Hereditary cancer risk assessment has grown from a limited concentration on a few well-described tumors and genetic mutations to an ever-widening understanding of cancer syndromes encompassing multiple tumor types across multiple generations. The identification of an increasing number of genetic abnormalities and the advances in our understanding of the role of genetics in the risk of developing a cancer have created new opportunities to impact patient care. Primary prevention (the possibility of changing outcomes associated with risk) and secondary prevention (the ability to identify cancers at earlier stages, with the goal of intervening at a time at which outcomes can be changed in a meaningful way) are becoming more of a reality as it becomes possible to recognize hereditary cancer syndromes.

With the advent of more accessible testing come challenges of maintaining rigor when defining and categorizing results and determining their significance. The broadening of our definitions of risk has already led to inclusion criteria that did not previously exist, such as the association of 

 mutations with an increased risk of ductal carcinoma in situ and triple-negative breast cancer.[1] Further refinements in our understanding of the relationship between specific disease biology and germline genetics will result in new associations between types of cancer and risk.

Newly identified genetic mutations associated with hereditary cancer syndromes have recently been classified into levels of risk. Specific gene mutations are associated with high or moderate risk, and society guidelines have acknowledged these risk levels and made varying recommendations for screening and prevention. At the same time, however, we have come to recognize that not all similarly identified genetic mutations have the previously ascribed clinical risk. General wisdom, supported by the literature, was that 

 mutations were highly penetrant, with the associated Li-Fraumeni syndrome resulting in diffuse and severe clinical cancer throughout the affected family-although it was acknowledged that this diagnosis, while serious, was quite rare. The widespread use of multigene panel testing has raised doubts about the preceding description being the single pattern of the gene’s expression. More cases of 

 mutations are being identified, and the familial patterns observed often differ from the traditional one. Also as a result of more widespread use of multigene panel testing, we are beginning to elucidate specific genetic syndromes in which we can predict phenotype on the basis of specific genotype, such as with the varying mutations in mismatch repair genes seen in Lynch syndrome. The collection of more data in a controlled, organized manner will allow us to continue to perfect our understanding of the effects of particular genetic mutations on specific organs. There are already several areas in which we have begun to see this: 1) in crossover syndromes, where genetic mutations originally regarded as causing cancer in one set of organs now, with the collection of more data via multigene panel testing, have been shown to increase cancer risk in organs not previously thought to be involved (eg, the apparent increase in breast cancer risk in patients with mutated 

[2]); and 2) in associations of new cancers with previously established gene patterns (eg, the presence of a high risk of uterine cancer in some 

 patients, as described recently by Shu[3]).

To determine how best to approach population risk analysis, we must look critically at our current risk models. Models such as Tyrer-Cuzick, BRCAPRO, Gail, and Claus take different factors into consideration and place differing emphases on those factors identified in multiple models. Typically, women above a defined threshold are deemed high-risk; however, using a continuum is a more appropriate approach to risk analysis, given that the models target specific populations and have not been validated in all populations or for all individuals.

As practicing clinicians, we often encounter situations where a patient is dropped into one or another “risk bucket” by the risk model calculation, yet our clinical judgment leads us to differ with this determination for that individual. Additionally, outcome data are often lacking for the generally accepted screening recommendations.

The development of a consensus in the medical community with regard to risk evaluation and medical management requires solid clinical data and will take time. New associations between genes and cancer risk will be identified, new mutations will be discovered, the significance of mutations already identified will be updated, and cofactors will be elucidated. From this bank of information, gene expressions can be tracked, interventions can be explored and validated, and ultimately, outcome studies of overall survival can be performed. Until these things are accomplished, we must rely on practiced clinical judgment.

Genetic testing is becoming commonplace. Practitioners from many medical specialties are ordering tests and making recommendations to patients. Testing in the United States is regularly ordered by gynecologists, primary care and family practice physicians, medical oncologists, surgical oncologists, genetic counselors, mid-level providers, and some radiology facilities. Each of these specialties serves patients and populations that may benefit from risk analysis and genetic testing. The challenge is to be sure that those offered testing are appropriate candidates, are counseled knowledgably, and, importantly, are afforded clinical follow-up once their risk level is determined. We have seen the heartbreak of situations where well-intentioned clinicians have offered testing in a medical setting without adequate follow-up in place.

Testing by medical providers is good when appropriate, but those ordering the testing need to understand the implications and have the ability to execute a plan of care. Genetic counselors are helpful in certain situations when available, but genetic counselors are not clinicians and do not have the ability to provide patient care-and sending the patient back to the referring physician is only adequate if that physician is versed in care of the particular clinical syndrome involved and knowledgeable about the associated risk. A clear and appropriate plan must be in place for the patient’s clinical follow-up. The challenge is to make appropriate risk assessment and genetic testing widely available, and also to give proper attention to the results. The ideal would be a coordinated team approach that includes clinicians, genetic counselors, and the patient’s medical providers, but this arrangement is a luxury found in only a few places in our country.

For some time, genetic testing has been predictive and prognostic. It is now assuming a therapeutic role as well. An example is the targeting of breast cancer patients with 

 mutations for treatment with poly (ADP-ribose) polymerase (PARP) inhibitors. This is the tip of the iceberg. Targeted cancer therapy, determined by an understanding of the genetics of the particular tumors involved, is on the horizon. Moreover, it is not too far in the future that whole-genome testing will be a reality. This will have enormous therapeutic potential and will open new avenues of thought, based on a better understanding of ourselves and disease processes. Use of the information gleaned from whole-genome testing will depend on the integrity of the scientific and medical communities, and preparations need to be put in place to handle this information in the best way possible for each individual patient.

Dr. Smith has served on the Speakers Bureau for Myriad Genetics. Ms. Sin has no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article. 

 National Comprehensive Cancer Network. Genetic/familial high-risk assessment: breast and ovarian. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). Version 2.2016. 

http://www.nccn.org/professionals/physician_gls/pdf/genetics_screening.pdf

 ten Broeke SW, Brohet RM, Tops CM, et al. Lynch syndrome caused by germline PMS2 mutations: delineating the cancer risk. J Clin Oncol. 2014;33:319-25.

 Shu CA, Pike MC, Jotwani AR, et al. Uterine cancer after risk-reducing salpingo-oophorectomy without hysterectomy in women with BRCA mutations. JAMA Oncol. 2016 Jun 30. [Epub ahead of print]

Articles

For some time, genetic testing has been predictive and prognostic. It is now assuming a therapeutic role as well. An example is the targeting of breast cancer patients with BRCA mutations for treatment with PARP inhibitors.

Clinical Hereditary Cancer Syndromes and Gene Panel Testing

Hematologic complications are routinely encountered in the management of cancer patients. Patients with cancer are up to 7 times more likely to develop a venous thromboembolism (VTE) compared with those without a diagnosis of cancer.[1] Furthermore, VTE is a leading cause of mortality in cancer patients, and contributes to increased morbidity and cost of care.[2-4] The management of cancer-associated thrombosis is especially challenging because of the simultaneous increased risk of bleeding observed in patients who receive anticoagulation.[5-7] Due to the delicate hemostatic balance in cancer patients, an understanding of both the clotting and bleeding risks in this population is crucial to effectively manage hematologic complications.

A 70-year-old man with recently diagnosed metastatic pancreatic cancer, currently receiving his second cycle of gemcitabine and nab-paclitaxel, is seen for follow-up. On exam, swelling and tenderness in the left calf is noted, and an emergent lower extremity ultrasound confirms the presence of a deep vein thrombosis (DVT). The patient’s creatinine level is 0.75 mg/dL (estimated glomerular filtration rate > 60 mL/min). The initiation of therapeutic anticoagulation with enoxaparin is recommended; however, the patient is very hesitant to perform daily injections and asks about the new oral anticoagulants he has seen advertised on television.

What is the recommended anticoagulant for cancer patients?

The most recent guidelines from the American Society of Clinical Oncology (ASCO)[8] and the American College of Chest Physicians[9] state that low-molecular-weight heparin (LMWH) remains the standard of care for management of thrombosis in cancer patients without severe renal impairment. This recommendation is based on evidence from the CLOT trial, which demonstrated a decrease in the risk of recurrent VTE (hazard ratio [HR], 0.48; 

 = .002) in dalteparin-treated patients compared with warfarin-treated patients, with no difference in either major bleeding rates or mortality.[10] Post-hoc analysis of this study revealed a survival benefit in the subgroup of patients without metastatic disease (HR for death at 12 months, 0.50 [95% CI, 0.27–0.95]; 

 = .03).[11] There have been no randomized studies directly comparing the different LMWH formulations with each other, or with fondaparinux.

