Genetic testing for hereditary predisposition to cancer is recognized as a standard aspect of oncology practice.[1] Identification of a pathogenic mutation in a cancer susceptibility gene enables an individual and his or her family to take proactive measures that may lead to the early detection of cancer, or, as in the case of prophylactic surgery, that may significantly reduce the risk of developing cancer.[2] In this month’s issue of ONCOLOGY, Plichta et al provide a comprehensive and thoughtful review of the current state of genetic testing for hereditary cancer susceptibility, and highlight the challenges that accompany multigene panel testing (“panel testing”).[3]

In clinical practice, panel testing may be ordered for patients who meet clinical guidelines for a single syndrome, such as hereditary breast and ovarian cancer syndrome. The objective in ordering a panel test is to identify a causative mutation by including other candidate genes.[4] Most health plans do not reimburse for panel testing, but the testing laboratories do not bill for unreimbursed costs as long as the core testing (such as testing for 

) is a covered service. An increasing number of patients who have undergone panel testing through an outside provider are being referred to surgical oncologists for prophylactic surgery and/or to medical genetics specialists for posttest genetic counseling. Of particular concern is the referral of patients for prophylactic surgery based on a misunderstanding of genetic test results. The results in question are often variants of uncertain significance, but increasingly they include pathogenic mutations in moderate- or low-penetrance genes for which there is no consensus or recommendation by the National Comprehensive Cancer Network (NCCN) or other professional organizations for risk-reducing surgery. These “near misses” are disturbing and validate the admonitions of the NCCN et al that genetic testing is best performed in the context of pretest genetic counseling, particularly when panel testing is being considered.[5] Nevertheless, the number of panel tests ordered continues to grow, based on the misconception that “one size fits all.” This flies in the face of the basic tenets of clinical judgment and precision medicine.

There are several reasons for the rapid adoption of panel testing. In part it has resulted from a highly competitive marketing environment among testing laboratories. Other factors include the reluctance of most health plans to affirmatively cover testing for genes such as 

, and the continued high price of genetic testing, despite the cost efficiencies of next-generation sequencing. For example, despite evidence that 

 mutations confer a 41% to 67% breast cancer risk in high-risk families, testing for 

 is not covered by most health plans.[6] A 

 mutation is therefore typically identified through a panel test. Thus, even among genetics professionals, testing decisions are often influenced by insurance considerations rather than clinical assessment and differential diagnoses.

Health plans direct providers to use specific laboratories that may not offer panel options that are the best fit for a particular patient’s personal/family history or that can accommodate their preference to test only for clinically actionable genes. When compelled to select a large panel that includes genes for which there is no suspicion, we are too often confronted with results that require a complex discussion with the patient and with information that is confusing or unnecessarily worrisome to family members at risk for the mutation.[7] Two examples of this include the p.I1307K mutation in 

, which is a low-penetrance variant common in persons of Ashkenazi Jewish heritage, and suspected somatic mosaicism in 

, which is being found in older patients who have received chemotherapy.[7,8] Panel testing for recessive disorders in the prenatal setting is also identifying questionable mutations (eg, in the fumarate hydratase gene [

]), prompting referrals for cancer genetic counseling.[9] The clinical implications of even some common mutations are ambiguous and vexing for the patient and family. Additionally, the screening costs for what may be a negligible risk (if any) is unlikely to be a wise use of healthcare dollars.

We concur with the authors that the protracted testing odysseys of the prepanel era were inefficient, stressful for the patient, and often uninformative.[3] Advocates of broad testing may properly assert that unexpected mutations found in clinically actionable genes such as 

 justify large panel testing. However, the finding of an 

 mutation in a breast cancer patient being tested for surgical decision purposes provides no useful information for the imminent decision and creates additional concerns for the patient/family. This incidental finding could have been identified in reflex testing performed after the patient’s surgery. In such a situation, there is also a temptation to attribute the breast cancer diagnosis to the 

 mutation, but this would be conjecture in the absence of an abnormal tumor immunohistochemistry result. Furthermore, first-degree family members who test negative for the 

 mutation might incorrectly conclude that they are at population risk of breast cancer, when their residual lifetime risk might be twofold and should be managed as such.

So, how might we reign in testing for cancer susceptibility without sacrificing important opportunities to identify carriers and reduce cancer incidence? Complex solutions involving detailed capture of medical/family history and algorithms for test selection (as proposed by the authors) will undoubtedly provide the best opportunity for genetic test selection with optimal sensitivity and specificity.[3] Unfortunately, the development and implementation of such solutions is likely several years away. We propose three interim steps that would address the issue of unfocused testing and improve identification of individuals at risk for hereditary cancer predisposition:

 Payers should cover panel testing based on published data.[10] This would eliminate the practice of selecting broad panels as an initial test, thereby reducing the number of variants identified. Genetic counselors and providers would then order reflex testing on an “as-needed” basis.

 Certain large laboratories only offer fixed panels. More laboratories should offer customized panel options, allowing for selection of suspect genes and omission of genes that are not suspect. This would facilitate more refined testing based on medical/family history and selection of clinically actionable genes. In addition, laboratories should offer the option of reflex testing within a designated time frame at no additional cost.

3) Improve access to variant interpretation.

 All Clinical Laboratory Improvement Amendments laboratories should submit variant data to public databases. Discordant interpretations of variants by individual laboratories should be eliminated to the greatest degree possible.

In summary, panel testing has important advantages but is being misused due to payer constraints and laboratory marketing pressures. Much testing is haphazard and results in utilization of limited genetic counseling resources in the discussion of variants of uncertain significance and low-penetrance gene mutations. This time would be better spent identifying clinically actionable genes. As the authors astutely point out, panel testing is no different than population screening in many cases.[3] Initiating controlled population screening by offering coverage for the three Ashkenazi Jewish founder mutations in 

 seems an obvious first step in maximizing cancer risk reduction through genetic testing.

The authors have no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article

 Garber JE, Offit K. Hereditary cancer predisposition syndromes. J Clin Oncol. 2005;23:276-92.

 Chai X, Friebel TM, Singer CF, et al. Use of risk-reducing surgeries in a prospective cohort of 1,499 BRCA1 and BRCA2 mutation carriers. Breast Cancer Res Treat. 2014;148:397-406.

 Plichta JK, Griffin M, Thakuria J, Hughes KS. What’s new in genetic testing for cancer susceptibility? Oncology (Williston Park). 2016;30:787-99.

 Walsh T, Casadei S, Lee MK, et al. Mutations in 12 genes for inherited ovarian, fallopian tube and peritoneal carcinoma identified by massively parallel sequencing. Proc Natl Acad Sci USA. 2011;108:18032-7.

