In this issue of ONCOLOGY, Barnea et al review the important topic of obesity and metabolic disease after therapy for childhood cancer.[1] This evolving issue is increasingly concerning, as studies regarding the causes of non-relapse late mortality in childhood cancer survivors consistently include cardiovascular disease as one of the major contributors to this mortality risk.[2,3] Our success at treating childhood cancer has resulted in an increasing number of survivors who are now adults, but who often lack appropriate follow-up, given their prior cancer treatment history and increased risk of cardiovascular and other chronic conditions.[4] Very few programs for ongoing follow-up of this adult-aged population exist, and these survivors are, for the most part, inadequately prepared to advocate for their own healthcare needs after they transition out of pediatric-based care.[5]

In the general population, a common theme behind cardiovascular risk is obesity, which establishes a state of insulin resistance and hyperlipidemia, and increases the risk of diabetes mellitus (DM).[6] Although obesity influences the development of cardiovascular risk factors in childhood cancer survivors, treatment exposure is the primary contributing factor.[7] In particular, as Barnea et al state in their review, radiation therapy plays an important role in the etiology of obesity, dyslipidemias, and insulin resistance seen in childhood cancer survivors; the risk is primarily related to three specific radiation exposures: total body irradiation (TBI) delivered as part of the preparative regimen prior to hematopoietic stem cell transplant (HCT), cranial radiation therapy (CRT) given for treatment of leukemia or brain tumors, and abdominal radiation used for certain solid tumors.[1]

In HCT survivors who have received TBI, an alteration in body composition characterized by a decrease in muscle mass and an increase in visceral fat mass in the setting of a lack of abdominal obesity has been described.[8] This pattern of “sarcopenic obesity” is associated with the development of insulin resistance and dyslipidemia, which, although the exact mechanisms are not clearly understood, is likely secondary to a loss of myocyte insulin receptors combined with an increase in visceral fat mass.

Leptin and adiponectin are adipocyte hormones involved in the regulation of appetite and energy expenditure and storage. In patients exposed to CRT, hypothalamic injury may result in a state of central leptin resistance, leading to higher leptin levels but loss of the inhibitory impact on appetite, thus contributing to obesity. Adiponectin, which normally enhances insulin secretion, glucose utilization, and fatty acid oxidation, is produced at levels inversely proportional to fat mass; thus, reduced levels in survivors with a higher fat mass may contribute to insulin resistance.[9] Studies of both acute lymphoblastic leukemia (ALL) survivors and those who received HCT have demonstrated higher levels of leptin and lower levels of adiponectin associated with insulin resistance in these patients.[10,11]

Several studies have now reported the link between abdominal radiation and the risk of DM. Correlations were observed between higher radiation doses to the tail of the pancreas, where insulin-producing pancreatic Ã cells reside, and a higher risk of DM.[1] This has primarily been seen in patients with abdominal solid tumors, such as neuroblastoma, Wilms tumor, and soft tissue sarcomas, in which relatively high doses of radiation are sometimes utilized.

Although treatment methods are extremely important risk factors in the causal pathway leading to obesity and metabolic syndrome in childhood cancer survivors, factors that impact the risk of these same outcomes in the general population, such as poor dietary habits and sedentary lifestyle, cannot be overlooked. Currently, the overall body of evidence remains limited, but childhood cancer survivors have been shown to be less physically active and less likely to adhere to healthy dietary guidelines as compared with healthy controls.[1] In addition to previously mentioned factors, other effects such as treatment-related neuropathy and cognitive limitations, as well as altered lifestyle habits acquired during prolonged treatment duration (2 to 3 years for ALL patients), may be significant. It is clear, however, in the general population that change of diet and lifestyle, weight loss, and increased physical activity are all powerful modifiers of the risk of cardiovascular disease and DM.[6]

Whether these interventions will have the same degree of positive impact and reduction in risk in childhood cancer survivors is unknown, although early studies have been encouraging.[1] However, it remains to be seen if the sarcopenic phenotype induced by radiation can be reversed with exercise alone. Much research is also still needed to explore the most effective intervention (cardiorespiratory fitness, muscle endurance, or strength training, etc) and timing in relation to treatment (during, after, and/or both), as well as how to help childhood cancer survivors maintain a physically active lifestyle and healthy diet for a lifetime.

Moving forward, additional research should also focus on determining whether genetic factors that impact susceptibility to cellular damage by chemotherapy and radiation, or those that affect regulation of metabolic pathways, are important among childhood cancer survivors. Pharmacologic interventions also need to be studied to determine whether there is a role for insulin-sensitizing agents in patients who are at high risk for DM. Coupled with this is a need for better screening recommendations for childhood cancer survivors as they transition into adulthood, as well as education of the primary care community regarding the long-term follow-up care of this unique and growing population. Changes and advancements in the way that cancer therapy is delivered, with less reliance on cytotoxic chemotherapy and elimination or reduction of radiation, and greater reliance on more targeted therapies, may ultimately eliminate or ameliorate some of the adverse outcomes in childhood cancer survivors.

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

 Barnea D, Raghunathan N, Novetsky Friedman D, Tonorezos ES. Obesity and metabolic disease after childhood cancer. Oncology (Williston Park). 2015;29:849-55.