Is there a role for DOACs in the treatment of VTE in cancer patients?

Although direct oral anticoagulants (DOACs) are an attractive option for some, they are not currently recommended for routine use in cancer patients, since they have not been directly compared with LMWH in prospective randomized clinical studies. The phase III randomized studies evaluating the safety and efficacy of the DOACs all used a comparator arm of vitamin K antagonists (VKAs), and only included a small proportion of highly selected cancer patients (Tables 1 and 2). A meta-analysis of 2,310 cancer patients from 9 separate randomized trials evaluating LMWH vs VKAs or DOACs vs VKAs found that treatment with LMWH resulted in a significant reduction in recurrent VTE compared with VKAs (relative risk [RR], 0.52 [95% CI, 0.36–0.74]), while treatment with DOACs compared with VKAs did not (RR, 0.66 [95% CI, 0.39–1.11]).[12] In a meta-analysis of the cancer patients enrolled in six of the phase III DOAC trials, the DOAC group had a significantly lower rate of recurrence compared with the VKA group (RR, 0.57 [95% CI, 0.36–0.91]; 

 = .02), without a significant increase in the rate of major bleeding (RR, 0.77 [95% CI, 0.44–1.33]; 

 = .35).[13] However, another meta-analysis found no difference in recurrence rates of VTE between the DOAC- and VKA-treated cancer patients (odds ratio, 0.63 [95% CI, 0.37–1.10]).[14] Pooled results of cancer patients enrolled in the phase III studies of dabigatran vs VKAs showed no difference in recurrent VTE or major bleeding rates.[15] Notably, the cancer patients included in these trials likely had a more favorable cancer prognosis (patients with a poor prognosis or those requiring long-term anticoagulation were excluded from these studies), which may have contributed to the observed effects. This is reflected in the overall lower recurrence rates observed in the VKA-treated groups in the DOAC trials (5.9%)[13] compared with the CLOT trial (11%).[10] No randomized controlled studies directly comparing DOACs with LMWH have been published thus far; however, there is an ongoing multicenter randomized study of edoxaban vs dalteparin in cancer patients (ClinicalTrials.gov identifier: NCT02073682).

In summary, LMWH remains the standard of care in cancer patients without significant renal impairment. Although the emerging data on DOACs in cancer patients are encouraging, further prospective studies comparing the efficacy and safety of DOACs with LMWH in this population are warranted before these agents can be routinely recommended. In patients who refuse injections or who are unable to receive LMWH for other reasons, VKAs or DOACs can be considered, with the understanding that data to support their use in this setting are limited. The choice between these oral agents will be dependent on factors including renal function, cost, and patient preference, and should ultimately involve a discussion with the patient on the risks and benefits of each particular option.

A 63-year-old heavy smoker is admitted to the hospital with a new diagnosis of metastatic lung adenocarcinoma. On admission he reports new chest pain and is hypoxic. Further workup reveals bilateral pulmonary emboli. His staging brain MRI also reveals multiple nonhemorrhagic metastatic lesions scattered throughout the brain.

What is the risk of intracranial hemorrhage in patients with brain metastases who receive therapeutic anticoagulation? What is the recommended management in this setting?

The management of VTE in cancer patients with intracranial metastasis is challenging because of the tenuous balance between clotting and bleeding, and the limited data to support the safety of anticoagulation in this setting. Studies evaluating the risk of intracranial hemorrhage (ICH) in cancer patients are limited to retrospective analyses. In a study of ICH, 51 cancer patients with central nervous system (CNS) metastasis were followed at a single center between 1980 and 1992; 3 (7%) of 42 patients who received anticoagulation for VTE experienced ICH.[16] In this study, patients were treated with intravenous heparin with transition to warfarin, with two of the three episodes of ICH occurring in the setting of supratherapeutic coagulation parameters and resulting in fatal outcomes.[16] Notably, 4 of the 10 patients who received an inferior vena cava (IVC) filter alone developed a recurrent VTE, and the 2 patients who received no therapy both died of autopsy-proven pulmonary emboli.[16] Another retrospective study of 74 patients with metastatic melanoma reported ICH in 2 of the 57 patients who received therapeutic anticoagulation.[17]

A recent retrospective matched-cohort study compared 104 patients who had intracranial metastasis treated with enoxaparin with a similar cohort of 189 patients who did not receive anticoagulation to evaluate whether treatment with enoxaparin was associated with an increased risk of hemorrhage.[18] While ICH was observed frequently, there was no difference in the 1-year incidence rate of ICH between the two groups (19% in the enoxaparin group vs 21% in the untreated group; HR, 1.02; 

 = .97). Melanoma and renal cell carcinoma patients had a fourfold increased risk of ICH compared with lung cancer patients, although there was no difference in the rates of ICH in the enoxaparin-treated cohort vs untreated cohort in subgroup analysis (35% vs 34%; 

 = .80).[18] Although these studies suggest anticoagulation may be safe, these results should be interpreted with caution due to their retrospective nature and the potential inherent bias of clinicians to select patients at lower bleeding risk to receive anticoagulation.

According to current ASCO guidelines, the presence of brain metastases is not an absolute contraindication to anticoagulation.[8] Although data supporting the safety of anticoagulation in the setting of brain metastases are limited, we agree with these recommendations that therapeutic anticoagulation should be initiated in most cancer patients with intracranial metastases who have an acute VTE, with careful analysis of the risks of bleeding vs clotting in each case. In this particular clinical case, given that lung cancer generally carries a lower risk of ICH compared with other tumor types, and there is an absence of active bleeding on imaging, we would recommend treatment with LMWH.

Should placement of an IVC filter be considered in this patient? What are the indications for IVC filter placement in cancer patients?

The role of IVC filters in cancer patients is controversial, as there are limited data to support their efficacy in this population. In the randomized controlled PREPIC study of permanent IVC filter placement plus anticoagulation vs anticoagulation alone, the risk of pulmonary embolism was reduced with IVC filter placement, but the rate of recurrent DVT was increased, with no effect on survival.[19] However, cancer patients only comprised a minority of this study population (16% of patients who received a filter and 12% who did not receive a filter), and both treatment groups received some type of therapeutic anticoagulation.[19] Importantly, the placement of an IVC filter is not without complications in the cancer population, largely due to the hypercoagulable state of malignancy. In one retrospective analysis of 49 cancer patients with CNS metastases and VTE, 12% developed recurrent pulmonary emboli, and 57% developed IVC or filter thrombosis, recurrent DVT, or post-thrombotic syndrome.[20] In general, IVC filter placement should only be considered in cases where anticoagulation is clearly contraindicated. The benefits of IVC filter placement should also be considered in the context of cancer prognosis, as those with advanced disease are less likely to benefit from filter placement.[21,22] If an IVC filter is placed, a retrievable filter should be utilized and removed as soon as safely possible. In this particular clinical scenario, we recommend anticoagulation with LMWH over IVC filter placement.

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.

 Blom JW, Doggen CJ, Osanto S, Rosendaal FR. Malignancies, prothrombotic mutations, and the risk of venous thrombosis. JAMA. 2005;293:715-22.

 Khorana AA, Francis CW, Culakova E, et al. Thromboembolism is a leading cause of death in cancer patients receiving outpatient chemotherapy. 

 Gussoni G, Frasson S, La Regina M, et al. Three-month mortality rate and clinical predictors in patients with venous thromboembolism and cancer. Findings from the RIETE registry. Thromb Res. 2013;131:24-30.

 Khorana AA, Dalal MR, Lin J, Connolly GC. Health care costs associated with venous thromboembolism in selected high-risk ambulatory patients with solid tumors undergoing chemotherapy in the United States. Clinicoecon Outcomes Res. 2013;5:101-8.

 Prandoni P, Lensing AW, Piccioli A, et al. Recurrent venous thromboembolism and bleeding complications during anticoagulant treatment in patients with cancer and venous thrombosis. Blood. 2002;100:3484-8.

 Monreal M, Falga C, Valdes M, et al. Fatal pulmonary embolism and fatal bleeding in cancer patients with venous thromboembolism: findings from the RIETE registry. J Thromb Haemost. 2006;4:1950-6.

 Hutten BA, Prins MH, Gent M, et al. Incidence of recurrent thromboembolic and bleeding complications among patients with venous thromboembolism in relation to both malignancy and achieved international normalized ratio: a retrospective analysis. J Clin Oncol. 2000;18:3078-83.