 Daly MB, Pilarski R, Axilbund JE, et al. Genetic/familial high-risk assessment: breast and ovarian. Version 2.2015. J Natl Compr Canc Netw. 2016;14:153-62.

 Antoniou AC, Casadei S, Heikkinen T, et al. Breast cancer risk in families with mutations in PALB2. N Engl J Med. 2014;371:497-506.

 Slavin TP, Niell-Swiller M, Solomon I, et al. Clinical application of multigene panels: challenges of next-generation counseling and cancer risk management. Front Oncol. 2015;5:208.

 Boursi B, Sella T, Liberman E, et al. The APC p.I1307K polymorphism is a significant risk factor for CRC in average risk Ashkenazi Jews. Eur J Cancer. 2013;49:3680-5.

 Alam NA, Rowan AJ, Wortham NC, et al. Genetic and functional analyses of FH mutations in multiple cutaneous and uterine leiomyomatosis, hereditary leiomyomatosis and renal cancer, and fumarate hydratase deficiency. Hum Mol Genet. 2003;12:1241-52.

 LaDuca H, Stuenkel AJ, Dolinsky JS, et al. Utilization of multigene panels in hereditary cancer predisposition testing: analysis of more than 2,000 patients. Genet Med. 2014;16:830-7.

Articles

Panel testing has important advantages but is being misused due to payer constraints and laboratory marketing pressures. Much testing is haphazard and results in utilization of limited genetic counseling resources in the discussion of variants of uncertain significance and low-penetrance gene mutations.

Ready, Fire, Aim: Addressing Issues Associated With Multigene Panel Testing for Cancer Susceptibility

The Rationale for Use of Antibiotic Prophylaxis in Patients With Neutropenia

Patients receiving cytotoxic chemotherapy for malignancy are at high risk for infection-related complications. Factors that may precipitate an infection include immunologic compromise; multiple comorbidities; malnutrition; and breaches in natural barriers, caused by medical procedures, radiation therapy, mucositis, and central venous catheter placement. Notably, the degree of severity and the duration of neutropenia associated with cytotoxic chemotherapy are critical determinants of the development of invasive bacterial infections-a relationship initially described by Bodey and colleagues in 1966 in patients with acute leukemia.[1] Many chemotherapy agents injure the mucosal linings of the body, particularly in the gastrointestinal tract (from oral cavity to anus), conferring a high risk for enteric bacterial translocation and subsequent systemic infection. In the setting of neutropenia, even common enteric bacterial bloodstream infections (BSIs) may become quickly fatal when unopposed by effector white cells (neutrophils). Febrile neutropenia is often the only clinical hallmark of serious infections, primarily bacteremia. Febrile neutropenia is defined as a one-time oral temperature of > 38.3°C (approximately 100.9°F) or a sustained temperature of > 38°C (100.4°F) for ≥ 1 hour in a patient who has an absolute neutrophil count (ANC) of < 500 cells/mm

 or an ANC expected to decrease to < 500 cells/mm

 within a 48-hour period.[2] Therefore, patients with febrile neutropenia require urgent evaluation and initiation of empiric therapy with broad-spectrum antibiotics.

More than 80% of patients receiving chemotherapy for leukemia or undergoing allogeneic hematopoietic stem cell transplantation (HSCT) will experience at least 1 episode of febrile neutropenia.[2-5] Conversely, only 5% to 30% of patients receiving chemotherapy for a solid tumor will have febrile neutropenia, with the highest rates occurring during the first cycle of treatment.[2,5,6] Febrile neutropenia is associated with an overall mortality rate of approximately 8% in patients with solid tumors and rates ranging from 14% to 34% in patients with leukemia.[7] Up to 40% to 60% of episodes are due to a clinically or microbiologically documented infection, with approximately 20% to 30% of patients having a BSI.[3,7,8] Gram-negative rods (GNRs), particularly Enterobacteriaceae (including 

, are historically the most common pathogens in this population, and if not treated promptly and aggressively, infections with these microorganisms are rapidly fatal.[9] Even with adequate early empiric antibiotic treatment, bacteremia due to GNRs in the setting of neutropenia is associated with crude mortality rates as high as 34% to 50%.[7,10] Therefore, antibacterial prophylaxis for neutropenic patients has been proposed in an effort to reduce febrile neutropenia, infection (particularly with gram-negative pathogens), and mortality in high-risk populations. Initial studies evaluating nonabsorbable antibiotics vs the combination trimethoprim-sulfamethoxazole revealed no consistent benefits.[11,12]

In the 1990s, antibiotic prophylaxis with fluoroquinolones showed excellent activity against gram-negative pathogens, with good tolerability and high oral bioavailability. In 2005, a large randomized controlled trial published by Bucaneve et al demonstrated significant reductions in febrile neutropenia and in documented bacteremias in patients whose hematologic malignancies were treated with levofloxacin, compared with placebo.[4] Several meta-analyses of the numerous published studies of fluoroquinolone prophylaxis have also shown it to be associated with reductions in both febrile neutropenia and infections due to GNRs, with one study providing evidence for decreased mortality among patients receiving prophylaxis.[13-15] However, these studies were not able to characterize the impact of fluoroquinolone prophylaxis on colonizing flora and the risk for development of resistance to fluoroquinolones.

Antibiotic Prophylaxis in an Era of Increasing Antimicrobial Resistance

The use of fluoroquinolones for antibacterial prophylaxis and treatment is associated with increased rates of infection due to fluoroquinolone-resistant organisms, in particular with fluoroquinolone-resistant 

.[16] In fact, centers that routinely used fluoroquinolone prophylaxis have reported resistance in 

 isolates exceeding 30% to 50%, and rates are significantly higher in the oncology patient population, compared with the general population.[17,18] Accordingly, it is plausible that these drugs could eventually cease to be effective infection prophylaxis for patients at centers where the incidence of resistance is particularly high. However, the threshold level of fluoroquinolone resistance within a given population or center at which this could occur is unknown. Our ability to gauge this landscape is limited by many factors, including the lack of national data on BSIs in patients with neutropenia and the ever-changing epidemiology of infections in patients with neutropenia, since even at the time of publication the data are already antiquated. As a result, it is difficult to make an enduring recommendation regarding prophylaxis, with some centers moving toward omitting antibiotic prophylaxis altogether in selected high-risk populations, in order to mitigate the problem of rising antibiotic resistance. In these settings, patients are simply closely monitored for signs and symptoms of developing infection. In the absence of routine prophylaxis, these centers have uncovered increased rates of GNR bacteremia, but no change in mortality.[19,20]