 Mertens AC, Liu Q, Neglia JP, et al. Cause-specific late mortality among 5-year survivors of childhood cancer: the Childhood Cancer Survivor Study. J Natl Cancer Inst. 2008;100:1368-79.

 Reulen RC, Winter DL, Frobisher C, et al. Long-term cause-specific mortality among survivors of childhood cancer. JAMA. 2010;304:172-9.

 Robison LL, Hudson MM. Survivors of childhood and adolescent cancer: life-long risks and responsibilities. Nat Rev Cancer. 2014;14:61-70.

 Henderson TO, Friedman DL, Meadows AT. Childhood cancer survivors: transition to adult-focused risk-based care. Pediatrics. 2010;126:129-36.

 Steinberger J, Daniels SR, Eckel RH, et al. Progress and challenges in metabolic syndrome in children and adolescents: a scientific statement from the American Heart Association Atherosclerosis, Hypertension, and Obesity in the Young Committee of the Council on Cardiovascular Disease in the Young; Council on Cardiovascular Nursing; and Council on Nutrition, Physical Activity, and Metabolism. Circulation. 2009;119:628-47.

 Lipshultz SE, Adams MJ, Colan SD, et al. Long-term cardiovascular toxicity in children, adolescents, and young adults who receive cancer therapy: pathophysiology, course, monitoring, management, prevention, and research directions: A scientific statement from the American Heart Association. Circulation. 2013;128:1927-95.

 Baker KS, Chow E, Steinberger J. Metabolic syndrome and cardiovascular risk in survivors after hematopoietic cell transplantation. Bone Marrow Transplant. 2012;47:619-25.

 Antuna-Puente B, Feve B, Fellahi S, Bastard JP. Adipokines: the missing link between insulin resistance and obesity. Diabetes Metab. 2008;34:2-11.

 Oeffinger KC, Adams-Huet B, Victor RG, et al. Insulin resistance and risk factors for cardiovascular disease in young adult survivors of childhood acute lymphoblastic leukemia. J Clin Oncol. 2009;27:3698-704.

 Chow EJ, Simmons JH, Roth CL, et al. Increased cardiometabolic traits in pediatric survivors of acute lymphoblastic leukemia treated with total body irradiation. Biol Blood Marrow Transplant. 2010;16:1674-81.

Articles

This evolving issue is increasingly concerning, as studies regarding the causes of non-relapse late mortality in childhood cancer survivors consistently include cardiovascular disease as one of the major contributors to this mortality risk.

Childhood Cancer Survivors: Cured but With Long-Term Health Risks

Weinberg and colleagues elegantly describe recent advances and future possibilities in the treatment of pancreatic adenocarcinoma.[1] I respectfully disagree with the authors that advances in this area of oncology have been “significant,” especially when considered in relation to developments in other similarly aggressive cancers. Drugs that have been approved over the past 2 decades continue to be nontargeted cytotoxic agents. Moreover, the median survival of patients with metastatic pancreatic cancer remains under 12 months even among clinical trial participants-and is much shorter for the overall population of patients with metastatic disease.[2] While combination therapies delay the worsening of performance status, they do not effectively palliate symptoms in the majority of patients because of the low frequency of objective tumor responses.[3,4] In addition, intermediate- and long-term use of cytotoxic regimens (FOLFIRINOX [fluorouracil, leucovorin, irinotecan, and oxaliplatin], gemcitabine/nab-paclitaxel) is often limited by fatigue and neuropathy.[3,4] Quality of life is a major consideration, and for that reason oncologists adopt various “regimen deviations” to improve tolerance-for example, dropping a drug from FOLFIRINOX or administering gemcitabine/nab-paclitaxel on an every-2-weeks schedule. Our goal in treating metastatic disease must be the sequential use of tolerable regimens in order to maximize exposure to active drugs, an approach that worked in advanced colorectal cancer. The availability of other agents, such as the recently approved liposomal irinotecan, for use after failure on gemcitabine-based treatment, may facilitate that kind of strategy, although the benefit may still be modest.

Undoubtedly we are discouraged by the very limited success in treating pancreatic cancer, a characteristic of pancreatic cancer trials during much of the period from the late 1990s through the early 2000s, when a “gemcitabine plus drug X” testing platform was being used. In those years, popular targets such as the epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF)/VEGF receptor were investigated in large clinical trials that demonstrated no benefit except for the very marginal and clinically irrelevant improvement with erlotinib.[5] These trials taught us the futility of single-molecule or single-pathway targeting in a highly molecularly complex and redundant disease, especially when the targets are tested in molecularly unselected patients. Unlike diseases such as lung cancer, in which activating and actionable mutations lead to dramatic outcomes in patient subsets, no actionable mutations have been discovered in pancreatic cancer, except for the very-difficult-to-target 

 mutations[6,7] that affect the majority of patients. This led the pancreatic cancer research community to reconsider the merits of large randomized trials in which agents are tested with minimal scientific rationale and in unselected patients. A consensus was reached in 2008 on the need to focus on improving our understanding of the biology of pancreatic cancer, on enhancing use of preclinical models, and on testing promising agents in well-designed pilot trials before launching large and expensive studies.[8] This shift in focus largely explains the absence of any national phase III trials in advanced pancreatic cancer for a long time.