 Lyman GH, Khorana AA, Kuderer NM, et al. Venous thromboembolism prophylaxis and treatment in patients with cancer: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol. 2013;31:2189-204.

 Kearon C, Akl EA, Ornelas J, et al. Antithrombotic therapy for VTE disease: CHEST Guideline and Expert Panel Report. Chest. 2016;149:315-52.

 Lee AY, Levine MN, Baker RI, et al. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med. 2003;349:146-53.

 Lee AY, Rickles FR, Julian JA, et al. Randomized comparison of low molecular weight heparin and coumarin derivatives on the survival of patients with cancer and venous thromboembolism. J Clin Oncol. 2005;23:2123-9.

 Carrier M, Cameron C, Delluc A, et al. Efficacy and safety of anticoagulant therapy for the treatment of acute cancer-associated thrombosis: a systematic review and meta-analysis. Thromb Res. 2014;134:1214-9.

 van Es N, Coppens M, Schulman S, et al. Direct oral anticoagulants compared with vitamin K antagonists for acute venous thromboembolism: evidence from phase 3 trials. Blood. 2014;124:1968-75.

 Vedovati MC, Germini F, Agnelli G, Becattini C. Direct oral anticoagulants in patients with VTE and cancer: a systematic review and meta-analysis. Chest. 2015;147:475-83.

 Schulman S, Goldhaber SZ, Kearon C, et al. Treatment with dabigatran or warfarin in patients with venous thromboembolism and cancer. Thromb Haemost. 2015;114:150-7.

 Schiff D, DeAngelis LM. Therapy of venous thromboembolism in patients with brain metastases. Cancer. 1994;73:493-8.

 Alvarado G, Noor R, Bassett R, et al. Risk of intracranial hemorrhage with anticoagulation therapy in melanoma patients with brain metastases. Melanoma Res. 2012;22:310-5.

 Donato J, Campigotto F, Uhlmann EJ, et al. Intracranial hemorrhage in patients with brain metastases treated with therapeutic enoxaparin: a matched cohort study. Blood. 2015;126:494-9.

 PREPIC Study Group. Eight-year follow-up of patients with permanent vena cava filters in the prevention of pulmonary embolism: the PREPIC (Prevention du Risque d’Embolie Pulmonaire par Interruption Cave) randomized study. Circulation. 2005;112:416-22.

 Levin JM, Schiff D, Loeffler JS, et al. Complications of therapy for venous thromboembolic disease in patients with brain tumors. Neurology. 1993;43:1111-4.

 Wallace MJ, Jean JL, Gupta S, et al. Use of inferior vena caval filters and survival in patients with malignancy. Cancer. 2004;101:1902-7.

 Barginear MF, Lesser M, Akerman ML, et al. Need for inferior vena cava filters in cancer patients: a surrogate marker for poor outcome. Clinical and applied thrombosis/hemostasis. Clin Appl Thromb Hemost. 2009;15:263-9.

 Prins MH, Lensing AW, Bauersachs R, et al. Oral rivaroxaban versus standard therapy for the treatment of symptomatic venous thromboembolism: a pooled analysis of the EINSTEIN-DVT and PE randomized studies. Thromb J. 2013;11:21.

 Agnelli G, Buller HR, Cohen A, et al. Oral apixaban for the treatment of venous thromboembolism in cancer patients: results from the AMPLIFY trial. J Thromb Haemost. 2015;13:2187-91.

 Raskob GE, Buller H, Angchaisuksiri P, et al. Edoxaban for long-term treatment of venous thromboembolism in cancer patients. Blood. 2013;122(suppl 21):abstr 211.

Due to the delicate hemostatic balance in cancer patients, an understanding of both the clotting and bleeding risks in this population is crucial to effectively manage hematologic complications.  

Clotting and Bleeding in Oncology Patients: Clinical Scenarios and Challenges

In this issue of ONCOLOGY, Dr. Zagar and colleagues review the epidemiology and biology of breast cancer brain metastases and provide an overview of the diagnosis, symptom management, and treatment issues for this entity.[1] Specifically, the evidence for surgery, stereotactic radiosurgery (SRS), whole-brain radiotherapy (WBRT), and various systemic therapy options for breast cancer brain metastases is reviewed, and the need for a multidisciplinary approach is emphasized. This overview also highlights several unique challenges and opportunities germane to the management of breast cancer brain metastases.

First, the growing burden of this devastating complication of breast cancer across all subtypes warrants emphasis. Specifically, it is estimated that as many as 24% to 34% of women with stage IV breast cancer now develop brain metastases.[2] Furthermore, women appear to be living longer after a diagnosis of breast cancer brain metastases, regardless of subtype. For example, according to a retrospective, single-institution study of women with breast cancer brain metastases between 2003 and 2009, overall survival after systemic treatment and WBRT was 13 months for women with human epidermal growth factor receptor 2 (HER2)-positive breast cancer but only 4 months for women with triple-negative breast cancer (TNBC).[3] However, in the modern era of HER2-directed therapy, median survival now exceeds 3 years after a diagnosis of HER2-positive breast cancer brain metastases, according to two recent reports.[4,5]

Furthermore, median survival for women diagnosed with TNBC brain metastases now approximates 1 year.[4,6] Thus, outcomes appear to have improved both for women with HER2-positive breast cancer brain metastases and those with TNBC brain metastases in recent years.

It is important to note, however, that the majority of women with metastatic breast cancer have hormone receptor–positive disease. Therefore, although the incidence rate of brain metastases is lower in this population compared with the HER2-positive and triple-negative populations, the absolute burden of brain metastases may be greatest in this population. This issue was highlighted in a recent retrospective study completed at Memorial Sloan Kettering Cancer Center, in which outcomes for 113 consecutive women with breast cancer brain metastases treated with SRS or WBRT between January 2009 and December 2011 were reported.[6] In that study, the median survival for women with HER2-positive and triple-negative disease was 32.8 months and 11.3 months, respectively-results that were consistent with other contemporary reports.[3-5] However, approximately half of the women (52%) treated with brain radiotherapy (RT) had hormone receptor–positive disease (with a median survival of only 12.7 months after breast cancer brain metastasis diagnosis). Thus, although the relative incidence rate of breast cancer brain metastases is considerably higher for women with HER2-positive disease or TNBC, the absolute prevalence of breast cancer brain metastases is highest for women with hormone receptor–positive disease, and therapeutic innovation across all subtypes is needed.

Second, despite successful systemic therapy innovation across almost all other areas of breast cancer management, there are currently no drugs approved by the US Food and Drug Administration for the indication of breast cancer brain metastasis-in part because the same innovative systemic therapies have not translated into substantial clinical benefits for patients with this particular complication. As previously outlined, outcomes have improved for women with HER2-positive breast cancer brain metastases in recent years; however, this trend likely reflects innovation in local therapies (including SRS)[7] and a fundamental change in the biology of HER2-positive breast cancer brain metastases as a consequence of adjuvant HER2-directed therapy,[4,5] rather than being the result of any impact of palliative systemic therapy for breast cancer brain metastases (given that no trials have demonstrated a survival benefit in this population to date).

In light of the modest inroads in the systemic management of breast cancer brain metastases, perhaps it is time to go back to the drawing board and rethink existing models and paradigms of management. For example:

1) Why do one-third of breast cancer brain metastases develop in the cerebellum? Is it simply a function of blood flow, or is there a biologic driver within certain breast cancers that favors that specific location for metastasis? Is there a specific biologic advantage to the cerebellar microenvironment? And if there is an innate biologic driver or an advantage to the milieu, can relevant targeted therapies be developed?

2) Do we need to rethink the concept of the “blood-brain barrier,” a label that suggests a near-impenetrable wall to novel systemic therapies, when in fact, many drugs successfully penetrate the brain parenchyma but simply don’t elicit robust responses in that specific setting?

3) Should we advocate for surgery whenever feasible in order to establish modern tissue banks that will allow for further scientific interrogation?

4) Should we be looking to other tumor types for insight? For example, should bevacizumab, which has a complicated history in breast cancer, but which recently demonstrated benefits in patients with the central nervous system tumor glioblastoma multiforme, be revisited in this specific setting?

5) Do we need to be exploring different strategies altogether? Brain RT, for example, may be particularly effective when combined with modern immunotherapy strategies, not only in the treatment of central nervous system disease, but also for the treatment of disease outside the RT portal (the so-called abscopal effect reported in other tumor types); this strategy is currently under investigation (ClinicalTrials.gov identifier: NCT02563925).

In short, the inability to establish substantial inroads in the systemic treatment of breast cancer brain metastases to date requires that the research community develop new insights and establish new strategies if we are to successfully innovate in this area.

