Letters

1. Chlebowski RT, Rohan TE, Manson JE, et al. Breast cancer after use of estrogen plus progestin and estrogen alone: analyses of data from 2 Women’s Health Initiative randomized clinical trials. JAMA Oncol. 2015;1(3):296-305.

sive notion that 17p- signifies a more aggressive form of CLL. However, this statement is misleading. A number of patients with CLL with 17p- enjoy an indolent course2 in which any form of therapy, especially aggressive, will be disadvantageous. Despite the authors’ citation that “there is a clinical heterogeneity in patients with 17p deletions,” this fact is never sufficiently emphasized (see their Figure 2). As a result, the most crucial practical point is missed: that a 17p- CLL is not always ominous, and it may not necessitate chemoimmunotherapy. The National Comprehensive Cancer Network guidelines3 also blend all CLL patients with 17p- anomaly together on the basis of a low response rate to immunochemotherapy, thus exaggerating a pessimistic outlook of this cohort. Most importantly, the guidelines lack the affirmation that not only is it acceptable, but actually prudent, to avoid the treatment even for potentially “high risk” patients if the disease remains silent. European patients with CLL evidently benefit from a more explicit (and judicious) recommendation: for asymptomatic patients, molecular studies are irrelevant because the first line of treatment for this category of patients is nonexistent.4 The molecular aspects of CLL as paramount determinants of the prognosis have been rightfully emphasized. However, it must be made clear—there are currently no established prognostic molecular markers in CLL, no matter how deleterious they may appear, that should incite treatment of asymptomatic patients. Unfortunately, current guidelines and numerous reviews are still not limpid about this. The authors are correct stating that it is still unknown “whether early therapy in asymptomatic but high-risk patients is beneficial.” But it would seem irrational and perhaps unethical at this time to attempt to treat individuals with CLL, who continue to thrive despite their diagnosis, with any newer and potentially harmful therapies.

2. Joshi PA, Jackson HW, Beristain AG, et al. Progesterone induces adult mammary stem cell expansion. Nature. 2010;465(7299):803-807.

Leonid L. Yavorkovsky, MD, PhD

3. Joshi PA, Waterhouse PD, Kannan N, et al. RANK signalling amplifies WNT-responsive mammary progenitors through R-SPONDIN1. Stem Cell Reports. 2015;5(1):31-44.

Author Affiliation: Oncology/Hematology Division, Kaiser Permanente San Jose Medical Center, San Jose, California.

4. Wang J, Gupta A, Hu H, Chatterton RT, Clevenger CV, Khan SA. Comment on “Progesterone/RANKL is a major regulatory axis in the human breast.” Sci Transl Med. 2013;5(215):215le4.

Corresponding Author: Leonid L. Yavorkovsky, MD, PhD, Kaiser Permanente San Jose Medical Center, Oncology/Hematology Division, 270 International Circle, San Jose, CA 95119 ([email protected]).

5. Greendale GA, Reboussin BA, Sie A, et al; Postmenopausal Estrogen/Progestin Interventions (PEPI) Investigators. Effects of estrogen and estrogen-progestin on mammographic parenchymal density. Ann Intern Med. 1999;130(4, pt 1):262-269.

Conflict of Interest Disclosures: None reported.

estrogen therapy, we do not think that it is sufficient for deciphering the significant increase in breast cancer risk with combined E+P therapy. Medroxyprogesterone could nullify estrogen-induced apoptosis, but it is not clear how it would then promote cancer development. Hormone actions are complex, and several mechanisms are probably involved in dictating menopausal hormone therapy effects on breast cancer risk. On the basis of compelling mouse2 and human studies,3 progesterone, be it endogenous, natural, synthetic, progestin, or progestogen, is likely to be instrumental for initiating key mitogenic signals that propel increases in stem and/or progenitor cells, thus contributing to cancer pathogenesis. Purna A. Joshi, MSc, PhD Pamela J. Goodwin, MD, MSc, FRCPC Rama Khokha, PhD Author Affiliations: Princess Margaret Cancer Centre/University Health Network, Toronto, Ontario, Canada (Joshi, Khokha); Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada (Goodwin). Corresponding Author: Rama Khokha, PhD, Princess Margaret Cancer Centre/ University Health Network, 101 College St, Toronto Medical Discovery Tower at MaRS, 101 College St, Toronto, ON M5G 1L7, Canada (rama.khokha@utoronto .ca). Conflict of Interest Disclosures: None reported. Funding/Support: Dr Joshi holds a fellowship from the Canadian Breast Cancer Foundation. Drs Goodwin and Khokha acknowledge funding support from Hold’em for Life (Toronto, Ontario, Canada), the Breast Cancer Research Foundation, and the Canadian Cancer Society Research Institute. Role of the Funder/Sponsor: The funders had no role in the preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Prognosis in Chronic Lymphocytic Leukemia To the Editor: The review “Predicting Prognosis in Chronic Lymphocytic Leukemia in the Contemporary Era”1 summarizes the modern understanding of how the outlook for patients with the most common leukemia in the Western hemisphere can be predicted by exploiting molecular achievements. Unfortunately, a prognostic value of molecular aberrations, if applied outside a clinical context, continues to be unreliable and may be easily misperceived. Chronic lymphocytic leukemia (CLL) may surprise by taking an unpredictable path with no regard to its genetic defect(s). The authors’ upfront statement that “patients with 17p13.1 deletion have poor response to chemoimmunotherapy and are treated differently” echoes the perva988