Where do we stand now? There is undoubtedly a rapidly growing interest in pancreatic cancer research among basic researchers, which is helped by the willingness of pharmaceutical companies to be engaged with this “stubborn” disease. Positive and timely advances have also been the result of the efforts of advocacy groups, spearheaded by the Pancreatic Cancer Action Network, which engage the public, cancer researchers, and funding agencies. More than before, critical areas of research in pancreatic cancer are being identified and actively pursued. This coincides with intensive efforts to tackle the challenge of targeting mutated

, an early carcinogenic event that drives the pancreatic malignant process.

Weinberg and colleagues have nicely described several promising therapies. In the setting of a disease with no targetable kinase overactivity (mutation or amplification) and with plenty of difficult-to-target tumor suppressor gene mutations (eg, 

),[5] the hope is to identify treatment modalities that exploit other aspects of pancreatic cancer biology. Exploiting DNA repair deficiencies, such as 

 mutations, is an emerging personalized treatment modality that uses currently approved drugs.[9,10] Targeting the dense stroma that characterizes pancreatic adenocarcinoma is moving closer to being a real possibility, with exciting early data on the activity of pegylated hyaluronidase in hyaluronan-overexpressing patients.[11] The stroma has traditionally been described as a barrier to effective delivery of anticancer drugs. However, the biology of the stroma must be carefully evaluated to ensure that stromal targeting does not worsen the cancer by removing elements that have a negative influence on the tumor cells. The failure of targeting the Hedgehog pathway in patients[12] highlighted the perils of undertaking translational research without careful attention to preclinical modeling. Immunotherapy is also being actively pursued, although the antitumor activity of single immune checkpoint inhibitors (eg, programmed death 1 [PD-1] or programmed death ligand 1 [PD-L1] inhibitors) has not yet been demonstrated in this disease. Nevertheless, this class of agents may be very valuable when combined with vaccines (eg, GVAX [granulocyte-macrophage colony-stimulating factor–secreting allogeneic pancreatic tumor cells]) or agents that perturb the immune and inflammatory components of the pancreatic cancer microenvironment (eg, Bruton tyrosine kinase inhibitors). Trials of such combinations are in progress (ClinicalTrials.gov identifiers: NCT02451982, NCT02362048).

The ultimate benefit to patients will come from a demonstration of clinically worthwhile benefits of new drugs that have been tested in well-designed and adequately powered clinical trials performed in an expedited fashion. Current national figures for participation in clinical trials by patients with pancreatic cancer are exceedingly low.[13] One reason for the low numbers is that the eligibility of patients with advanced disease for participation in clinical trials is often limited to those with favorable performance status (0 or 1 on the Eastern Cooperative Oncology Group [ECOG] scale). Studies must also be pursued in patients with unfavorable performance status (2 or 3 on the ECOG scale) and in the elderly, who represent a sizable percentage of patients with pancreatic cancer. And of course, community oncologists must encourage patients to participate in clinical trials. Also, treatment strategies must address clinical problems that affect quality of life (eg, cachexia) and that interfere with treatment outcome. Drugs such as ruxolitinib (now in phase III clinical trials) may prove useful in this regard: ruxolitinib mitigates cachexia and helps patients feel better, thereby enabling them to receive more treatment. Gemcitabine/nab-paclitaxel and FOLFIRINOX may be described as treatment standards, but in reality they are weak standards. An empirical research strategy of “gemcitabine/nab-paclitaxel plus drug X” or “FOLFIRINOX plus drug Y” that lacks a robust scientific rationale must not be regarded as an acceptable developmental path. Finally, a major limitation on the evaluation of new agents in pancreatic cancer is the ability to access tumor tissue, a challenge because of the paucity of material obtained through diagnostic needle biopsies. There is active research to explore the utility of blood (liquid biopsy) and to improve tissue yield from tumor sampling.[14,15] The reliability of circulating tumor cells or other molecules (eg, free DNA, micro RNAs) in representing the underlying disease is yet to be determined.

Dr. Philip serves on advisory boards for and consults for Celgene, Halozyme Therapeutics, and Merrimack Pharmaceuticals; he receives research support from Celgene, Immunomedics, Incyte, and Momenta Pharmaceuticals

 Weinberg BA, Yabar CS, Brody JR, Pishvaian MJ. Current standards and novel treatment options for metastatic pancreatic adenocarcinoma. Oncology (Williston Park). 2015;29:809-20;886.

 Philip PA, Chansky K, LeBlanc M, et al. Historical controls for metastatic pancreatic cancer: benchmarks for planning and analyzing single-arm phase II trials. Clin Cancer Res. 2014;20:4176-85.

 Conroy T, Desseigne F, Ychou M, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011;364:1817-25.

 Von Hoff DD, Ervin T, Arena FP, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 2013;369:1691-703.

 Moore MJ, Goldstein D, Hamm J, et al. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 2007;25:1960-6.