Finally, one of the biggest obstacles to therapeutic innovation in the setting of breast cancer brain metastases is the variance in therapeutic strategies across individual and institutional practices, which, in turn, not only creates potential barriers to clinical trial enrollment but also limits the interpretability of retrospective studies. For example, some patients with multiple brain metastases receive SRS to the dominant lesions and for any number of subsequent recurrences (sometimes receiving 30 or more treatments over a relatively short period of time), whereas very similar patients treated at a different institution might receive upfront WBRT followed by local treatment as indicated. Although treatment recommendations must ultimately be tailored to the individual, the development of evidence-based, multidisciplinary, consensus guidelines would provide an important resource for clinicians struggling with best-practice decisions in the setting of breast cancer brain metastases; such guidelines would also facilitate efficient clinical trial conduct.

Brain metastasis remains a relatively common and particularly devastating complication of breast cancer and has proven a particularly challenging area for therapeutic innovation. The challenge has been further compounded by increasing incidence rates combined with modest improvements in survival that have, in turn, culminated in a growing burden of disease. If the challenge of breast cancer brain metastases is to be effectively addressed and innovation achieved, established dogmas about the disease and barriers to systemic therapy should be challenged. And if clinical management is to be effective, a multidisciplinary approach, as advocated by Dr. Zagar and colleagues, is almost certainly required and would likely benefit from evidence-based consensus guidelines that promote standardized practice. It is hoped that innovation, collaboration, and consensus will translate into improved quality of life and, ultimately, improved survival for women with this serious complication of breast cancer.

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

 Zagar TM, Van Swearingen AED, Kaidar-Person O, et al. Multidisciplinary management of breast cancer brain metastases. Oncology (Williston Park). 2016;30:923-33.

 Rostami R, Mittal S, Rostami P, et al. Brain metastasis in breast cancer: a comprehensive literature review. J Neurooncol. 2016;127:407-14.

 Niwinska A, Murawska M, Pogoda K. Breast cancer subtypes and response to systemic treatment after whole-brain radiotherapy in patients with brain metastases. Cancer. 2010;116:4238-47.

 McKee MJ, Keith K, Deal AM, et al. A multidisciplinary breast cancer brain metastases clinic: the University of North Carolina experience. Oncologist. 2016;21:16-20.

 Mounsey L, Deal AM, Benbow JM, et al. A changing natural history of HER2-positive breast cancer metastatic to the brain in the era of new, targeted therapies. J Clin Oncol. 2016;34(suppl):abstr 584.

 Morikawa A, Diab A, Patil S, et al. Radiation therapy for breast cancer (BC) with central nervous system (CNS) metastases: a contemporary experience at Memorial Sloan-Kettering Cancer Center (MSKCC). J Clin Oncol. 2013;31(suppl 26):abstr 144.

 Yang TJ, Oh JH, Folkert MR, et al. Outcomes and prognostic factors in women with 1 to 3 breast cancer brain metastases treated with definitive stereotactic radiosurgery. Int J Radiat Oncol Biol Phys. 2014;90:18-25.

Brain metastasis remains a relatively common and particularly devastating complication of breast cancer and has proven a particularly challenging area for therapeutic innovation.

Breast Cancer Brain Metastasis: An Ongoing Clinical Challenge and Opportunity for Innovation

In their comprehensive review, Drs. Lin and Diefenbach discuss the scientific rationale for, and the clinical outcomes associated with, the use of checkpoint inhibitors for treatment of Hodgkin lymphoma.[1] The authors detail the mechanisms that lead to overexpression of programmed death ligands 1 and 2 (PD-L1 and PD-L2) on Hodgkin lymphoma tumor cells, a process that, in turn, causes dampening of the immune response against Hodgkin and Reed-Sternberg (HRS) cells. They also describe clinical trials that have incorporated checkpoint inhibition as a therapeutic strategy in Hodgkin lymphoma, including monoclonal antibody therapy against cytotoxic T-lymphocyte–associated antigen 4 and programmed death 1 (PD-1). As the authors describe, there are still many open questions regarding the use of checkpoint inhibitors in Hodgkin lymphoma, including the mechanisms of action underlying checkpoint blockade and the therapeutic applications in this patient population.[2-4]

Upregulation of PD-L1 and PD-L2, leading to evasion of the immune system, is a clear pathogenic mechanism in Hodgkin lymphoma. The recurrent chromosomal translocation of the 9p24.1 region in Hodgkin lymphoma leads to increased expression of PD-L1 and PD-L2, as well as amplification of the Janus kinase 2 

) locus, resulting in transcriptional activation of PD-L1.[5] Even in patients without genetic amplification of 

, alternate mechanisms promote enhanced PD-L1 and PD-L2 expression; these mechanisms include increases in JAK/STAT signaling, production of interferon gamma, and expression of an Epstein-Barr virus–associated protein, latent membrane protein 1.[6,7] The anti–PD-1 antibodies nivolumab and pembrolizumab interfere with the inhibitory interaction between PD-1 and PD-L1/PD-L2, leading to heightened immune responses against HRS cells. However, the mechanism by which checkpoint inhibitors enhance the T-cell or alternate effector cell response against the tumor cells is unclear. Further, biomarkers to predict differential responses to checkpoint inhibitors in Hodgkin lymphoma have not been elucidated.

In melanoma and lung cancer, higher levels of somatic mutation and higher tumor neoantigen burden have been reported to correlate with response to checkpoint blockade.[8,9] However, in Hodgkin lymphoma, the somatic mutational burden is difficult to characterize in patients treated with anti–PD-1 antibodies. This is due to the relative paucity of HRS cells in pathologic specimens, which hinders efforts to perform routine and comprehensive sequencing assessments. In solid tumors, a postulated mechanism of action for checkpoint blockade is presentation of tumor neoantigens by major histocompatibility complex (MHC) class I molecules on tumor cells, resulting in a CD8-positive T-cell–mediated response against the tumor. Intriguingly, in Hodgkin lymphoma, frequent inactivating mutations of the Î²-2-microglobulin (

) gene have been described that trigger the loss of MHC class I expression on HRS cells, making CD8-positive T cells unlikely effector cells in Hodgkin lymphoma.[10] Therefore, CD4-positive T cells may be the predominant effector cells in the anti-PD1–mediated antitumor response in HL, but, as Drs. Lin and Diefenbach describe, downregulation of MHC class II molecules has also been observed in Hodgkin lymphoma. Thus, there are unresolved questions about how checkpoint inhibitors may mediate antitumor responses in Hodgkin lymphoma; hypotheses include antitumor effects achieved via CD4-positive T-cell–mediated responses independent of MHC class II interaction, natural killer cell–mediated responses, and inhibition of regulatory T cells.[7]

Unlike in solid tumors, the degree of PD-L1 or PD-L2 expression in Hodgkin lymphoma is not a biomarker of response to checkpoint blockade. The recent phase Ib study of pembrolizumab described a treatment-induced expansion of T cells (both CD4 and CD8 subsets) and natural killer cells, as well as increases in gene signatures of interferon gamma, T-cell–receptor signaling, and immune-related genes; however, these changes were not clearly correlated with response.[3] Efforts to identify biomarkers of response to checkpoint blockade therapy are ongoing.

Data from initial phase I and II studies of the anti–PD-1 antibodies nivolumab and pembrolizumab demonstrated impressive overall response rates for these agents, ranging from 65% to 87%.[2-4] However, only 15% to 20% of patients achieved a complete response. Nevertheless, many patients who experience a partial response or stable disease derive significant clinical benefit from anti–PD-1 antibody therapy and can remain on treatment for a prolonged period of time. As Drs. Lin and Diefenbach report in their review, an update of the CheckMate-039 study at the 2015 American Society of Hematology Annual Meeting demonstrated that there is promising durability of response with nivolumab, with evidence of persistent complete and partial responses even after cessation of therapy. Also notable in this study was a single patient whose disease progressed after therapy was discontinued but who achieved a second complete response after reinitiation of treatment with nivolumab.[11]

These data give rise to the clinical question of how to optimally manage patients with relapsed or refractory Hodgkin lymphoma who respond to anti–PD-1 therapy. There are several potential management options: 1) continue checkpoint inhibition indefinitely; 2) stop therapy after achievement of best response and observe the patient, while reserving the potential option of re-treatment in the future; or 3) initiate consolidation therapy with allogeneic stem cell transplantation (SCT).[12] Given the current limited follow-up period with the use of immune checkpoint inhibitors in Hodgkin lymphoma, we do not know how durable the treatment responses will be, and it is unlikely that they have curative potential. Although allogeneic SCT has been considered potentially curative in refractory Hodgkin lymphoma, there may be an enhanced graft-vs-tumor effect after use of immune checkpoint blockade therapy in conjunction with allogeneic SCT, and this approach carries a substantial risk of treatment-related morbidity and mortality. Furthermore, these risks, particularly for graft-vs-host disease and veno-occlusive disease, may be increased following therapy with checkpoint inhibitors.[13] Currently, there are insufficient data to formulate a uniform management algorithm for patients with relapsed or refractory Hodgkin lymphoma who respond to treatment with anti–PD-1 agents. The treatment approach needs to be determined on an individual basis, and various factors must be considered, including, but not limited to: the age of the patient, his or her functional status and concomitant comorbidities, SCT sources and donor availability, depth of response to prior anti–PD-1 antibody therapy, the prior therapies received, and patient preferences.