In addition to its association with the emergence of fluoroquinolone-resistant 

, use of fluoroquinolone prophylaxis is also linked to an increased risk of colonization and infection with other multidrug-resistant organisms, including other Enterobacteriaceae, 

 and vancomycin-resistant enterococci.[21-23] BSIs caused by these multidrug-resistant organisms can present a clinical dilemma, since treatment options are often limited (fluoroquinolones eliminated as potential therapeutic agents) and initial empiric antibiotic choices may not be effective.[21,22,24] Infections due to these organisms are associated with higher rates of mortality,[9,25] and the use of fluoroquinolones is linked to increased rates of colonization and infection with 

.[26] In addition, in 2015 a US Food and Drug Administration advisory panel evaluated risks of fluoroquinolones and called for limiting their use in patients with sinusitis, bronchitis, and urinary tract infection, due to concerns about the risk of adverse drug reactions, including tendonitis/tendon rupture, peripheral neuropathy, and cardiac arrhythmias.[27] Therefore, it is important for centers to continue to evaluate their practice based on local antibiograms and patient outcomes.

Who Should Receive Antibiotic Prophylaxis?

Current National Comprehensive Cancer Network (NCCN) guidelines define patients at low risk for febrile neutropenia as those with neutropenia lasting less than 7 days or those receiving chemotherapy for solid tumors, and so do not recommend antibiotic prophylaxis for these populations. Patients undergoing autologous HSCT or receiving chemotherapy for a hematologic malignancy who have an anticipated 7- to 10-day duration of neutropenia are considered to be at intermediate risk. Patients categorized as high risk are those expected to have neutropenia lasting more than 10 days, including patients undergoing allogeneic HSCT. The NCCN guidelines recommend consideration of bacterial prophylaxis with a fluoroquinolone in intermediate-risk and high-risk patients.[28,29] The Infectious Diseases Society of America and the American Society of Clinical Oncology both recommend antibacterial prophylaxis with a fluoroquinolone in patients who are expected to remain profoundly neutropenic (with an ANC < 100 cells/mm

) for more than 7 days.[2,5] Interestingly, the guidelines developed by the Australian Consensus Guidelines 2011 Steering Committee do not recommend the use of fluoroquinolone prophylaxis for neutropenic patients in general.[30]

Our institution follows NCCN recommendations and provides antimicrobial prophylaxis with levofloxacin at an oral dosage of 500 mg daily during neutropenic periods to patients with hematologic malignancies who are either receiving induction and consolidation chemotherapy for leukemia or undergoing HSCT. After 10 years of performing autologous stem cell transplants without the use of fluoroquinolone prophylaxis, and after encountering several cases of severe sepsis due to fluoroquinolone-susceptible organisms, we recently revised our practice to now include fluoroquinolone prophylaxis. As suggested by current NCCN guidelines, we will monitor the incidence of fluoroquinolone-resistant pathogens in this population and reassess this practice periodically.

If patients develop febrile neutropenia, our practice is to stop levofloxacin while they are receiving empiric treatment with cefepime, piperacillin-tazobactam, or meropenem. If no infectious etiology is identified, we recommend switching back to levofloxacin prophylaxis for the duration of the neutropenia if the patient defervesces and remains afebrile for 48 hours. We stop the prophylaxis as soon as the ANC is > 500 cells/mm

, as long as the ANC is increasing. We do not recommend prophylaxis in patients receiving chemotherapy for solid tumors or for any other neutropenia events anticipated to be classified as “low risk.”

Despite more than 50 years of clinical experience and research, the prevention of febrile neutropenia and bacterial infections in oncology patients remains a challenge. Current guidelines recommend antimicrobial prophylaxis with fluoroquinolones in patients at high risk for infection-related morbidity and mortality, but this practice provides a short-term benefit to individual patients. While fluoroquinolone prophylaxis has reduced some of the collateral damage of intensive chemotherapy, the direct and indirect adverse effects of these agents may limit their utility. It is imperative that we consider the long-term implications of this practice on our population as a whole. We have reservations about the durability of success with fluoroquinolone prophylaxis and advocate for continuous reevaluation of this practice, using information from ongoing studies and national data.

 Bodey GP, Buckley M, Sathe YS, Freireich EJ. Quantitative relationships between circulating leukocytes and infection in patients with acute leukemia. Ann Intern Med. 1966;64:328-40.

 Freifeld AG, Bow EJ, Sepkowitz KA, et al. Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis. 2011;52:e56-e93.

 Celebi H, Akan H, Akcaglayan E, et al. Febrile neutropenia in allogeneic and autologous peripheral blood stem cell transplantation and conventional chemotherapy for malignancies. Bone Marrow Transplant. 2000;26:211-4.

 Bucaneve G, Micozzi A, Menichetti F, et al. Levofloxacin to prevent bacterial infection in patients with cancer and neutropenia. N Engl J Med. 2005;353:977-87.

 Flowers CR, Seidenfeld J, Bow EJ, et al. Antimicrobial prophylaxis and outpatient management of fever and neutropenia in adults treated for malignancy: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol. 2013;31:794-810.

 Cullen M, Steven N, Billingham L, et al. Antibacterial prophylaxis after chemotherapy for solid tumors and lymphomas. N Engl J Med. 2005; 353:988-98.

 Kuderer NM, Dale DC, Crawford J, et al. Mortality, morbidity, and cost associated with febrile neutropenia in adult cancer patients. Cancer. 2006;106:2258-66.

 Feld R. Bloodstream infections in cancer patients with febrile neutropenia. Int J Antimicrob Agents. 2008;32(suppl 1):S30-S33.

 Kang CI, Kim SH, Park WB, et al. Bloodstream infections caused by antibiotic-resistant gram-negative bacilli: risk factors for mortality and impact of inappropriate initial antimicrobial therapy on outcome. Antimicrob Agents Chemother. 2005;49:760-6.

 Elting LS, Rubenstein EB, Rolston KV, Bodey GP. Outcomes of bacteremia in patients with cancer and neutropenia: observations from two decades of epidemiological and clinical trials. Clin Infect Dis. 1997;25:247-59.

 Weiser B, Lange M, Fialk MA, et al. Prophylactic trimethoprim-sulfamethoxazole during consolidation chemotherapy for acute leukemia: a controlled trial. Ann Intern Med. 1981;95:436-8.

 Gualtieri RJ, Donowitz GR, Kaiser DL, et al. Double-blind randomized study of prophylactic trimethoprim/sulfamethoxazole in granulocytopenic patients with hematologic malignancies. Am J Med. 1983;74:934-40.