 Ryan DP, Hong TS, Bardeesy N. Pancreatic adenocarcinoma. N Engl J Med. 2014; 371:1039-49.

 Kirsten L, Bryant KL, Mancias JD, et al. KRAS: feeding pancreatic cancer proliferation. Trends Biochem Sci. 2014;39:91-100.

 Philip PA, Mooney M, Jaffe D, et al. Consensus report of the National Cancer Institute Clinical Trials Planning Meeting on Pancreas Cancer Treatment. J Clin Oncol. 2009;27: 5660-9.

 Golan T, Kanji ZS, Epelbaum R, et al. Overall survival and clinical characteristics of pancreatic cancer in BRCA mutation carriers. Br J Cancer. 2014;111:1132-8.

 Waddell N, Pajic M, Patch A-M, et al. Whole genomes redefine the mutational landscape of pancreatic cancer. Nature. 2015;518:495-501.

 Hingorani SR, Harris WP, Hendifar AG, et al. High response rate and PFS with PEGPH20 added to nab-paclitaxel/gemcitabine in stage IV previously untreated pancreatic cancer patients with high-HA tumors: interim results of a randomized phase II study. J Clin Oncol. 2015;33(suppl):abstr 4006.

 Lee JJ, Perera RM, Wang H, et al. Stromal response to Hedgehog signaling restrains pancreatic cancer progression. Proc Natl Acad Sci USA. 2014;111:E3091-E3100.

 Hoos WA, James PA, Rahib L, et al. Pancreatic cancer clinical trials and accrual in the United States. J Clin Oncol. 2013;31:3312-4.

 Crowley E, Di Nicolantonio F, Loupakis F, et al. Liquid biopsy: monitoring cancer-genetics in the blood. Nature Rev Clin Oncol. 2013;10:472-84.

 Krebs MG, Metcalf RL, Carter L, et al. Molecular analysis of circulating tumor cells-biology and biomarkers. Nature Rev Clin Oncol. 2014;11:129-44.

The ultimate benefit to patients will come from a demonstration of clinically worthwhile benefits of new drugs that have been tested in well-designed and adequately powered clinical trials performed in an expedited fashion.

Systemic Therapy of Pancreatic Cancer: Better Science, Faster Progress

The biologic rationale for the initial evaluation of preoperative chemotherapy or neoadjuvant chemotherapy in patients with early-stage breast cancer was based on experimental and clinical observations regarding primary tumor cell growth and dissemination.[1-3] Additional clinical justification was provided by the demonstration of equivalent survival among patients who underwent breast-conserving surgery (BCS) rather than mastectomy,[4,5] as well as the demonstration of benefit from adjuvant chemotherapy irrespective of pathologic nodal status.[6] As a result, neoadjuvant chemotherapy was compared against adjuvant chemotherapy in clinical trials, with the intent to convert patients requiring mastectomy into candidates for BCS.

Several large randomized trials, assessing neoadjuvant chemotherapy vs adjuvant chemotherapy in patients with operable breast cancer, showed no significant differences in long-term outcomes and confirmed that neoadjuvant chemotherapy significantly increased rates of BCS.[7-10] They also showed that achievement of pathologic complete response (pCR) in the breast and axillary nodes was significantly correlated with improved long-term outcomes. As a result, pCR can be used as a surrogate endpoint for efficacy of neoadjuvant chemotherapy, one which is currently accepted by the US Food and Drug Administration (FDA) as a pathway toward accelerated approval of new drugs for the treatment of early-stage breast cancer.[11]

Thus, neoadjuvant chemotherapy has become a reasonable alternative to adjuvant chemotherapy for patients with operable breast cancer, and it has several potential clinical advantages in addition to increasing the rates of BCS. By reducing the size of the primary tumor with neoadjuvant chemotherapy, there is potential for improving the cosmetic result of BCS, even for patients who were BCS candidates at presentation. This approach also downstages axillary lymph nodes in a significant proportion of patients-approximately 20% to 30% of those receiving anthracycline-containing regimens,[7,9] close to 40% when treatment includes an anthracycline plus a taxane,[10,12] and in more than 50% of patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer who receive chemotherapy plus anti-HER2 therapy. This observation has important clinical implications, since patients with involved axillary nodes at presentation can be downstaged with neoadjuvant chemotherapy and converted to candidates for sentinel lymph node biopsy (SLNB) alone, thereby avoiding axillary node dissection if the sentinel lymph nodes (SLNs) are negative.

Another potential advantage of neoadjuvant chemotherapy is that it enables clinicians to evaluate proven and putative biomarkers and correlate them with clinical and pathologic response-and, eventually, outcome.[13] Thus, one could rapidly gain biologic insight into the nature and function of such biomarkers relative to chemosensitivity or chemoresistance,[14,15] which, in turn, can facilitate the selection of appropriate candidates for particular neoadjuvant regimens while avoiding unnecessary toxicity in patients unlikely to benefit.