Ultimately, the management goal is not for patients with relapsed/refractory disease to live with chronic Hodgkin lymphoma while receiving immune checkpoint blockade therapy, but rather to cure more patients with first- or second-line therapy. There are multiple ongoing efforts to incorporate checkpoint blockade therapy earlier in the disease course to improve outcomes, particularly in high-risk patients. The results of clinical trials in Hodgkin lymphoma in which immune checkpoint blockade is combined with chemotherapy, radiotherapy, and antibody-drug conjugates are highly anticipated. Indeed, immune checkpoint inhibitors hold great promise to further increase the curability rates of future patients with Hodgkin lymphoma.

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

 Lin RJ, Diefenbach CS. Checkpoint inhibition in Hodgkin lymphoma: saving the best for last? Oncology (Williston Park). 2016;30:914-20.

 Ansell SM, Lesokhin AM, Borrello I, et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin’s lymphoma. N Engl J Med. 2015;372:311-9.

 Armand P, Shipp MA, Ribrag V, et al. Programmed death-1 blockade with pembrolizumab in patients with classical Hodgkin lymphoma after brentuximab vedotin failure. J Clin Oncol. 2016;34:1-9.

 Younes A, Santoro A, Shipp M, et al. Nivolumab for classical Hodgkin’s lymphoma after failure of both autologous stem-cell transplant and brentuximab vedotin: a multicentre, single-arm phase 2 trial. Lancet Oncol. 2016;17:1283-94.

 Green MR, Monti S, Rodig SJ, et al. Integrative analysis reveals selective 9p24.1 amplification, increased PD-1 ligand expression, and further induction via JAK2 in nodular sclerosing Hodgkin lymphoma and primary mediastinal large B-cell lymphoma. Blood. 2010;116:3268-77.

 Green MR, Rodig S, Juszczynski P, et al. Constitutive AP-1 activity and EBV infection induce PD-L1 in Hodgkin lymphomas and posttransplant lymphoproliferative disorders: implications for targeted therapy. Clin Cancer Res. 2012;18:1611-8.

 Vardhana S, Younes A. The immune microenvironment in Hodgkin lymphoma: T-cells, B-cells, and immune checkpoints. Haematologica. 2016;101:794-802.

 Snyder A, Makarov V, Merghoub T, et al. Genetic bases for clinical response to CTLA-4 blockade in melanoma. N Engl J Med. 2014;371:2189-99.

 Rizvi NA, Hellmann MD, Snyder A, et al. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science. 2015;348:124-8.

 Reichel J, Chadburn A, Rubinstein PG, et al. Flow sorting and exome sequencing reveal the oncogenome of primary Hodgkin and Reed-Sternberg cells. Blood. 2015;125:1061-72.

 Ansell SM, Armand P, Timmerman JM, et al. Nivolumab in patients with relapsed or refractory classical Hodgkin lymphoma: clinical outcomes from extended follow-up of a phase I study (CA209-039). Blood. 2015;126(suppl):abstr 583.

 Issa A, Westin J. What to do with success? The optimist’s creed in relapsed Hodgkin lymphoma. Clin Lymphoma Myeloma Leuk. 2016 June 8. [Epub ahead of print]

 Merryman RW, Kim HT, Zinzani PL, et al. Safety and efficacy of allogeneic hematopoietic stem cell transplant (HSCT) after treatment with programmed cell death 1 (PD-1) inhibitors. Blood. 2015;126(suppl):abstr 2018.

Ultimately, the management goal is not for patients with relapsed/refractory disease to live with chronic Hodgkin lymphoma while receiving immune checkpoint blockade therapy, but rather to cure more patients with first- or second-line therapy. 

The Emerging Role of Checkpoint Inhibitor Therapy in Hodgkin Lymphoma

At the End of the Day, Bad Biology Trumps Surgery

The practice of routine complete lymph node dissection (CLND) after removing a positive sentinel lymph node (SLN) in patients with melanoma, known as “selective lymphadenectomy,” has been embraced as the standard of care. However, many surgeons have questioned the strength of the evidence supporting this obligatory transition to CLND. Along with the important goal of reducing treatment-related morbidity without compromising oncologic outcomes, attention has been focused on determining whether the practice of CLND is worth the endured surgical morbidity.

The long-term results of the Multicenter Selective Lymphadenectomy Trial (MSLT)-1,[1] combined with results from other studies, offer convincing evidence that SLN biopsy provides relevant staging/prognostic information.[2] Furthermore, improved melanoma-specific survival, enhanced regional lymph node basin disease control, and reduced surgical morbidity have been achieved with SLN biopsy for the node-positive subset of patients (who represent approximately 20% of patients who undergo biopsy), compared with treating patients when they develop clinically palpable nodal disease. These data support the proof of concept that treating regional lymph node disease early is of clinical value. However, since all of the patients with a positive SLN in the MSLT-1 trial underwent CLND, it is difficult to determine the fractional benefit of CLND beyond what is achieved with removal of the SLNs. Theoretically, the only patients who can derive benefit from CLND are those who also harbor additional microscopic disease in non-SLNs, representing approximately 10% to 20% of SLN-positive patients. Several studies have demonstrated that patients with microscopic non–SLN involvement have a particularly unfavorable prognosis, suggesting that early treatment of nodal disease beyond SLNs has little impact on melanoma-specific survival.[3] Many have come to the conclusion that most, if not all, of the survival benefits observed in the MSLT-1 trial are attributable to the removal of SLNs alone. This notion has a fair amount of support, as an analysis of a Surveillance, Epidemiology, and End Results database demonstrated that only 50% of patients with a positive SLN actually undergo CLND,[4] reflecting the level of clinical equipoise that exists within the at-large surgical community. Publications of nonrandomized studies comparing the outcomes of SLN-positive patients who underwent CLND with those who had only an SLN biopsy suggest that CLND provides no significant survival advantage.[5,6] These studies are retrospective, have imbalances in prognostic factors and significant surgeon and patient bias, and include only short-term follow-up in the group without CLND. Therefore, these results should not support a change in practice to one that routinely omits CLND, but illustrates the current level of equipoise and the importance of the long-term outcomes of randomized trials.

Two prospective randomized trials in the SLN-positive patient population have been completed, comparing observation with nodal basin ultrasound vs CLND.[1] The MSLT-2 trial completed accrual 2 years ago (ClinicalTrials.gov identifier: NCT00297895). Unfortunately, a prevailing feeling is that a significant amount of selection bias existed in the accrual process by both surgeons and patients in favor of patients who were predicted to have a low risk of harboring additional positive nodes. Combined with the routine use of ultrasound surveillance, many feel that this scenario likely reduces the potential impact of the CLND treatment arm. If the long-term survival difference is insignificant, proponents of CLND will argue that the trial was underpowered to answer the question. Opponents will argue that these results accurately reflect the most common patient population we treat and that a rational, safe, and less morbid alternative treatment strategy for this low-risk group is ultrasound surveillance.

The German Dermatologic Cooperative Oncology Group (DeCOG)-SLT trial studied a similar but smaller group of patients. The preliminary results of this trial were recently published in 

 after a median follow-up of 3 years.[7] The demographics of this trial clearly favored the group of patients with a low risk for non–SLN involvement, as almost 70% were in the < 1-mm SLN tumor burden subgroup. Unfortunately, the report does not provide complete data on the percentage of patients in the CLND treatment arm who had additional positive nodes, but an incomplete analysis detected a frequency rate of 18%. Regardless, no difference in melanoma-specific survival was observed in the overall cohort or in either ad hoc nodal burden subset. Therefore, at this point, there is no evidence that CLND will impact survival outcome.

