NEWS & VIEWS are available about counselling patients with fear of having breast cancer and about the outcome of such counselling. The ease with which plastic surgeons are marketing breast-modifying operations has also changed the attitude of the public towards breast surgery.8 Even health pro­ fessionals often overestimate cosmetic out­ comes and underestimate the risks of breast surgery, such as the side effects of surgery itself (pain), cutaneous numbness, etc. 9 The fact that cosmetic surgery of the breast is perceived as an acceptable approach by a large part of the female population may induce women to make the drastic decision to undergo CPM, especially when driven by the fear of cancer reappearance in the c­ontralateral breast. Moreover, drastic surgical solutions have become a socially acceptable and even glam­ orous approach due to a celebrity’s attitude —the Angelina Jolie effect. Ms Jolie’s state­ ments have enhanced awareness of health issues related to BRCA mutation c­arriers, and have also influenced the choice of many women at risk of breast cancer to elect the more extensive surgical approach.10 The fear of cancer recurrence in the con­ tralateral breast is fueled by the need of many survivors of unilateral breast cancer to undergo regular, generally annually, clinical, laboratory and imaging testing. These patients perceive these tests as a regular trauma­tic event and little research has been conducted to identify factors that could provide support to women during their f­ollow-­up procedures. Such efforts, if identified, might reduce extensive surgical approaches, such as CPM, due to anxiety concerning surveillance procedures. Although CPM might be a reasonable option for women with demonstrated high genetic risk, all women would benefit from assistance in decision making during treatment planning. When pathological character­istics of the tumour and extent of the disease are explained to patients, discus­ sions regarding genetic risk may aid patients and care givers in deciding whether CPM might be a suitable option. Patients consider­ ing CPM motivated primarily by fear might also benefit from appropriate counselling. Breast Health Program, European Institute of Oncology, Via G. Ripamonti 435, 20141 Milan, Italy (A.G.). IBCSG Statistical Center, Department of Biostatistics and Computational Biology, Dana–Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA (S.G.). Correspondence to: A.G. [email protected]

444  |  AUGUST 2014  |  VOLUME 11

Competing interests The authors declare no competing interests. 1.

Pesce, C. E. et al. Changing surgical trends in young patients with early stage breast cancer, 2003 to 2010: a report from the national cancer data base. J. Am. Coll. Surg. 219, 19–28 (2014). 2. Hawley, S. T. et al. Social and clinical determinants of contralateral prophylactic mastectomy. JAMA Surg. 149, 582–589 (2014). 3. Yi, M. et al. Factors affecting the decision of breast cancer patients to undergo contralateral prophylactic mastectomy. Cancer Prev. Res. (Phila.) 3, 1026–1034 (2010). 4. Brewster, A. M. & Parker, P. A. Current knowledge on contralateral prophylactic mastectomy among women with sporadic breast cancer. Oncologist 16, 935–941 (2011). 5. Lostumbo, L., Carbine, N., Wallace, J. & Ezzo, J. Prophylactic mastectomy for the prevention of breast cancer. Cochrane Database Syst. Rev. 4, Art. No.: CD002748 (2004)

http://onlinelibrary.wiley.com/doi/10.1002/ 14651858.CD002748.pub2/abstract. 6. Finch, A. P. et al. Impact of oophorectomy on cancer incidence and mortality in women with a BRCA1 or BRCA2 mutation. J. Clin. Oncol. 32, 1547–1553 (2014). 7. Preventive mastectomy. Wikipedia.org [online], http://en.wikipedia.org/wiki/ Preventive_mastectomy (2014). 8. Crerand, C. E., Infield, A. L. & Sarwer, D. B. Psychological considerations in cosmetic breast augmentation. Plast. Surg. Nurs. 27, 146–154 (2007). 9. Kling, R. E. et al. The scope of plastic surgery according to 2434 allopathic medical students in the United States. Plast. Reconstr. Surg. 133, 947–956 (2014). 10. Borzekowski, D., Guan, Y., Smith, K. C., Erby, L. H. & Roter, D. L. The Angelina effect: immediate reach, grasp, and impact of going public. Genet. Med. http://dx.doi.org/ 10.1038/gim.2013.181 (2013).