The article by Dr. Santa-Maria and colleagues in this issue of ONCOLOGY provides a comprehensive and yet extremely succinct review of the evolution and current state of the art of neoadjuvant chemotherapy.[16] It addresses many of the questions regarding locoregional and systemic therapy that are associated with neoadjuvant chemotherapy, and provides useful recommendations for how best to incorporate it into everyday clinical practice. First, as the authors note, the indications for neoadjuvant chemotherapy have expanded to consider not only the extent of the disease but also its biology. Thus, this approach is currently utilized not just for patients with locally advanced/large operable breast cancers who need downstaging, but is also used for those who, based on their tumor subtype, have chemoresponsive disease and an increased probability of pCR (by virtue of their inherent disease biology and the availability of effective therapy). The authors also correctly identify the limitations of neoadjuvant chemotherapy and discuss why it should be avoided in certain patient subgroups (ie, those with low probability of pCR and those for whom the use and appropriate type of chemotherapy are not clear until pathologic nodal status becomes known).

Regarding imaging assessment before neoadjuvant chemotherapy, Dr. Santa-Maria and colleagues emphasize the increased sensitivity of breast magnetic resonance imaging (MRI) in determining the extent of the primary breast tumor, but they also caution that MRI may overestimate tumor size. They recommend that the decision to use MRI be individualized, if BCS is desired. They also describe in detail the clinical and radiologic evaluation of the axilla before neoadjuvant chemotherapy is administered, and its implications for successful application of SLNB after neoadjuvant chemotherapy, particularly for patients with axillary nodal involvement at presentation who become pathologically node-negative after neoadjuvant chemotherapy. The authors appropriately point out the limitations of performing SLNB before treatment with neoadjuvant chemotherapy in patients with clinically negative axilla, correctly concluding that the ideal approach for such patients is to perform the SLNB after patients have received neoadjuvant chemotherapy.

The importance of a multidisciplinary approach for neoadjuvant chemotherapy candidates is discussed in detail. Such an approach is paramount for successful outcomes. Ideally, it should go beyond the initial involvement of surgical, medical, and radiation oncologists to include the multidisciplinary tumor board, pathologists, radiologists, plastic surgeons, genetic counselors, and clinical research personnel, since all of these specialists have important contributions to make to the patient’s plan of care from the beginning.

The article provides a thoughtful review of systemic therapy considerations for neoadjuvant chemotherapy. As the authors point out, this approach provides little benefit to patients with hormone-responsive breast cancer and favorable histology, who generally have very low pCR rates. On the opposite end of the spectrum, the authors discuss and critique both the evolving success of neoadjuvant chemotherapy plus anti-HER2 therapy in HER2-positive breast cancer, and the correlation between increases in pCR rates with more active neoadjuvant chemotherapy regimens and improvements in outcomes observed in adjuvant/neoadjuvant trials. Similarly, they review in depth several recent studies showing that increased pCR rates for patients with triple-negative breast cancer can be achieved when neoadjuvant chemotherapy is supplemented with bevacizumab, platinum salts, and poly (ADP-ribose) polymerase (PARP) inhibitors. In addition, Dr. Santa-Maria and colleagues emphasize the clinical research advantages of evaluating new agents in patients who have residual disease after neoadjuvant chemotherapy. This is a desirable setting, since treatment is targeted only to high-risk patients with tumors proven resistant to existing therapies; therefore, use of new experimental therapies is justified. Given the high event rate, smaller trials and shorter follow-up are required for success, and prognostic profiling data can be obtained from cells that are resistant to prior neoadjuvant chemotherapy.

Dr. Santa-Maria and colleagues provide a thoughtful discussion of surgical issues with respect to the breast and axilla following neoadjuvant chemotherapy, and the evolving integration of locoregional radiation therapy (RT) in the neoadjuvant setting. They review the performance of SLNB for patients who present with clinically negative axilla and those who present with documented axillary nodal involvement. They conclude that SLNB after neoadjuvant therapy is feasible for patients with initial node-positive disease, provided that: (1) more than two SLNs are removed, (2) dual-agent mapping is employed, and (3) SLNB is combined with localization and retrieval of biopsy-proven positive lymph nodes that were marked with a clip at initial core needle biopsy or fine-needle aspiration biopsy.

Lastly, regarding the use of post-mastectomy RT and regional nodal RT after neoadjuvant chemotherapy, the authors recognize the controversy, particularly for patients who present with axillary nodal involvement and achieve pCR in the nodes following such treatment. Studies evaluating risk of locoregional recurrence after neoadjuvant chemotherapy have consistently shown lower risk for patients who achieve pCR, compared with those who do not.[17,18] The authors describe the ongoing randomized phase III trial by the National Surgical Adjuvant Breast and Bowel Project (NSABP) and the Radiation Therapy Oncology Group (RTOG), NSABP B-51/RTOG 1304, which addresses the role of post-mastectomy and regional nodal RT in patients with positive axillary nodes before neoadjuvant chemotherapy who convert to pathologically negative axillary nodes afterwards. This study will help us to determine which patients can safely avoid post-mastectomy and/or regional nodal RT in the setting of nodal pCR.[19]

In summary, Dr. Santa-Maria and colleagues should be commended for their well-written and timely review of the current practice of neoadjuvant chemotherapy in early-stage breast cancer, as well as controversies and future directions in this setting. Although several such reviews exist, the authors’ approach is informative and comprehensive, and their article addresses all major issues on the topic, while being clear and concise.