 Engels EA, Lau J, Barza M. Efficacy of quinolone prophylaxis in neutropenic cancer patients: a meta-analysis. J Clin Oncol. 1998;16:1179-87.

 Gafter-Gvili A, Fraser A, Paul M, Leibovici L. Meta-analysis: antibiotic prophylaxis reduces mortality in neutropenic patients. Ann Intern Med. 2005;142:979-95.

 Leibovici L, Paul M, Cullen M, et al. Antibiotic prophylaxis in neutropenic patients: new evidence, practical decisions. Cancer. 2006;107:1743-51.

 Cometta A, Calandra T, Bille J, Glauser MP. Escherichia coli resistant to fluoroquinolones in patients with cancer and neutropenia. N Engl J Med. 1994;330:1240-1.

 Freifeld AG, Zinner S, Bow EJ. Antibiotic resistance: impact on managing cancer patients with fever and infection. In: DeVita VT, Lawrence TS, Rosenberg SA; Ovid Technologies Inc. Devita, Hellman, and Rosenberg’s cancer principles & practice of oncology. Philadelphia: Wolters Kluwer; 2015.

 See I, Freifeld AG, Magill SS. Causative organisms and associated antimicrobial resistance in healthcare-associated, central line-associated bloodstream infections from oncology settings, 2009-2012. Clin Infect Dis. 2016;62:1203-9.

 Gudiol C, Bodro M, Simonetti A, et al. Changing aetiology, clinical features, antimicrobial resistance, and outcomes of bloodstream infection in neutropenic cancer patients. Clin Microbiol Infect. 2013;19:474-9.

 Heidenreich D, Kreil S, Nolte F, et al. Allogeneic hematopoietic cell transplantation without fluconazole and fluoroquinolone prophylaxis. Ann Hematol. 2016;95:287-93.

 Ford CD, Lopansri BK, Haydoura S, et al. Frequency, risk factors, and outcomes of vancomycin-resistant Enterococcus colonization and infection in patients with newly diagnosed acute leukemia: different patterns in patients with acute myelogenous and acute lymphoblastic leukemia. Infect Control Hosp Epidemiol. 2015;36:47-53.

 Garnica M, Nouer SA, Pellegrino FL, et al. Ciprofloxacin prophylaxis in high risk neutropenic patients: effects on outcomes, antimicrobial therapy and resistance. BMC Infect Dis. 2013;13:356.

 Rangaraj G, Granwehr BP, Jiang Y, et al. Perils of quinolone exposure in cancer patients: breakthrough bacteremia with multidrug-resistant organisms. Cancer. 2010;116:967-73.

 Bow EJ. Fluoroquinolones, antimicrobial resistance and neutropenic cancer patients. Curr Opin Infect Dis. 2011;24:545-53.

 Macesic N, Morrissey CO, Cheng AC, et al. Changing microbial epidemiology in hematopoietic stem cell transplant recipients: increasing resistance over a 9-year period. Transpl Infect Dis. 2014;16:887-96.

 Loo VG, Poirier L, Miller MA, et al. A predominantly clonal multi-institutional outbreak of Clostridium difficile-associated diarrhea with high morbidity and mortality. N Engl J Med. 2005;353:2442-9.

 US Food and Drug Administration. Joint Meeting of the Antimicrobial Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee. The benefits and risks of systemic fluoroquinolone antibacterial drugs for the treatment of acute bacterial sinusitis (ABS), acute bacterial exacerbation of chronic bronchitis in patients who have chronic obstructive pulmonary disease (ABECB-COPD), and uncomplicated urinary tract infections (uUTI). November 5, 2015. 

http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Anti-InfectiveDrugsAdvisoryCommittee/UCM467383.pdf

 van der Velden WJ, Herbers AH, Netea MG, Blijlevens NM. Mucosal barrier injury, fever and infection in neutropenic patients with cancer: introducing the paradigm febrile mucositis. Br J Haematol. 2014;167:441-52.

 Baden LR, Bensinger W, Angarone M, et al. Prevention and treatment of cancer-related infections. J Natl Compr Canc Netw. 2012;10:1412-45.

 Slavin MA, Lingaratnam S, Mileshkin L, et al. Use of antibacterial prophylaxis for patients with neutropenia. Australian Consensus Guidelines 2011 Steering Committee. Intern Med J. 2011;41:102-9.

Current guidelines recommend antimicrobial prophylaxis with fluoroquinolones in patients at high risk for infection-related morbidity and mortality, but this practice provides a short-term benefit to individual patients. 

When to Use Prophylactic Antibiotics in Neutropenic Patients

Women with ductal carcinoma in situ (DCIS) are at risk for local recurrence and occurrence of a new primary in either breast following breast conservation therapy (BCT). Prevention of local recurrence or a new occurrence, particularly of invasive cancer, which, in principle, could metastasize, is a laudable goal. Many times, the physician concentrates on survival while the patients live with the fear of local recurrence every day, which is exacerbated by the side effects of treatment and follow-up screenings. Despite the much higher risk of local recurrence with lumpectomy and radiation compared with mastectomy, multiple retrospective studies and prospective randomized trials have established that survival is the same[1,2]; however, this may not be so for the individual patient, depending on the type of recurrence. Approximately half of recurrences are invasive disease and are more likely to occur in young women and those with high nuclear grade histology. Salvage mastectomy after BCT with radiation for an invasive recurrence results in a 10-year overall cause-specific survival rate of 95%. The European Organisation for Research and Treatment of Cancer (EORTC) 10853 trial reported that the hazard of dying after an invasive recurrence was five times higher compared with no local recurrence. The National Surgical Adjuvant Breast and Bowel Project (NSABP) B-17 trial reported a hazard ratio for breast cancer death after recurrence of 7.06, with a 10-year probability of breast cancer death of 10.4%.[1]

Disease recurrence is even higher in patients with DCIS who undergo lumpectomy without radiation.[3] In a recent Surveillance, Epidemiology, and End Results (SEER) study of local recurrence after treatment for DCIS, 69.5% of patients underwent BCT but only 43% were treated with radiotherapy.[4] As per multiple prospective randomized trials, there is no doubt that when conserving the breast, adjuvant radiation decreases local recurrence (16% absolute reduction and 50% relative risk at 10 years, collectively). The addition of an antiestrogen decreases local recurrence and recurrences elsewhere, but has no effect on survival.[1-6] In the NSABP B-24 trial, which was a follow-up to the B-17 trial, patients undergoing BCT with radiation were randomized to receive 5 years of tamoxifen vs placebo. After a median follow-up of 163 months, the absolute reduction in local recurrence was significant for invasive recurrence (9% vs 6.6%) but not for in situ recurrence (7.6% vs 6.7%). The rate of contralateral breast cancer was reduced from 8.1% to 4.9% with the use of tamoxifen (

 = .0231). Last year, the Radiation Therapy Oncology Group (RTOG) 9804 study found that in favorable tumors with 7-year follow-up, the local failure rate was 0.9% with radiation and 6.7% in the observation arm.[7] However, overall survival was similar in both arms. Still, most patients did not benefit from the addition of radiation.