HAEMATOLOGICAL CANCER

The translocation behind follicular lymphoma development Clémentine Sarkozy and Bertrand Coiffier

Healthy individuals carrying the t(14;18) translocation might never develop follicular lymphoma (FL). However, individuals with more than 1 in 10,000 cells carrying this translocation are at high-risk of developing FL. The identification of this high-risk population will help define the pathways driving FL and designing targeted therapies to use before its development. Sarkozy, C. & Coiffier, B. Nat. Rev. Clin. Oncol. 11, 444–445 (2014); published online 17 June 2014; doi:10.1038/nrclinonc.2014.100

Follicular lymphoma (FL) is the second most frequent non-Hodgkin lymphoma (NHL) after diffuse large B‑cell lymphoma, repre­ senting 20–30% of NHL cases. It is a hetero­ geneous disease and whereas some patients present with an indolent clinical course with multiple relapses that can span two decades, others have a more-aggressive form with poor survival. FL patho­genesis involves a multi-hit process—including epi­genetic reprogramming, acquisition of somatic mutations, and modifications in the microenvironment—in which the genetic hallmark and initiating event of the disease is the t(14;18) t­r anslocation that causes BCL2 overexpression.1 Cells bearing the t(14;18) translocation are present in the blood of 50–70% of healthy indivi­duals, indicating that BCL2 over­ expression is not sufficient for development of FL; in fact, only very few of these indivi­duals will develop the disease.2 In a recent study, Roulland and colleagues3 analysed a cohort of approximately 520,000 healthy participants, and determined that indivi­duals carrying



more than one cell with the t(14;18) trans­ location per 10,000 blood cells had a 23-fold higher risk of developing FL. Of note, this pre­ dictive value was accurate regardless of dis­ ease onset and was still relevant 15 years before FL diagnosis.3 More impor­tantly, the authors showed the clonal relationship between the committed t(14;18) cells in healthy indivi­ duals and the FL cells, demonstrating the e­xistence of a B‑cell pre‑malignant state in FL.3 The utility of the early detection of this trans­location is questionable. In fact, the detection of such cells in healthy indivi­ duals will likely provoke stress and anxiety. However, the longitudinal follow-up of these patients represents a great opportu­ nity for the development of epidemiologi­ cal studies to identify potential roles of the micro­environment in determining FL pro­ gression. Therefore, the early identifica­ tion of healthy individuals who will likely develop FL together with the use of power­ ful biological tools, such as next-generation sequencing, might lead to a different attitude to treat these ‘healthy individuals’. www.nature.com/nrclinonc

© 2014 Macmillan Publishers Limited. All rights reserved

NEWS & VIEWS Will this discovery change our daily prac­ tice? To answer this question, we have to analyse our clinical approach to asympto­ matic FL. Currently, there is no recommen­ dation or standard of care for asymptomatic patients and patients with a low tumour burden. Given the incurability of the dis­ease, for a long time delaying treatment following the ‘watch and wait’ approach has been pre­ ferred to an interventional strategy. However, since the introduction of the monoclonal antibody rituximab, the paradigm of the incurability of FL for both symptomatic and asymptomatic patients has been challenged by several authors. Prolonged therapy with rituximab allows long-term disease-free sur­ vival, as shown in the PRIMA study.4 Patients who received chemo-­immunotherapy fol­ lowed by rituxi­m ab every 2 months for 2 years have less progression and relapses than those without mainten­ance therapy.4 Whether early treatment of the subgroup of healthy individuals with a proportion of cells with the t(14;18) translocation higher than 1 in 10,000, might prevent evolution to FL and change the history of the disease is unknown. However, it is virtually impos­ sible to answer such a question, owing to the objective difficulty in conducting random­ ized trials in a­symptomatic patients or in healthy individuals.

‘‘

The utility of the early detection of this translocation is questionable

’’

This discovery, therefore, might not change our daily therapeutic practice; however, the identification of these healthy individuals at high-risk of developing FL will enable the molecular characterization of these ‘potential’ patients, thus contri­ buting to define the different steps that ultimately lead to disease occurrence. The multi-hit process leading to the develop­ ment of FL includes early and late genetic events, and the hierarchy in somatic muta­ tions occurring during FL pathogenesis has been recently described.5 The character­ ization of the high-risk healthy population, therefore, could allow the development of personalized therapy, that could target the secondary genetic events that occur after the primary t(14;18) translocation. Through next-­g eneration sequencing and copy number analysis, different studies confir­ med that the overt FL clone and the trans­ formed clone, corresponding to an aggressive subtype of FL, arise from divergent evolution