Dr. Mamounas has served on the advisory boards of Celgene, Genomic Health, Novartis, and Pfizer, and he currently serves on the speakers bureaus of Genentech/Roche and Genomic Health

 Skipper HE. Kinetics of mammary tumor cell growth and implications for therapy. Cancer. 1971;28:1479-99.

 Goldie JH, Coldman AJ. A mathematic model for relating the drug sensitivity of tumors to their spontaneous mutation rate. Cancer Treat Rep. 1979;63:1727-33.

 Fisher B, Gunduz N, Saffer EA. Influence of the interval between primary tumor removal and chemotherapy on kinetics and growth of metastases. Cancer Res. 1983;43:1488-92.

 Fisher B, Redmond C, Poisson R, et al. Eight-year results of a randomized clinical trial comparing total mastectomy and lumpectomy with or without irradiation in the treatment of breast cancer. N Engl J Med. 1989;320:822-8.

 Veronesi U, Saccozzi R, Del Vecchio M, et al. Comparing radical mastectomy with quadrantectomy, axillary dissection, and radiotherapy in patients with small cancers of the breast. N Engl J Med. 1981;305:6-11.

 Early Breast Cancer Trialists’ Collaborative Group. Systemic treatment of early breast cancer by hormonal, cytotoxic, or immune therapy. 133 randomised trials involving 31,000 recurrences and 24,000 deaths among 75,000 women. Lancet. 1992;339:71-85.

 Fisher B, Brown A, Mamounas E, et al. Effect of preoperative chemotherapy on local-regional disease in women with operable breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-18. J Clin Oncol. 1997;15:2483-93.

 Fisher B, Bryant J, Wolmark N, et al. Effect of preoperative chemotherapy on the outcome of women with operable breast cancer. J Clin Oncol. 1998;16:2672-85.

 van der Hage JA, van de Velde CJ, Julien JP, et al. Preoperative chemotherapy in primary operable breast cancer: results from the European Organization for Research and Treatment of Cancer trial 10902. J Clin Oncol. 2001;19:4224-37.

 Gianni L, Baselga J, Eiermann W, et al. First report of the European Cooperative Trial in operable breast cancer (ECTO): effect of primary systemic therapy. Proc Am Soc Clin Oncol. 2002;21:abstr 132.

 Prowell TM, Pazdur R. Pathological complete response and accelerated drug approval in early breast cancer. N Engl J Med. 2012;366:2438-41.

 Bear HD, Anderson S, Brown A, et al. The effect on tumor response of adding sequential preoperative docetaxel to preoperative doxorubicin and cyclophosphamide: preliminary results from National Surgical Adjuvant Breast and Bowel Project Protocol B-27. J Clin Oncol. 2003;21:4165-74.

 Fisher B, Mamounas EP. Preoperative chemotherapy: a model for studying the biology and therapy of primary breast cancer. J Clin Oncol. 1995;13:537-40.

 Pusztai L, Ayers M, Simman FW, et al. Emerging science: prospective validation of gene expression profiling-based prediction of complete pathologic response to neoadjuvant paclitaxel/FAC chemotherapy in breast cancer. Proc Am Soc Clin Oncol. 2003;22:abstr 1.

 Paik S, Shak S, Tang G, et al. Multi-gene RT-PCR assay for predicting recurrence in node negative breast cancer patients - NSABP studies B-20 and B-14. Breast Cancer Res Treat. 2003;82(suppl 10):abstr 16.

 Santa-Maria CA, Camp M, Cimino-Mathews A, et al. Neoadjuvant therapy for early-stage breast cancer: current practice, controversies, and future directions. Oncology (Williston Park). 2015;29:828-38.

 Buchholz TA, Tucker SL, Masullo L, et al. Predictors of local-regional recurrence after neoadjuvant chemotherapy and mastectomy without radiation. J Clin Oncol. 2002;20:17-23.

 Mamounas EP, Anderson SJ, Dignam JJ, et al. Predictors of locoregional recurrence after neoadjuvant chemotherapy: results from combined analysis of National Surgical Adjuvant Breast and Bowel Project B-18 and B-27. J Clin Oncol. 2012;30:3960-6.

 Mamounas EP, White JR, Bandos H, et al. NSABP B-51/RTOG 1304: randomized phase III clinical trial evaluating the role of postmastectomy chest wall and regional nodal XRT (CWRNRT) and post-lumpectomy RNRT in patients (pts) with documented positive axillary (Ax) nodes before neoadjuvant chemotherapy (NC) who convert to pathologically negative Ax nodes after NC. J Clin Oncol. 2014;32(suppl 5s):abstr TPS1141.

The biologic rationale for the initial evaluation of preoperative chemotherapy or neoadjuvant chemotherapy in patients with early-stage breast cancer was based on experimental and clinical observations regarding primary tumor cell growth and dissemination.