1. Nabhan C, Raca G, Wang YL. Predicting prognosis in chronic lymphocytic leukemia in the contemporary era [published online May 7, 2015]. JAMA Oncol. doi:10.1001/jamaoncol.2015.0779. 2. Tam CS, Shanafelt TD, Wierda WG, et al. De novo deletion 17p13.1 chronic lymphocytic leukemia shows significant clinical heterogeneity: the M. D. Anderson and Mayo Clinic experience. Blood. 2009;114(5):957-964. 3. National Comprehensive Cancer Network. Non-Hodgkin’s Lymphomas (Version 2.2015). http://www.nccn.org/professionals/physician_gls/pdf/nhl.pdf. Accessed May 9, 2015. 4. Eichhorst B, Dreyling M, Robak T, Montserrat E, Hallek M; ESMO Guidelines Working Group. Chronic lymphocytic leukemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2011;22(Suppl 6): vi50-vi54.

In Reply We thank Dr Yavorkovsky for his interest in our review article that summarized the current state of molecular prognostication for chronic lymphocytic leukemia (CLL) and appreciate his interest and constructive comments. We

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Letters

agree with his contention that treatment decisions cannot be based solely on molecular data without considering clinical context. In fact, in our review, we clearly state that despite improvements in molecular prognostication in CLL, indications to initiate therapy remain based on the International Working Group Criteria (IW-CLL) that rely heavily on clinical presentation, disease burden, and stage, without molecular data.1 Having said that, we believe that this is an evolving process that is likely to change in the years ahead. In the era of precision medicine, targeted therapies, and better understanding of the underlying disease biology, it would be critical to tailor intervention to the underlying biological process that might have led to disease development. Yavorkovsky specifically discusses 17p13.1 deletion, stating that the presence of this deletion does not necessarily predict poor prognosis. Actually, in our review, we cited the same reference that Yavorkovsky cites and suggested that some patients with 17p13.1 deletion could potentially enjoy an indolent course.2 Furthermore, we emphasized that the presence of this deletion should not lead to treatment initiation in the absence of any of the aforementioned IW-CLL criteria. However, these patients should be closely monitored because they might have increased risk of early disease progression. Moreover, as new therapies such as ibrutinib, idelalisib, and venetoclax have demonstrated significant activity in 17p13.1deleted patients,3 clinical trials are now ongoing to explore whether early initiation of treatment in asymptomatic patients with this deletion is warranted. We clearly stated that none of the regulatory bodies recommend early treatment initiation outside the context of clinical trials. We agree with Yavorkovsky that guidelines should simply be suggestions on how best to approach a disease and should never replace clinical judgment and experience. While Yavorkovsky suggests that European recommendations that advocate against molecular testing are welcome, we propose that these recommendations were generated in an era in which treatments that target higher-risk disease molecularly were not available. Molecular testing not only aids in a better discussion with patients but also can guide treatment decisions in the future once management is indicated clinically. In summary, we agree with Yavorkovsky that treating asymptomatic patients regardless of their molecular profile is currently not recommended outside clinical trials, and we emphasized this notion throughout our review. However, we disagree that testing is not needed and suggest that knowing more about the biological characteristics of a disease is only destined to help patients if used properly and judiciously. Finally, and similar to other malignant neoplasms, it is more likely than not that treatment decisions for CLL in the years ahead

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will be based on molecular information that supplements clinical data to aid in decision making. Chadi Nabhan, MD Gordana Raca, MD, PhD Y. Lynn Wang, MD, PhD Author Affiliations: Section of Hematology and Oncology, Department of Medicine, University of Chicago, Chicago, Illinois (Nabhan, Raca); Section of Hematology/Oncology, Cancer Cytogenetics Laboratory, University of Chicago, Chicago, Illinois (Raca); Division of Genomic and Molecular Pathology, Department of Pathology, University of Chicago, Chicago, Illinois (Wang). Corresponding Author: Chadi Nabhan, MD, Section of Hematology and Oncology, Department of Medicine, University of Chicago Medicine, 5841 S Maryland Ave, MC2115, Chicago, IL 60637 ([email protected] .edu). Conflict of Interest Disclosures: Dr Nabhan receives research funding from Genentech. No other disclosures are reported. 1. Hallek M, Cheson BD, Catovsky D, et al; International Workshop on Chronic Lymphocytic Leukemia. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines. Blood. 2008;111(12):5446-5456. 2. Tam CS, Shanafelt TD, Wierda WG, et al. De novo deletion 17p13.1 chronic lymphocytic leukemia shows significant clinical heterogeneity: the M. D. Anderson and Mayo Clinic experience. Blood. 2009;114(5):957-964. 3. Awan FT, Byrd JC. New strategies in chronic lymphocytic leukemia: shifting treatment paradigms. Clin Cancer Res. 2014;20(23):5869-5874.

CORRECTION Incorrect Author Name Spelling: In the Special Communication titled “Improving Patient Safety in Clinical Oncology: Applying Lessons From Normal Accident Theory” published in the May 14, 2015, online issue of JAMA Oncology (10.1001 /jamaoncol.2015.0891), an author’s name was misspelled. The correct spelling is Ian Buchanan, MD, MPH. This article was corrected online.

Error in Figure: There was an error in the Figure in the Original Investigation by Guérin et al,1 “Physician Underestimation of the Risk of Gastrointestinal Stromal Tumor Recurrence After Resection,” published online in JAMA Oncology on July 23, 2015. The treatment durations at the bottom of the figure,

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