Key point ■■ The number of t(14;18) cells may help identify healthy individuals who will develop follicular lymphoma

of a common mutated precursor through the acquisition of distinct genetic events.6,7 Furthermore, it has been recently reported that, in FL, early events or early driver muta­ tions in epigenetic modifiers—such as EZH2, MLL, CREBBP—and in antiapoptotic genes promote the evolution of the initial domi­ nant clone. 6 Conversely, late events, not pres­­ent at diagnosis, occur in genes respon­ sible for regulating cell-cycle progression, DNA damage responses and NF‑κB signal­ ling that promote the transformation of FL to its aggressive subtype.6 The early events described above will induce genetic insta­ bility that might then promote late ‘genetic’ events and subsequent transformation. On the basis of these data, the identification and molecular characterization of these early events could allow these mutations to be targeted with specific inhibitors before the occurrence of secondary genetic alterations, and ultimately might prevent the evolution of the t(14;18) cells into FL cells. Among the available agents, BTK, PI3K, BCL2 or EZH2 inhibitors have shown promising results in the treatment of symptomatic patients with overt FL.8 Using these therapeutics to target precise early events in the FL pathogenesis is an appealing strategy that could prevent the evolution of FL in healthy patients pre­ senting a high number of t(14;18) cells and additional genetic abnormalities. Although these agents present fewer adverse effects than chemo­therapy, their late adverse effects are still unknown. More observations are, therefore, needed before high-risk healthy patients can receive preventive treatment. The t(14;18) cells have distinctive traffick­ ing properties and were found in lymph nodes and in the spleen of healthy indivi­ duals.3 The important role of the micro­ environment has been raised many times in FL. We recently reported that the presence of circulating lymphoma cells in patients with FL represented a poor prognosis and was associa­ted with high tumour burden and bone marrow involvement.9 Interestingly, this poor prognosis was erased by mainten­ ance therapy with rituximab.9 Whether these patients harbour particular forms of FL that have specific interactions with the micro­environment is currently under investigation. In this context, healthy indivi­ duals with more than 1/10,000 t(14;18)

NATURE REVIEWS | CLINICAL ONCOLOGY

cells provide an opportunity to study the traffick­ing properties of these cells and how they are linked to differential interaction with the micro­environment. Such studies might be of particular interest for tailored therapy, especially with the develop­ment of drugs that specifically target components of the tumour microenvironment, such as lenalidomide or an anti-PD1 antibody. These observations highlight the rationale for the use of immuno­modulating agent, including lenalidomide, for the treatment of FL, currently under i­nvestigation in the RELEVANCE phase III study.10 In conclusion, the article by Rolland et al.3 opens fantastic opportunities to study the early development of FL and to isolate early genetic abnormalities that could be targeted earlier in the history of the disease. Hospices Civils de Lyon (HCL), Université Claude Bernard Lyon 1, Service d’Hématologie, Centre Hospitalier Lyon Sud (CHLS), 165 Chemin du Grand Revoyet, 69310 Pierre‑Bénite, France (C.S., B.C.). Correspondence to: B.C. [email protected] Competing interests The authors declare no competing interests. 1.

Roulland, S. et al. Early steps of follicular lymphoma pathogenesis. Adv. Immunol. 111, 1–46 (2011). 2. Roulland, S. et al. Follicular lymphoma-like B cells in healthy individuals: a novel intermediate step in early lymphomagenesis. J. Exp. Med. 203, 2425–2431 (2006). 3. Roulland, S. et al. t(14;18) Translocation: a predictive blood biomarker for follicular lymphoma. J. Clin. Oncol. 32, 1347–1355 (2014). 4. Salles, G. et al. Rituximab maintenance for 2 years in patients with high tumour burden follicular lymphoma responding to rituximab plus chemotherapy (PRIMA): a phase 3, randomised controlled trial. Lancet 377, 42–51 (2011). 5. Green, M. et al. Hierarchy in somatic mutations arising during genomic evolution and progression of follicular lymphoma. Blood 121, 1604–1611 (2013). 6. Okosun, J. et al. Integrated genomic analysis identifies recurrent mutations and evolution patterns driving the initiation and progression of follicular lymphoma. Nat. Genet. 46, 176–181 (2014). 7. Pasqualucci, L. et al. Genetics of follicular lymphoma transformation. Cell Rep. 6, 130–140 (2014). 8. Murawski, N. & Pfreundschuh, M. New drugs for aggressive B‑cell and T‑cell lymphomas. Lancet Oncol. 11, 1074–1085 (2010). 9. Sarkozy, C. et al. Rituximab maintenance obviates the poor prognosis associated with circulating lymphoma cells in patients with follicular lymphoma. Blood 123, 2740–2742 (2014). 10. US National Library of Medicine. ClinicalTrials.gov [online], https://clinicaltrials.gov/ct2/show/NC T01476787?term=NCT01476787&rank=1 (2014).

VOLUME 11  |  AUGUST 2014  |  445 © 2014 Macmillan Publishers Limited. All rights reserved