Patients are increasingly choosing mastectomy, including contralateral mastectomy.[8] Some would consider lumpectomy alone to be undertreatment and bilateral mastectomy, overtreatment. Recent predictive tools utilizing pathologic and molecular markers, as well as prospective trials, have failed to identify a group that does not benefit from radiation, although such studies can differentiate who will benefit the most. Young age, estrogen and progesterone receptor negativity, HER2/

 gene amplification, p21 positivity, and increasing pathologic size (difficult to measure accurately), as well as close or positive margins, all increase the risk of recurrence. The NSABP B-17 and EORTC 10853 randomized trials, the international collaborative DCIS study, the University of Southern California/Van Nuys experience, and others reported an increased risk of local recurrence in patients with close or positive surgical margins.[1-3,9-11] Recently, a consensus panel on DCIS performed a study-level meta-analysis-which was based on a meta-analysis and sponsored by the Society of Surgical Oncology and the American Society for Radiation Oncology-of the relationship between margin distance and local recurrence. The groups looked at women older than 50 years with DCIS undergoing BCT, and at local recurrence rates by numeric margin, with a follow-up of more than 4 years (20 studies were reviewed, with a total of 7,883 patients and 865 local recurrences). Median follow-up was 78.3 months, and 71% of patients had whole-breast radiation. The odds ratios relative to positive margins for 2 mm (0.32), 3 mm (0.30), and 10 mm (0.32) showed similar reductions in the odds of local recurrence, which was greater for positive margins > 0 or 1 mm (0.45).[12] Clearly, no tumor on ink is not sufficient for DCIS.

A multigene expression assay, the Oncotype DX DCIS Score, has also been developed to assist in decision making for DCIS patients and to assess the risk of local recurrence based on tumor genotype.[13,14] According to two validation studies, the Oncotype DX DCIS Score provides a probability of 10-year risk of any breast recurrence (DCIS or invasive), as well as invasive recurrence among women undergoing BCT alone.

Considerable effort has been made to improve the choices available to patients with DCIS. Hypofractionated whole-breast radiation and partial breast irradiation can be used in women with favorable risk factors. We have published work on the utilization of glutamine to prevent radiation injury and post-radiation pain.[15] In addition, we have studied the utilization of intracavitary hyperthermia (via radiofrequency) in favorable tumors as an alternative to radiation, which adds an additional 1-cm sterilization of the tumor bed to the lumpectomy procedure (similar to radiation), while maintaining a pristine breast for salvage procedures, if necessary.[16] We have also published work describing improved methods and cosmesis for bilateral total skin-sparing mastectomy, even for salvage treatment after radiation.[17] Research must continue to define risk-benefit categories in order to improve existing treatments and develop better alternative treatments.

Others have suggested that follow-up for patients diagnosed with DCIS should be performed with core needle biopsy. However, a systematic review and meta-analysis of local recurrence rates for DCIS showed that the 10-year local recurrence rate was 3% for mastectomy, 13% for BCT with radiation, and 25% for BCT alone vs 36% for core needle biopsy alone.[18] This is problematic at the present time, as our imaging and biopsy procedures are not 100% accurate. I believe that it is the patient’s choice, since we are treating the whole patient and not just her breasts. Thus, our job as clinicians is to educate patients on their risks and choices as best we can, and to take into consideration their preferences, as well as their social situation in terms of their ability to reliably adhere to follow up. I would not attempt to determine what kind of surgery a patient should have until I have completely understood her preferences. This should be the goal of all surgeons, but sometimes we let data get in the way instead of having it lead the way.

The author has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

 Wapnir IL, Dignam JJ, Fisher B, et al. Long-term outcomes of invasive ipsilateral breast tumor recurrences after lumpectomy in NSABP B-17 and B-24 randomized clinical trials for DCIS. J Natl Cancer Inst. 2011;103:478-88.

 Donker M, LitiÃ¨re S, Werutsky G, et al. Breast-conserving treatment with or without radiotherapy in ductal carcinoma in situ: 15-year recurrence rates and outcome after a recurrence, from the EORTC 10853 randomized phase III trial. J Clin Oncol. 2013;31:4054-9.

 Virnig BA, Wang SY, Shamilyan T, et al. Ductal carcinoma in situ: risk factors and impact of screening. J Natl Cancer Inst Monogr. 2010;2010:113-6.

 Worni M, Akushevich I, Greenup R, et al. Trends in treatment patterns and outcomes for ductal carcinoma in situ. J Natl Cancer Inst. 2015;107:djv263.

 Cuzick J, Sestak I, Pinder SE, et al. Effect of tamoxifen and radiotherapy in women with locally excised ductal carcinoma in situ: long-term results from the UK/ANZ DCIS trial. Lancet Oncol. 2011;12:21-9.

 WÃ¤rnberg F, Garmo H, Emdin S, et al. Effect of radiotherapy after breast-conserving surgery for ductal carcinoma in situ: 20 years follow-up in the randomized SweDCIS trial. J Clin Oncol. 2014;32:3613-8.

 McCormick B, Winter K, Hudis C, et al. RTOG 9804: a prospective randomized trial for good-risk ductal carcinoma in situ comparing radiotherapy with observation. J Clin Oncol. 2015;33:709-15.

 Hoskin TL, Hieken TJ, Degnim AC, et al. Use of immediate breast reconstruction and choice for contralateral prophylactic mastectomy. Surgery. 2016;159:1199-209.

 Emdin SO, Granstrand B, Ringberg A, et al. SweDCIS: radiotherapy after sector resection for ductal carcinoma in situ of the breast. Results of a randomised trial in a population offered mammography screening. Acta Oncol. 2006;45:536-43.

 Early Breast Cancer Trialists’ Collaborative Group (EBCTCG); Correa C, McGale P, Taylor C, et al. Overview of the randomized trials of radiotherapy in ductal carcinoma in situ of the breast. J Natl Cancer Inst Monogr. 2010;2010:162-77.

 Silverstein MJ, Lagios MD. Treatment selection for patients with ductal carcinoma in situ (DCIS) of the breast using the University of Southern California/Van Nuys (USC/VNPI) prognostic index. Breast J. 2015;21:127-32.