This should not be a surprise to anyone, given that the only patients who can potentially derive benefit-the patients with non–SLN involvement-represent only 18% of the patients who were randomized. This is a similar scenario as in the MSLT-1 trial, where the only patients who could derive benefit were the 20% with a positive SLN. Unfortunately, the DeCOG trial is particularly underpowered because only 270 patients were randomized in each arm, and with an 18% non–SLN involvement rate, assessment of impact of CLND on natural history would be based on 40 patients in each arm at most-hardly a robust analysis even if it were to be performed. The MSLT-2 trial is larger, and therefore will have more non–SLN-positive patients for such a subset analysis, which will compare outcomes of patients randomized to CLND with those who were randomized to observation and underwent a lymphadenectomy to treat the development of clinically palpable nodal disease. This analysis would be of great interest.

Although it is logical to presume that early treatment of any microscopic nodal disease (sentinel or nonsentinel) should be equally effective in preventing nodal disease progression, and should result in the same favorable survival impact as observed in MSLT-1, the biology of patients with non–SLN metastases appears to be more unfavorable, and less likely to derive benefit with surgery. Hence, why bad biology trumps surgery.

Assessment of Other “Benefits” of CLND

Advocates of CLND argue that the potential for improved survival is not the only reason for recommending the procedure. Accurate staging (prognostic assessment), adjuvant trial eligibility, and regional nodal disease control are also important goals in the comprehensive management of melanoma patients with early nodal metastases.[8,9]

Certainly the number of positive nodes and the presence of non–SLN involvement affect the predicted risk for distant disease relapse.[10] Such risk assessment is critical when determining the risk/benefit ratio of receiving systemic adjuvant therapy, particularly given the associated high toxicity profiles of the three currently approved therapies (high-dose interferon, pegylated interferon, and high-dose ipilimumab). Unfortunately, consistent overall survival benefits have not been demonstrated with either of the interferon regimens, and long-term overall survival outcomes for adjuvant ipilimumab are not yet available. Furthermore, the routine application of CLND will upstage less than 20% of the patients, and if the primary tumor is ulcerated or if three SLNs are involved, an even smaller percentage of patients will benefit from the additional information obtained.[11] Overall, it seems like the routine practice of CLND for all SLN-positive patients is a high price to pay in terms of cost and surgical morbidity, considering the limited number of patients who can benefit from the additional staging information.

Another offered benefit of CLND is eligibility for the currently accruing high-priority adjuvant trial randomizing patients with nodal metastases to the current standard adjuvant therapy vs anti–programmed death 1 therapy. This trial mandates CLND for trial participation. While I feel this is an unfortunate mandate, as the critical endpoints should be distant relapse–free survival and overall survival, neither of which would likely be impacted by the small increase in regional nodal basin failures, it is a problem that will hopefully disappear once the trial has completed accrual.

Durable regional nodal basin disease control is more likely to be achieved when the regional lymphadenectomy is performed to treat microscopic nodal disease as opposed to clinically apparent nodal metastases.[12] Furthermore, recent studies have shown that the short- and long-term surgical morbidity of the regional dissection is lower when treating SLN metastases vs treating patients who have palpable nodal disease.[13] Long-term morbidity is particularly high if adjuvant nodal basin irradiation is applied. Although the evidence to support these assertions is fairly robust, the morbidity of CLND in the best of settings and hands is still significant. Again, why subject every patient to the cost and morbidity of an operation when only a select few can actually derive benefit? It would seem to make sense that a more selective approach, based on predictors for the presence of non–SLN involvement, would be a rational strategy. Furthermore, the clinical scenario of actually losing regional disease control and its associated significant morbidity is really a fear propagated by the CLND supporters. Such clinical scenarios are extremely rare occurrences and should not happen in patients who are followed closely with a careful physical examination selectively supplemented by ultrasound. Such an approach would likely identify clinical nodal involvement early and with less burden of disease, which in turn will reduce the need for adjuvant basin irradiation and avoid its associated treatment morbidities.

Little high-level evidence exists in support of the routine use of CLND in patients with positive SLNs, particularly if melanoma-specific survival is the only desired endpoint. This adopted “standard of care” is based in surgical dogma rather than surgical science. While we need to wait for the long-term results of the previously described randomized trials, it is reasonable to offer patients a selective approach based on their underlying comorbidities, predicted risk of non–SLN involvement and surgical morbidity, and the mutually agreed upon goals for treatment. Ironically, the patients who can benefit the most from CLND in terms of regional nodal basin disease control are the patients who are least likely to experience a survival benefit.

 Morton DL, Thompson JF, Cochran AJ, et al. Final trial report of sentinel-node biopsy versus nodal observation in melanoma. N Engl J Med. 2014;370:599-609.

 Balch CM, Gershenwald JE, Soong SJ, Thompson JF. Update on the melanoma staging system: the importance of sentinel node staging and primary tumor mitotic rate. J Surg Oncol. 2011;104:379-85.

 Bamboat ZM, Konstantinidis IT, Kuk D, et al. Observation after a positive sentinel lymph node biopsy in patients with melanoma. Ann Surg Oncol. 2014;21:3117-23.

 Bilimoria KY, Balch CM, Bentrem DJ, et al. Complete lymph node dissection for sentinel node-positive melanoma: assessment of practice patterns in the United States. Ann Surg Oncol. 2008;15:1566-76.

 Wong SL, Morton DL, Thompson JF, et al. Melanoma patients with positive sentinel nodes who did not undergo completion lymphadenectomy: a multi-institutional study. Ann Surg Oncol. 2006;13:809-16.

 Melstrom LG, Taylor E, Kuk D, et al. International multi-institutional management and outcome of melanoma patients with positive sentinel lymph nodes in more than one nodal basin. Ann Surg Oncol. 2014;21:4324-9.

 Leiter U, Stadler R, Mauch C, et al. Complete lymph node dissection versus no dissection in patients with sentinel lymph node biopsy positive melanoma (DeCOG-SLT): a multicentre, randomised, phase 3 trial. Lancet Oncol. 2016;17:757-67.

 Ariyan C, Brady MS, GÃ¶nen M, et al. Positive nonsentinel node status predicts mortality in patients with cutaneous melanoma. Ann Surg Oncol. 2009;16:186-90.

 Brown RE, Ross MI, Edwards MJ, et al. The prognostic significance of nonsentinel lymph node metastasis in melanoma. Ann Surg Oncol. 2010;17:3330-5.

 Kunte C, Geimer T, Baumert J, et al. Analysis of predictive factors for the outcome of complete lymph node dissection in melanoma patients with metastatic sentinel lymph nodes. J Am Acad Dermatol. 2011;64:655-62.

 Guggenheim M, Dummer R, Jung FJ, et al. The influence of sentinel lymph node tumour burden on additional lymph node involvement and disease-free survival in cutaneous melanoma-a retrospective analysis of 392 cases. Br J Cancer. 2008;98:1922-8.

 Gershenwald JE, Andtbacka RH, Prieto VG, et al. Microscopic tumor burden in sentinel lymph nodes predicts synchronous nonsentinel lymph node involvement in patients with melanoma. J Clin Oncol. 2008;26:4296-303.

 Kretschmer L, Thoms KM, Peeters S, et al. Postoperative morbidity of lymph node excision for cutaneous melanoma-sentinel lymphonodectomy versus complete regional lymph node dissection. Melanoma Res. 2008;18:16-21.

Ironically, the patients who can benefit the most from CLND in terms of regional nodal basin disease control are the patients who are least likely to experience a survival benefit.

COUNTERPOINT: Surgical Management of Lymph Node Basin in Sentinel Lymph Node–Positive Melanoma

Why Complete Lymph Node Dissection Remains the Standard of Care

A positive sentinel lymph node (SLN) is the most important prognostic factor in patients with clinically localized melanoma.[1,2] Complete lymph node dissection (CLND; by definition, lymph node dissection of the sentinel node–positive basin) and nodal basin observation with delayed (therapeutic) lymphadenectomy reserved for patients who experience resectable nodal recurrence represent two competing management philosophies. These approaches are being prospectively compared in randomized trials in which melanoma patients with at least one positive SLN are randomized to either CLND or nodal observation: the large Multicenter Selective Lymphadenectomy Trials (MSLT-1 and MSLT-2)[2,3] and the much smaller German Dermatologic Cooperative Oncology Group (DeCOG)-SLT trial.[4] Until mature results from these studies are available, the standard of care remains CLND, based upon prospective evidence of lesser morbidity and superior survival. Outside of a clinical trial, this standard-of-care approach to the SLN-positive basin should be abandoned only with the greatest of caution.

