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Genetic variants associated with breast cancer (March 2021)

A number of genes have been implicated in increasing the risk for breast cancer. Now, an international cohort study evaluated 34 putative breast cancer susceptibility genes in 113,000 women from 25 countries [1]; a separate cohort study from the United States evaluated 28 genes in 64,000 women [2]. In addition to BRCA1 and BRCA2, variants in PALB2, BARD1, RAD51C, RAD51D, ATM, and CHEK2 were associated with increased risk of breast cancer in both studies. Given the size and design of these studies, they provide the most comprehensive assessment of risk to date. Carriers of pathogenic variants of these genes should be counseled regarding their breast cancer risks and mitigation strategies.

Adjuvant nivolumab for advanced urothelial carcinoma (March 2021)

Adjuvant checkpoint inhibitor immunotherapy is under investigation in select patients with advanced urothelial carcinoma and high-risk (eg, muscle-invasive or node positive) disease after radical cystectomy. In a phase III trial of over 700 patients with high-risk disease after radical cystectomy who had received neoadjuvant chemotherapy or were ineligible for adjuvant cisplatin-based chemotherapy, one year of adjuvant immunotherapy with nivolumab improved disease-free survival compared with placebo (median 21 versus 11 months) [3]. While promising, adjuvant immunotherapy remains experimental for patients with advanced urothelial carcinoma and high-risk disease after radical cystectomy, and we await regulatory approval before incorporating this approach into routine clinical practice.

Sequential chemoradiation in high risk, early cervical cancer (March 2021)

For patients at high risk of recurrence from cervical cancer, adjuvant concurrent chemotherapy and radiation are commonly administered. However, in a randomized trial in patients with early cervical cancer and at least one adverse risk factor, sequential chemotherapy and radiation improved disease-free survival relative to concurrent treatment [4]. Although these results are promising, we continue to suggest concurrent rather than sequential chemotherapy and radiation for patients with early cervical cancer receiving adjuvant treatment, given previous evidence of efficacy of this approach.

Adjuvant radiation therapy in patients with atypical meningioma (March 2021)

In patients with atypical meningioma, accumulating observational data support the use of adjuvant radiation therapy (RT) to decrease risk of recurrence, which is elevated even after complete surgical resection. In a retrospective cohort study of 230 patients with atypical meningioma, postoperative RT was associated with an approximately 80 percent lower hazard of recurrence compared with surveillance [5]. Ten-year progression-free survival was improved for both incompletely resected tumors (64 versus 54 percent) and completely resected tumors (93 versus 63 percent). Absent randomized trials, these data support our preference for early RT in most patients with atypical meningioma, including those with gross total resection, provided their risk of toxicity from RT is not increased.

Hyperfractionation schedules in limited stage-small cell lung cancer (March 2021)

For patients with limited-stage small cell lung cancer (LS-SCLC), accelerated hyperfractionation radiation regimens typically administer 45 Gy in 1.5 Gy doses. However, in a randomized open-label phase II trial including 170 patients, those assigned to thoracic radiotherapy of 60 Gy in 40 fractions experienced improved two-year overall survival rates relative to those assigned to 45 Gy in 30 fractions (75 versus 48 percent) [6]. Serious toxicities occurred in 43 percent of patients in the 60 Gy group and 54 percent in the 45 Gy group. For patients with LS-SCLC receiving hyperfractionated radiation regimens, we continue to suggest a total dose of 45 Gy, based on previous safety data, but recognize that 60 Gy may be an acceptable alternative.

1. Breast Cancer Association Consortium, Dorling L, Carvalho S, Allen J, et al. Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women. N Engl J Med 2021;384(5):428.

2. Hu C, Hart SN, Gnanaolivu R, et al. A Population-Based Study of Genes Previously Implicated in Breast Cancer. N Engl J Med. 2021;384(5):440.

3. Bajorin DF, Witjes JA, Gshwend J, et al. First results from the phase 3 CheckMate 274 trial of adjuvant nivolumab vs placebo in patients who underwent radical surgery for high-risk muscle-invasive urothelial carcinoma (MIUC). J Clin Oncol. 2021;39; 6S.

4. Huang H, Feng YL, Wan T, et al. Effectiveness of Sequential Chemoradiation vs Concurrent Chemoradiation or Radiation Alone in Adjuvant Treatment After Hysterectomy for Cervical Cancer: The STARS Phase 3 Randomized Clinical Trial. JAMA Oncol. 2021;7(3):361.

5. Lee G, Lamba N, Niemierko A, et al. Adjuvant Radiation Therapy Versus Surveillance After Surgical Resection of Atypical Meningiomas. Int J Radiat Oncol Biol Phys. 2021;109(1):252.

6. Gronberg BH, Killingberg KT, FlottenO, et al. High-dose versus standard-dose twice-daily thoracic radiotherapy for patients with limited stage small-cell lung cancer: an open-label, randomised, phase 2 trial. Lancet Oncol. 2021;22(3):321.

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