 Marinovich ML, Azizi L, Macaskill P, et al. The association of surgical margins and local recurrence in women with DCIS with breast conservation therapy: a meta-analysis. J Clin Oncol. 2016;34(suppl):abstr 1020.

 Solin LJ, Gray R, Baehner FL, et al. A multigene expression assay to predict local recurrence risk for ductal carcinoma in situ of the breast. J Natl Cancer Inst. 2013;105:701-10.

 Rakovitch E, Nofech-Mozes S, Hanna W, et al. A population-based validation study of the DCIS score predicting recurrence risk in individuals treated by breast-conserving surgery alone. Breast Cancer Res Treat. 2015;152:389-98.

 Rubio I, Suva LJ, Todorova V, et al. Oral glutamine reduces radiation morbidity in breast conservation surgery. J Parenter Enteral Nutr. 2013;37:623-30.

 Klimberg VS, Ochoa D, Henry-Tillman R, et al. Long-term results of phase II ablation after breast lumpectomy added to extend intraoperative margins (ABLATE I) trial. J Am Coll Surg. 2014;218:741-9.

 Boneti C, Yuen J, Santiago C, et al. Oncologic safety of nipple skin-sparing or total skin-sparing mastectomies with immediate reconstruction. J Am Coll Surg. 2011;212:686-93.

 Stuart KE, Houssami N, Taylor R, et al. Long-term outcomes of ductal carcinoma in situ of the breast: a systematic review, meta-analysis and meta-regression analysis. BMC Cancer. 2015;15:890.

Despite the much higher risk of local recurrence with lumpectomy and radiation compared with mastectomy, multiple retrospective studies and prospective randomized trials have established that survival is the same; however, this may not be so for the individual patient, depending on the type of recurrence.

Data on Ductal Carcinoma In Situ Encumbered by Opinion

. Earlier this year, both the US Preventive Services Task Force and the American Cancer Society changed their recommendations, saying that women should begin annual breast cancer screening at age 45, instead of 40. Is there concern that this change will affect early detection and, subsequently, outcomes for the disease?

 These guidelines make sense for the average woman. The data support these changes to the guidelines. However, there is a lot of anxiety on the part of women that this kind of change will leave them at risk. The lack of consensus on the guidelines contributes to this concern. The task force guidelines recommend that women in their 40s have a conversation with their primary physician to assess their risk, as well as discuss the pros and cons of screening, and make an informed choice. The problem is that we do not have standards for breast cancer risk assessment. One size does not fit all! We now know that breast cancer is not one disease, but rather many diseases-some that grow quickly and others that are so slow growing that they may never come to clinical attention. We do not treat these conditions the same, so it does not make sense that we screen for them in the same way. However, today, the only real risk stratification we use is age. What we need is a modern-era trial that helps us build the evidence for the optimal screening method. The WISDOM study (

easures of risk; ClinicalTrials.gov identifier: NCT02620852) is a Patient-Centered Outcomes Research Institute–funded effort from the Athena Breast Health Network that is comparing personalized screening (based on inherited factors-including 9 genes and about 200 single nucleotide polymorphisms-breast density, exposures, and lifestyle) with annual screening starting at age 40. In the personalized arm, we will assign women based on their risk, an age to start and stop, and frequency and modality for screening. We will learn who is at risk for what kind of cancer, and determine if this new approach is just as safe, less morbid (fewer recalls, false-positive biopsies), preferred by women, and whether it promotes prevention. This is an important step forward. It will be open to women across California this year, and across many sites in the United States the following year.

In prostate cancer, there has been a similar controversy, largely due to the high frequency of small tumors in healthy men, which commonly do not grow or cause problems in a man’s lifetime. If screening with the prostate-specific antigen (PSA) blood test is conducted, and all men with any degree of suspicion undergo biopsy, and then if all these men are treated, there will almost certainly be men in whom a prostate cancer death will be prevented, but far more men will be treated unnecessarily. However, with the development of methods to incorporate a range of factors (eg, age, family history, PSA, rectal examination findings, other more sophisticated detection tests, and even genomic factors), we can better predict who is most likely to harbor an aggressive tumor, then perform a biopsy, and, if an aggressive tumor is confirmed, treat him to prevent death. The previous large-scale screening studies showed a reduction in mortality (in the European study[1]), but no change in the US trial, probably due to the high PSA testing rate in men who were not in the PSA testing arm of the US study.[2] What we simply don’t know now is whether implementing screening and treatment, targeted for tumors that are most likely to take a man’s life, will maintain the dramatic fall in prostate cancer death rates that we’ve seen over the past 20 years. Ideally, a study similar to the WISDOM study in breast cancer ought to be conducted for prostate cancer.

 Lately, there has been a lot of discussion around reclassifying certain early-stage cancers, so that they aren’t actually considered “cancer” anymore. How do you currently approach these indolent tumors in your practice?

 We have validated an “ultra-low-risk” threshold on the 70-gene test for invasive cancers in postmenopausal women that shows that there are tumors with very low risk of metastatic recurrence after surgical excision alone. This is for cancers that appear as clinical masses. Finding these early would not improve the chance of survival, since the survival rate of these cancers is already high. So, precursors of these cancers certainly do not need to be found early. It is likely that many cases of ductal carcinoma in situ (DCIS) are precursors of such cancers. DCIS is certainly not an emergency, and depending on the clinical circumstance (if it is hormone receptor–positive), it is possible to try alternatives to surgical excision as a first step. These include watchful waiting or endocrine risk reduction (tamoxifen, if premenopausal, or raloxifene or an aromatase inhibitor, if postmenopausal). There are a number of trials starting around the world (LORD and LORIS in the Netherlands and the United Kingdom, respectively, and COMET in the United States, as well as a registry through the Athena Breast Health Network[3-5]) that are testing alternative approaches to surgery. We have treated DCIS the same way for over 2 decades and have not made much progress in advancing treatment options. We need to learn a lesson from our colleagues in prostate cancer, who took low-risk prostate cancer and offered watch-and-wait options with excellent results at 10 years, changing the standard approach to the management of Gleason 3+3 prostate cancer. The lesson is that if you don’t try a different approach, you can not improve treatment options.

In prostate cancer, we have seen a dramatic change in the management of early-stage tumors. Low-grade, low-volume tumors, which are the most common in American men, are increasingly managed with active surveillance. In this approach, low-grade tumors are monitored carefully, and treatment is reserved for those men who develop signs suggesting that the tumor may cause them harm. In so doing, over half of men may be spared treatment. Increasingly, we are also developing methods, similar to those for screening, which incorporate a range of factors that will predict high-risk tumors, and will personalize follow-up to the tumor’s risk in an individual patient. As such, follow-up may be more intense in a younger man and less frequent in an older man in whom the risk of disease progression at 15 to 20 years is a lesser concern.