SLN biopsy was designed to restrict lymphadenectomy only to the 15% to 20% of patients with microscopic nodal involvement at the time of presentation,[5] not to definitively treat microscopic tumor metastases. The rationale for an observational approach is to avoid the morbidity of lymphadenectomy (specifically to avoid the possibility of lymphedema) for two subsets of patients who never manifest isolated recurrence in the lymph node basin: those who have no melanoma remaining in the nodal basin and those who experience distant treatment failure at or before the time of nodal recurrence. The percentages of patients in these subsets remain to be defined, and no accepted criteria can predict which patients are most likely to develop isolated nodal recurrence, and hence eventually require lymphadenectomy. Importantly, when eventual nodal recurrence makes delayed lymphadenectomy necessary, the procedure is actually associated with considerably higher morbidity than would have occurred had CLND been done promptly after SLN biopsy. Prospective data from the pioneering MSLT-1 trial indicate that patients undergoing delayed lymphadenectomy after nodal basin recurrence have significantly increased risk of complications, especially lymphedema, compared with patients who undergo CLND.[6] Moreover, postoperative lymphedema was more likely to be moderate or severe after delayed lymphadenectomy.[6] In the MSLT-1 trial, patients with isolated nodal recurrence had more total lymph nodes involved by melanoma than patients randomized to SLN biopsy who had a positive biopsy (all of whom were to have CLND; an average of 3.2 lymph nodes involved with metastatic melanoma vs only 1.4 positive nodes, respectively; 

 < .0001),[2] and were more likely to meet established criteria for adjuvant radiation,[7] which further increases the risk of postoperative lymphedema. Additionally, patients who underwent delayed lymphadenectomy had significantly longer hospital stays compared with those undergoing CLND.[6] Therefore, the benefit some patients may derive by avoidance of lymphadenectomy is counterbalanced by higher morbidity, including increased risk of moderate to severe lymphedema and longer hospital stays in the event that a delayed CLND is required following observation.

Increased morbidity is not the only risk patients who forego standard-of-care CLND may face. The MSLT-1 trial demonstrated that patients with a positive SLN undergoing CLND had far better melanoma-specific survival than those patients who manifested nodal recurrence either on the observation arm or after a false-negative SLN biopsy (10-year melanoma-specific survival rates: 62.1% vs 41.5% and 34.4%, respectively).[2] These data strongly suggest that unresected, clinically occult regional nodal disease can adversely affect melanoma-specific survival. Importantly, the survival curves for these groups did not begin to diverge until year 2 or beyond after initial surgery, and continued to widen for the entire 10-year period, which means preliminary results from the relatively small DeCOG-SLT study-with its 3-year median follow-up[4]-cannot be relied upon to justify changing the standard of care away from CLND. Furthermore, SLN-positive patients who defer lymphadenectomy until clinically detected nodal recurrence may present with unresectable disease, representing a missed opportunity for regional disease control. Unfortunately, uncontrolled regional disease can result in problems that even today’s more effective systemic melanoma treatments do not always mitigate. At present, optimum follow-up strategies for monitoring the SLN-positive nodal basin in patients who chose to forego CLND have not been defined. However, it is clear that nodal basin recurrence can occur years or even decades after initial surgery,[2] so patients who choose nodal observation are committed to long-term follow-up of uncertain value.

CLND also offers additional staging and prognostic information that influence subsequent adjuvant systemic therapy options. For example, metastases in nonsentinel nodes upstage patients with non-ulcerated primaries from stage IIIA to IIIB or IIIC. Currently, lymphadenectomy is an eligibility requirement for cutting-edge adjuvant therapy trials such as Southwest Oncology Group (SWOG) 1404 (ClinicalTrials.gov identifier: NCT02506153), which randomizes stage III melanoma patients to an anti–programmed death 1 antibody or standard-of-care adjuvant therapy (high-dose interferon or high-dose ipilimumab). Offering our SLN-positive patients access to all standard and investigational adjuvant therapy options is yet another reason why standard-of-care CLND should not be abandoned lightly.

In summary, CLND as standard of care for patients with SLN-positive metastatic melanoma is supported by a wealth of compelling prospective data. Patients choosing nodal observation, but ultimately requiring delayed lymphadenectomy, risk unresectable regional recurrence and increased morbidity, a longer stay in the hospital, and potentially poorer survival. This is a high price for many patients to pay in order for an undefined fraction of others to avoid lymphadenectomy entirely (but not the need for decade-long follow-up of the nodal basin). Consequently, until we have better ways of defining those patients who have been cured by SLN biopsy alone (or the long-term results of current prospective trials indicate otherwise), nodal observation should be chosen by SLN-positive patients only after very careful consideration, and not routinely recommended by surgeons or oncologists as a proven alternative to avoiding CLND.

Dr. Sarnaik serves on the scientific advisory board of B4CC, Inc; Dr. Zager serves on the scientific advisory board of Amgen, Inc, Castle Biosciences, Inc, and Delcath, Inc; Dr. Sondak serves on the scientific advisory board of Bristol-Myers Squibb, Inc, and Merck, Inc.

 Gershenwald JE, Thompson W, Mansfield PF, et al. Multi-institutional melanoma lymphatic mapping experience: the prognostic value of sentinel lymph node status in 612 stage I or II melanoma patients. J Clin Oncol. 1999;17:976-83.

 Morton DL. Overview and update of the phase III Multicenter Selective Lymphadenectomy Trials (MSLT-I and MSLT-II) in melanoma. Clin Exp Metastasis. 2012;29:699-706.

 Morton DL, Wen DR, Wong JH, et al. Technical details of intraoperative lymphatic mapping for early stage melanoma. Arch Surg. 1992;127:392-9.

 Faries MB, Thompson JF, Cochran A, et al. The impact on morbidity and length of stay of early versus delayed complete lymphadenectomy in melanoma: results of the Multicenter Selective Lymphadenectomy Trial (I). Ann Surg Oncol. 2010;17:3324-9.

 Henderson MA, Burmeister BH, Ainslie J, et al. Adjuvant lymph-node field radiotherapy versus observation only in patients with melanoma at high risk of further lymph-node field relapse after lymphadenectomy (ANZMTG 01.02/TROG 02.01): 6-year follow-up of a phase 3, randomised controlled trial. Lancet Oncol. 2015;16:1049-60.

CLND as standard of care for patients with SLN-positive metastatic melanoma is supported by a wealth of compelling prospective data. 

POINT: Surgical Management of Lymph Node Basin in Sentinel Lymph Node–Positive Melanoma

Can you describe the CRISPR technology currently being used to “edit” genes? 

 CRISPR is a bacterial endonuclease system that uses an RNA guide to cut DNA in a sequence-specific manner. Currently, the type II CRISPR/Cas9 from the bacteria 

) is the most widely used CRISPR system for gene editing in human cells. The 

 CRISPR/Cas9 has been successfully deployed to generate both gene knockout and specific mutations, including substitution, insertion, deletion, and translocation in the genome. Compared with other gene editing technologies, such as zinc-finger nucleases and transcription activator–like effector nucleases, the ease of use and the high efficiency of CRISPR/Cas9 makes it a particularly powerful tool for gene editing. Variants of the Cas9 protein have also been created to either silence or activate gene expression without physically altering the genome. In addition to the

 CRISPR/Cas9, other bacterial CRISPR systems, such as the

 CRISPR/Cas9, are being explored for gene editing.

How will this research someday translate into clinical practice, specifically for cancer patients?

 CRISPR is currently used in the laboratory setting to screen human cancer cell lines for drug targets and to create mouse cancer models for preclinical studies. As a direct therapeutic tool, CRISPR has broad applications in gene therapy. For example, CRISPR has been successfully used to correct disease mutations associated with type I tyrosinemia, Î²-thalassemia, cystic fibrosis, and Duchenne muscular dystrophy in preclinical studies. Furthermore, CRISPR has demonstrated utility in eliminating persistent viral infection from hepatitis B and HIV in preclinical studies. These promising findings provide support for advancing CRISPR to clinical studies. In the cancer arena, one exciting application of CRISPR as a therapeutic tool is to edit the patient’s immune cells to more effectively fight cancer. For example, clinical trials have been planned to knock out the immune checkpoint protein programmed death 1 using CRISPR in patient-derived T cells to stimulate the T cells’ ability to attack cancer cells.

Are there currently any barriers to the CRISPR research, financial or otherwise?