Neoadjuvant Therapy for Early-Stage Breast Cancer: A Model for Individualizing Outcomes and Tailoring Locoregional and Systemic Therapy

Neoadjuvant therapy for breast cancer, formerly limited to the treatment of patients with locally advanced tumors, has gradually become a common clinical practice. In this issue of ONCOLOGY, Dr. Santa-Maria and colleagues thoughtfully review the existing practice of neoadjuvant treatment; detail the considerations of a multidisciplinary approach; and discuss areas of controversy, including systemic treatment by tumor subtype, management of the axilla, and appropriate trial endpoints.[1] This commentary addresses our perspectives from a regulatory standpoint, as well as some controversies related to the use of neoadjuvant therapy as a platform for drug development. Clinical trials in the neoadjuvant setting have become common platforms from which to study new biomarkers, perform translational research, and assess drug activity more efficiently. The exponential increase in drug development in the neoadjuvant setting reinforces the need for a better understanding of the neoadjuvant endpoints needed to support regulatory approval.

Despite the fact that pathological complete response (pCR), the most commonly used endpoint in breast cancer neoadjuvant trials, had been proposed as a surrogate endpoint for prediction of long-term clinical benefit, this surrogacy had not been established. To overcome the challenges of interpreting pCR data across clinical trials and to better understand the relationship between pCR and long-term benefit, the US Food and Drug Administration (FDA) established the Collaborative Trials in Neoadjuvant Breast Cancer (CTNeoBC) international working group. The CTNeoBC conducted a pooled analysis using primary source data from nearly 12,000 patients enrolled in 12 international neoadjuvant randomized controlled trials.[2] The CTNeoBC pooled analysis showed that eradication of tumor from both the breast and the lymph nodes was more strongly associated with improved long-term outcome than was tumor eradication from the breast alone. Clinical findings from several groups, as discussed by Santa-Maria et al, as well as the CTNeoBC analysis, have demonstrated that the risk of death is reduced for patients who achieve a pCR, supporting the prognostic value of pCR for use in clinical practice. This prognostic value was found to be greatest in patients with aggressive tumor subtypes such as triple-negative, human epidermal growth factor receptor 2 (HER2)-positive, and high-risk hormone receptor–positive/HER2-negative. However, the CTNeoBC pooled analysis showed a weak association between the pCR rate and long-term outcome. Some possible explanations for these findings include tumor heterogeneity, limited targeted therapy, and the small absolute differences in pCR rates between treatment arms in the majority of trials that were included in this pooled analysis.[2] Although the NOAH trial suggested a possible correlation between pCR and long-term outcome, the Neoadjuvant Lapatinib and/or Trastuzumab Treatment Optimization (NeoALTTO) and Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization (ALTTO) trials showed conflicting results.[3-6] We hope that a future pooled analysis of targeted therapy trials, conducted in more specific breast cancer subtypes with anticipated greater absolute improvements in pCR rates, could help establish pCR as a surrogate endpoint for long-term outcomes.

The FDA recently granted accelerated approval to pertuzumab as the first neoadjuvant treatment for early-stage breast cancer.[7,8] Santa-Maria et al are correct in stating that the approval was based primarily on the NeoSphere trial. However, it is important to emphasize that, given the lack of experience with pCR as a regulatory endpoint and the uncertainty about the association between pCR rate and long-term outcome, the bar for approval in the neoadjuvant setting was set high.[9] Vital to the regulatory decision was the comprehensive clinical development program for pertuzumab, particularly the important improvement in overall survival that was observed in the CLEOPATRA trial.[8,10,11] Furthermore, the adjuvant APHINITY confirmatory trial was fully accrued and well underway at the time of accelerated approval, conforming to the FDA requirement for a post-marketing clinical trial to verify benefit.[12] This comprehensive development program, with a well-characterized safety profile in nearly 10,000 patients who had received pertuzumab, abated the potential risks of accelerated approval.[8]

Biomarker development is another area in which there is much interest in utilizing the neoadjuvant platform. With the advent of next-generation sequencing, new molecular discoveries demonstrating the complexities of breast cancer, and the success of immunotherapy in other malignancies, there is no shortage of potential biomarkers to examine. The neoadjuvant clinical platform allows for a real-time evaluation of biomarkers in the context of the tumor and surrounding microenvironment before, during, and after treatment. Genomic biomarkers are commonly examined in the neoadjuvant setting; this process has included the assessment of genes from multiple pathways, such as the phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway and the homologous recombination pathway involved in DNA repair.[13-17] In addition, multiple studies have examined the impact of tumor-infiltrating lymphocytes (TILs) as both prognostic and predictive indicators of neoadjuvant treatment response, and many have correlated various measurements of TILs with pCR.[18-24] It is likely, given the interest in immunotherapy, that we will see multiple further assessments of various immune-related biomarkers for the selection of immune therapies in the neoadjuvant setting. Furthermore, assessment of the residual tumor post neoadjuvant therapy could be very useful to identify various mechanisms of drug resistance.