 Treating breast cancer and prostate cancer no longer follows a one-size-fits-all approach, given the recent advances in genetics and genomics. In what areas do you think additional progress toward individualized therapy is still needed?

 We need to find better treatments for the highest-risk breast cancers. Women who have fast-growing cancers are not helped with screening. These cancers often arise between normal screens. Thus, we have to optimize treatment. One way of doing so is to start with systemic therapy first (neoadjuvant therapy), learning how tumors respond to treatment. In this setting, new agents can be introduced in the neoadjuvant period, and evaluated for the likelihood of improving the chance that the tumor will completely disappear with treatment. If tumors are eradicated in this treatment period, the chance of survival is much higher. The I-SPY 2 Trial is an example of how to accelerate that chance by testing new agents and combinations in the early high-risk setting[6,7] to discover which tumor types will benefit from which regimens, and therefore will have the greatest chance of success in a small targeted, confirmatory, phase III trial. Once we have improved treatments and better understand the pathways that are targeted, we can work on prevention (by learning who is at risk for what kind of cancer, eg, in the WISDOM study).

 In prostate cancer, unlike breast cancer, while there appears to be genetic risk factors, there seems to be a broad range of genetic variants that play a role. More common variants may only slightly increase the risk, and those variants that may have a higher risk are generally seen in only a small percentage of the population. A better method may not be the traditional constitutional genetic approach, but rather to assess genetic changes within the prostate. Even more impressive than our growing ability to examine circulating DNA is our ability to capture prostatic cells from voided urine and then perform detailed genetic analyses. These new methods must be incorporated into carefully designed early detection clinical trials to avoid the substantial biases that are often seen in studies that use “samples of convenience,” which are often collected without regard for selection biases that can confound conclusions.

 Despite evidence that many early-stage breast tumors are not aggressive, many women are still choosing to have mastectomies in order to prevent future disease recurrence. What do you think is the main reason for patients making this kind of treatment decision, and how can clinicians help their patients avoid overtreatment?

 Women are mostly motivated by fear. They are afraid that not taking action will result in them dying of their disease. As we develop better markers that can help us classify tumors as ultra-low-risk, and as we have more confidence in such tests, clinicians can help women feel more comfortable being less aggressive in their treatment selection. Initially, this may be difficult to change, because such an approach is time intensive and most physicians are rewarded for intervening and not taking any risk. However, when the risk is very low, we do a disservice to our patients by not pushing for better, more tailored treatments. Why not just do everything? Because all treatments have complications and side effects. A mastectomy can be psychologically difficult for women, complications from surgery can lead to chronic pain, and reconstructions can result in complications as well, and rarely look as good as the native breast. If treatment is not needed, all of the complications can be avoided. We can learn from the experiences of our colleagues in prostate cancer and perhaps use that to help us make a change in breast cancer.

A man with a low-grade, low-volume prostate cancer, when sitting in a physician’s office, may hear the words, “your biopsy showed prostate cancer,” and ignore the remainder of the conversation as they think about the impact of their cancer diagnosis. What many of us incorporate into our practice is a discussion of the possible outcomes of biopsy 

 it is performed. Thus, a man who receives the information is pre-educated that one of the outcomes could be a low-grade, low-volume tumor, which is often optimally managed with surveillance. Because of the sexual, urinary, gastrointestinal, and other side effects that can be seen with treatment, it is imperative that, at every step along the way in early detection of disease, men undergoing screening are aware of the implications of the findings 

. This approach mitigates the cancer anxiety and allows a better-educated patient to use his own priorities to make an informed decision that is best for him.

SchrÃ¶der FH, Hugosson J, Roobol MJ, et al. Screening and prostate cancer mortality: results of the European Randomised Study of Screening for Prostate Cancer (ERSPC) at 13 years of follow-up. Lancet. 2014;384:2027-35.

Shoag JE, Mittal S, Hu JC. Reevaluating PSA testing rates in the PLCO trial. N Engl J Med. 2016;374:1795-6.

 Elshof LE, Tryfonidis K, Slaets L, et al. Feasibility of a prospective, randomised, open-label, international multicentre, phase III, non-inferiority trial to assess the safety of active surveillance for low risk ductal carcinoma in situ-The LORD study. Eur J Cancer. 2015;51:1497-510.

 Francis A, Thomas J, Fallowfield L, et al. Addressing overtreatment of screen detected DCIS; the LORIS trial. Eur J Cancer. 2015;51:2296-303.

 Patient-Centered Outcomes Research Institute. Comparison of Operative versus Medical Endocrine Therapy for Low Risk DCIS: the COMET trial. 

http://www.pcori.org/research-results/2016/comparison-operative-versus-medical-endocrine-therapy-low-risk-dcis-comet

 Park JW, Liu MC, Yee D, et al. Adaptive randomization of neratinib in early breast cancer. N Engl J Med. 2016;375:11-22.

 Rugo HS, Olopade OI, DeMichele A, et al. Adaptive randomization of veliparib-carboplatin treatment in breast cancer. N Engl J Med. 2016;375:23-34.

In this interview we review recent breast cancer screening guidelines from the ACS and USPSTF, and discuss the changing way that early-stage breast and prostate cancers are being treated.

Laura Esserman and Ian Thompson Discuss Strategies for Screening and Treatment of Early-Stage Cancers, and How Clinicians Can Learn From Each Other’s Experiences

Prior to the advent of targeted therapies, there were few options other than chemotherapy for the treatment of patients with indolent B-cell lymphomas or chronic lymphocytic leukemia (CLL). Although chemotherapy could yield clinical responses, which improved when treatment was combined with anti-CD20 monoclonal antibodies-so-called chemoimmunotherapy[1]-it also could compromise bone marrow function and cause toxicities that were poorly tolerated by elderly patients.[2] Moreover, chemotherapy alone was not curative. Instead, patients generally relapsed after therapy, often developing disease that had acquired inactivating mutations in genes such as 

, which allowed their disease to become resistant to repeated use of chemotherapy. Because of this, and because of the large variation noted in the pace of disease progression among patients, therapy generally was not recommended unless a patient developed disease-related symptoms or complications. In this issue of ONCOLOGY, Drs. Choe and Ruan provide an excellent review of the emerging targeted therapies that can overcome the aforementioned problems.[3] By targeting kinases involved in B-cell receptor (BCR) signaling, or the anti-apoptotic protein B-cell lymphoma-2 (BCL-2), these newer drugs generally do not cause myelotoxicity, and may be effective even in patients with lymphomas that lack functional 

