisposition; contralateral annual mammogram may be offered to men with a history of breast cancer and a genetic predisposing mutation. Breast magnetic resonance imaging is not recommended routinely. Genetic counseling and germline genetic testing of cancer predisposition genes should be offered to all men with breast cancer.