Like other experimental gene therapies, safety is an important concern with CRISPR. The CRISPR/Cas9 enzyme has an inherent error rate that causes it to generate unwanted, off-target mutations in the genome. Progress has been made to evolve high-fidelity variants of Cas9 with reduced off-target errors. Because CRISPR/Cas9 introduces physical changes in the genome, additional safety measures must be included in CRISPR-edited cells to enable their safe removal from the patient in the event that these cells behave in unexpected ways in the body. When CRISPR is used for direct somatic gene correction in vivo, its effective delivery to the tissue of interest, and how it could avoid triggering undesired immune reactions, are two major challenges. In this setting, shuttle vectors based on adeno-associated virus are promising vehicles for tissue delivery. The current intellectual property landscape surrounding CRISPR technology is complex, and there are several uncertainties associated with CRISPR patent rights that could slow down the commercialization of this technology.

When can we expect to see the CRISPR technology in mainstream practice?

The first clinical trial using CRISPR to edit cancer patients’ T cells has been approved in the United States. If proven safe, the ultimate hope is that the CRISPR-edited immune cells will become more effective at fighting the patient’s tumor when they are put back into the body. Although gene therapy has faced many challenges in the past, there is cautious optimism that CRISPR will enable a new generation of gene therapy for the treatment of cancer.

In this interview we discuss the CRISPR technology currently being used to “edit” genes and when we might see the technology in mainstream practice.

Ji Luo Elucidates the CRISPR Gene Editing Technology, and How It May Affect Cancer Therapy in the Future

The use of chimeric antigen receptor (CAR)-modified T cells is a promising antineoplastic immunotherapy. As discussed by Drs. Frey and Porter in this issue of ONCOLOGY,[1] it involves genetic manipulation of autologous cytotoxic T cells to create a product capable of targeting specific tumor antigens. In theory, CAR-modified T cells can be developed to target any tumor antigen; however, specificity for tumor rather than host antigens is of paramount importance with regard to limiting toxicity. Because current CAR T-cell treatment approaches employ autologous T cells, issues such as the potential for graft-vs-host disease or the lack of donor availability are of no concern. Due to the early successes of CAR T-cell therapy reported for young patients with relapsed acute lymphoblastic leukemia (ALL) who have exhausted all conventional therapies, it is hoped that treatment with CAR-modified T cells could result in sustained remissions for patients without other therapeutic options.

ALL, chronic lymphocytic leukemia (CLL), and non-Hodgkin lymphoma (NHL) are B-cell malignancies that, despite recent advances in treatment, still result in a dismal prognosis for patients who become resistant to conventional chemotherapy and immunotherapy. In the early clinical trials of CD19-specific CAR-modified T-cell therapy, the durability of remissions observed in patients with relapsed/refractory hematologic malignancies has been unparalleled by outcomes from clinical trials of other therapies. As Drs. Frey and Porter discuss, the clinical trials with second-generation anti-CD19 CAR T cells have shown remission rates of 70% to 90% to date. Most notably, in a study by Maude et al, 15 of 27 responding pediatric patients with relapsed and refractory B-cell ALL who did not undergo post-remission stem cell transplants have remained in complete remission after 2 years.[2] In studies of CAR T-cell therapy in CLL, while reported overall response rates were not as robust as those seen in ALL trials, long-term molecular remissions were observed. Early data with anti-CD19 CAR T cells in NHL also suggest promising rates of response to treatment.[3,4] Interestingly, the specific lymphodepleting chemotherapy used may determine the duration of remission and overall response rates, especially in ALL and NHL. Although responses to CAR T-cell therapy have been observed without lymphodepletion, this pretreatment process allows superior engraftment and persistence of the CAR T cells in vivo. The optimal lymphodepleting chemotherapy may differ based on the particular malignancy and patient population being treated, and is an area of active investigation.

Ultimately, to extend the promise of CAR T-cell immunotherapy to a substantial number of cancer patients, CAR T cells must be developed that have specificity against the key tumor antigens for a specific tumor type. For example, multiple myeloma has demonstrated sensitivity to cellular immunotherapy with anti-CD19 CAR T cells, even though myeloma cells rarely express CD19. Due to this encouraging activity, three other more commonly expressed antigens-BCMA, CD38, and SLAMF7-are being investigated as potential targets.[5-8]

While the promise of CAR T-cell therapy is alluring, it is also a field in which unique toxicities pose new challenges. Cytokine release syndrome (CRS) and neurotoxicity are two of the more prominent side effects occurring in patients treated with CAR T-cell therapy. CRS has a wide spectrum of presentations, but when severe it can be life-threatening and requires immediate attention. The pathogenesis is thought to involve interleukin-6 secretion triggered by the in vivo activation and proliferation of CAR T cells. For this reason, the monoclonal anti–interleukin-6 antibody tocilizumab is a standard treatment for CRS. The pathogenesis of neurotoxicity caused by CAR T-cell therapy is not as well understood as that of CRS, but it may be associated with bulk of disease or dose and schedule of CAR T cells.

Additional logistical obstacles currently limit widespread application of CAR T-cell immunotherapy. It takes weeks to prepare CAR T cells; the process requires apheresis of autologous T cells, genetic modification and expansion of these cells, and several other steps before they can finally be reintroduced into the patient. This lengthy manufacturing process can be problematic because many patients may suffer from fulminant relapses that do not allow safe delays for cell manipulation and expansion of CAR T cells. In ALL, an additional limitation to optimizing CAR T-cell treatment is that most of the patients studied in clinical trials to date were children or young adults at the time of enrollment; therefore, the ability of older patients with comorbidities to tolerate unique immunotherapy toxicities from CAR T-cell therapy, such as neurotoxicity and CRS, is not well known.

Given that cellular immunotherapy is still in its infancy, there are still more questions than answers with regard to optimal patient selection, CAR T-cell design, and toxicity management. There is active interest in how to best temper the untoward effects of cellular immunotherapy. One attractive avenue could be through insertion of apoptosis-inducing genes that are activated in the presence of drugs. The gene would act as a “safety switch” to allow preferential removal of CAR T cells in case of severe toxicity. Another approach might be to engineer another targetable cell-surface antigen, such as CD20 or epidermal growth factor receptor, to the CAR itself. This would make the CAR T cell susceptible to the agents rituximab and cetuximab, respectively, similarly making possible a selective apoptosis. Such control over the CAR T cells may allow modulation of toxicity and make cellular immunotherapy more broadly applicable to patients who are not likely to tolerate severe CRS.

Identification of effective lymphodepletion strategies, optimization of patient selection, and management of novel toxicities remain challenges in the growing field of cellular immunotherapy. However, as the design of CAR T-cell therapies to treat specific hematologic and solid malignancies continues to evolve, these new approaches hold great promise for many patients with previously incurable malignancies.

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

 Frey NV, Porter DL. The promise of chimeric antigen receptor T-cell therapy. Oncology (Williston Park). 2016;30:880-8;890.

 Maude SL, Frey N, Shaw PA, et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med. 2014;371:1507-17.

 Turtle CJ, Berger C, Sommermeyer D, et al. Anti–CD19 chimeric antigen receptor–modified T cell therapy for B cel non-Hodgkin lymphoma and chronic lymphocytic leukemia: fludarabine and cyclophosphamide lymphodepletion improves in vivo expansion and persistence of CAR–T cells and clinical outcomes. Blood. 2015;126:184.

 Schuster SJ, Svoboda J, Dwivedy Nasta S, et al. Sustained remissions following chimeric antigen receptor modified T cells directed against CD19 in patients with relapsed or refractory CD19+ lymphomas. Blood. 2015;126:183.

 Carpenter RO, Evbuomwan MO, Pittaluga S, et al. B-cell maturation antigen is a promising target for adoptive T-cell therapy of multiple myeloma. Clin Cancer Res. 2013;19:2048-60.

 Mihara K, Yanagihara K, Takigahira M, et al. Activated T-cell-mediated immunotherapy with a chimeric receptor against CD38 in B-cell non-Hodgkin lymphoma. J Immunother. 2009;32:737-43.

 Danhof S, Gogishvili T, Koch S, et al. CAR-engineered T cells specific for the elotuzumab target SLAMF7 eliminate primary myeloma cells and confer selective fratricide of SLAMF7+ normal lymphocyte subsets. Blood. 2015;126:115.

 Drent E, Groen R, Noort WA, et al. CD38 chimeric antigen receptor engineered T cells as therapeutic tools for muliple myeloma. Blood. 2014;124:4759.

Identification of effective lymphodepletion strategies, optimization of patient selection, and management of novel toxicities remain challenges in the growing field of cellular immunotherapy. 

Oncology Vol 30 No 10