. It is certain that the advent of such targeted therapies has significantly improved the outlook for many patients with indolent non-Hodgkin lymphoma or CLL. Despite such advances, there still appears to be a role for chemoimmunotherapy in the management of patients with indolent lymphomas or CLL. For example, patients with CLL cells that have mutated 

 genes or that lack certain cytogenetic features, such as 17p deletion or 11q deletion, may respond well to chemoimmunotherapy and experience remissions lasting more than 5 years.[4-6] Also, some patients may not be inclined to make a commitment to treatment with targeted therapies for the remainder of their lives, or they may decide to discontinue targeted therapy upon experiencing side effects that become intolerable over time. It also is not established with certainty that the tolerability and durability of ibrutinib will be superior to results achieved with chemoimmunotherapy, at least for all patients, given that data on patients with CLL and small lymphocytic lymphoma treated for more than 4 years are currently lacking.[7] Therefore, when deciding on a course of therapy, it is important to consider an individual patient’s disease biology, as well as clinical and even social characteristics. Patients who desire therapy with a limited duration, or those who achieve a long-lasting remission without the need for continuous treatment, may find chemoimmunotherapy more attractive than the currently available targeted therapies. Ultimately, important information will be gained from comparative trials and exploratory studies investigating rational drug sequencing of these agents.

The value of using targeted therapy earlier in the management of patients with indolent lymphomas is uncertain. An ongoing phase III clinical trial will compare the outcomes of CLL patients with high-risk features, such as expression of 70-kDa zeta-associated protein (ZAP-70) or adverse cytogenetics, when they are treated with ibrutinib early vs when ibrutinib is initiated based on current treatment guidelines.[8] Until this question is resolved, it is recommended that patients be treated with ibrutinib or other targeted therapies when they become symptomatic or have disease-related complications, or if there is clear evidence of more rapid disease progression. There is significant interest in determining how to rationally combine or sequence targeted agents with existing therapies for lymphoma. The BCL-2 inhibitor venetoclax has been studied in combination with anti-CD20 monoclonal antibodies and with chemoimmunotherapy. Similarly, trials are exploring the use of BCR signaling inhibitors in conjunction with chemoimmunotherapy. Some investigators are testing whether it would be preferable for targeted therapies to be sequenced, rather than combined, in the management of CLL-for example, using BCR signaling inhibitors or chemoimmunotherapy to debulk the disease, followed by administration of a BCL-2 inhibitor to achieve a minimal residual disease–negative remission that might ultimately allow the patient to discontinue treatment altogether. There is also the possibility that targeted therapies by themselves may not be curative and that patients may develop resistance to these agents over time. Patients with resistance to ibrutinib appear to have a very poor prognosis, with a median survival of 3.1 months reported in one study.[9] Mutations in 

 have been found to account for some cases of ibrutinib resistance.[10,11] However, other mechanisms by which disease resistance or persistence may develop after treatment with ibrutinib, idelalisib, or venetoclax have not yet been elucidated. It also is likely that selected targeted agents used in the treatment of CLL may activate alternative signaling pathways that can serve as escape mechanisms. It is critical that we continue our study of the biology of these diseases to help define the optimal use of these agents.

Dr. Choi has received research funding from, and participated in advisory boards for, AbbVie and Pharmacyclics; he has also participated in a speakers bureau for Gilead. Dr. Kipps has received research funding from AbbVie; provided consultancy for AbbVie, Gilead, and Pharmacyclics; and participated in a speakers bureau for Gilead

 Hallek M, Fischer K, Fingerle-Rowson G, et al. Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial. Lancet. 2010;376:1164-74.

 Strati P, Wierda W, Burger J, et al. Myelosuppression after frontline fludarabine, cyclophosphamide, and rituximab in patients with chronic lymphocytic leukemia: analysis of persistent and new-onset cytopenia. Cancer. 2013;119:3805-11.

 Choe H, Ruan J. Next generation of targeted molecules for non-Hodgkin lymphomas: small-molecule inhibitors of intracellular targets and signaling pathways. Oncology (Williston Park). 2016;30:847-58.

 Fischer K, Bahlo J, Fink AM, et al. Long-term remissions after FCR chemoimmunotherapy in previously untreated patients with CLL: updated results of the CLL8 trial. Blood. 2016;127:208-15.

 Rossi D, Terzi-di-Bergamo L, De Paoli L, et al. Molecular prediction of durable remission after first-line fludarabine-cyclophosphamide-rituximab in chronic lymphocytic leukemia. Blood. 2015;126:1921-4.

 Thompson PA, Tam CS, O’Brien SM, et al. Fludarabine, cyclophosphamide, and rituximab treatment achieves long-term disease-free survival in IGHV-mutated chronic lymphocytic leukemia. Blood. 2016;127:303-9.

 Byrd JC, Furman RR, Coutre SE, et al. Three-year follow-up of treatment-naive and previously treated patients with CLL and SLL receiving single-agent ibrutinib. Blood. 2015;125:2497-506.

 Langerbeins P, Bahlo J, Rhein C, et al. Ibrutinib in early stage CLL: preliminary safety results of a placebo controlled phase III study. Blood. 2015;126(suppl 23):abstr 2934.

 Jain P, Keating M, Wierda W, et al. Outcomes of patients with chronic lymphocytic leukemia after discontinuing ibrutinib. Blood. 2015;125:2062-7.

 Furman RR, Cheng S, Lu P, et al. Ibrutinib resistance in chronic lymphocytic leukemia. N Engl J Med. 2014;370:2352-4.

 Woyach JA, Furman RR, Liu TM, et al. Resistance mechanisms for the Bruton’s tyrosine kinase inhibitor ibrutinib. N Engl J Med. 2014;370:2286-94.

Prior to the advent of targeted therapies, there were few options other than chemotherapy for the treatment of patients with indolent B-cell lymphomas or chronic lymphocytic leukemia.

Oncology Vol 30 No 9

Ready, Fire, Aim: Addressing Issues Associated With Multigene Panel Testing for Cancer Susceptibility

When to Use Prophylactic Antibiotics in Neutropenic Patients

Data on Ductal Carcinoma In Situ Encumbered by Opinion

Laura Esserman and Ian Thompson Discuss Strategies for Screening and Treatment of Early-Stage Cancers, and How Clinicians Can Learn From Each Other’s Experiences

How Do Targeted Therapies Change the Management of Indolent Lymphomas?