The pathological response to neoadjuvant therapy reflects a complex interaction between the tumor biology, the microenvironment, and systemic therapy. Thus, future innovative neoadjuvant trials that include and validate novel biomarkers are warranted, to identify patients with high-risk early breast cancer-such as those who do not attain a pCR or who, despite achieving a pCR, are destined to relapse. There is no consensus on whether these patients would benefit from additional targeted therapies in the neoadjuvant or adjuvant setting; this is a question to be answered by current ongoing and future trials. Given the complexity of breast cancer, reliable biomarkers that could predict treatment effectiveness have the potential to improve the breast cancer drug development process. Furthermore, tracking the biomarker response during therapy could also allow for a better understanding of the relationship between the biomarker and resistance pathways and/or long-term outcome. Additional breast cancer drug development in the neoadjuvant setting will provide a mechanism for innovative exploration and improvement on the conventional route of drug and biomarker development. We hope that, taken together, these approaches will translate into improved outcomes for our patients with early-stage breast cancer.

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

 Cortazar P, Zhang L, Untch M, et al. Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet. 2014;384:164-72.

 Baselga J, Bradbury I, Eidtmann H, et al. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial. Lancet. 2012;379:633-40.

 Piccart-Gebhart MJ, Holmes PA, Baselga J, et al. First results from the phase III ALTTO trial (BIG 2-06; NCCTG [Alliance] N063D) comparing one year of anti-HER2 therapy with lapatinib alone (L), trastuzumab alone (T), their sequence (T→ L), or their combination (T+L) in the adjuvant treatment of HER2-positive early breast cancer (EBC). J Clin Oncol. 2014;32(suppl 5s):abstr LBA4.

 Gianni L, Eiermann W, Semiglazov V, et al. Neoadjuvant and adjuvant trastuzumab in patients with HER2-positive locally advanced breast cancer (NOAH): follow-up of a randomised controlled superiority trial with a parallel HER2-negative cohort. Lancet Oncol. 2014;15:640-7.

 Gianni L, Eiermann W, Semiglazov V, et al. Neoadjuvant chemotherapy with trastuzumab followed by adjuvant trastuzumab versus neoadjuvant chemotherapy alone, in patients with HER2-positive locally advanced breast cancer (the NOAH trial): a randomised controlled superiority trial with a parallel HER2-negative cohort. Lancet. 2010;375:377-84.

 Gianni L, Pienkowski T, Im YH, et al. Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial. Lancet Oncol. 2012;13:25-32.

 Amiri-Kordestani L, Wedam S, Zhang L, et al. First FDA approval of neoadjuvant therapy for breast cancer: pertuzumab for the treatment of patients with HER2-positive breast cancer. Clin Cancer Res. 2014;20:5359-64.

 US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research. Guidance for industry. Pathologic complete response in neoadjuvant treatment of high-risk early-stage breast cancer: use as an endpoint to support accelerated approval. October 2014. 

http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm305501.pdf

 Baselga J, Cortes J, Kim SB, et al. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med. 2012;366:109-19.

 Swain SM, Kim SB, Cortes J, et al. Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA study): overall survival results from a randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol. 2013;14:461-71.

 US Food and Drug Administration, Oncologic Drugs Advisory Committee. Meeting announcement. February 8, 2011. 

http://www.fda.gov/AdvisoryCommittees/Calendar/ucm239360.htm

 Loibl S, von Minckwitz G, Schneeweiss A, et al. PIK3CA mutations are associated with lower rates of pathologic complete response to anti-human epidermal growth factor receptor 2 (HER2) therapy in primary HER2-overexpressing breast cancer. J Clin Oncol. 2014;32:3212-20.

 Jiang YZ, Yu KD, Bao J, et al. Favorable prognostic impact in loss of TP53 and PIK3CA mutations after neoadjuvant chemotherapy in breast cancer. Cancer Res. 2014;74:3399-407.

 Wang C, Zhang J, Wang Y, et al. Prevalence of BRCA1 mutations and responses to neoadjuvant chemotherapy among BRCA1 carriers and non-carriers with triple-negative breast cancer. Ann Oncol. 2015;26:523-8.

 Telli ML, Jensen KC, Kurian AW, et al. PrECOG 0105: Final efficacy results from a phase II study of gemcitabine (G) and carboplatin (C) plus iniparib (BSI-201) as neoadjuvant therapy for triple-negative (TN) and BRCA1/2 mutation-associated breast cancer. J Clin Oncol. 2013;31(suppl):abstr 1003.

 Arun B, Bayraktar S, Liu DD, et al. Response to neoadjuvant systemic therapy for breast cancer in BRCA mutation carriers and noncarriers: a single-institution experience. J Clin Oncol. 2011;29:3739-46.

 Denkert C, Loibl S, Noske A, et al. Tumor-associated lymphocytes as an independent predictor of response to neoadjuvant chemotherapy in breast cancer. J Clin Oncol. 2010;28:105-13.

 Yamaguchi R, Tanaka M, Yano A, et al. Tumor-infiltrating lymphocytes are important pathologic predictors for neoadjuvant chemotherapy in patients with breast cancer. Hum Pathol. 2012;43:1688-94.

 West NR, Milne K, Truong PT, et al. Tumor-infiltrating lymphocytes predict response to anthracycline-based chemotherapy in estrogen receptor-negative breast cancer. Breast Cancer Res. 2011;13:R126.

 Issa-Nummer Y, Darb-Esfahani S, Loibl S, et al. Prospective validation of immunological infiltrate for prediction of response to neoadjuvant chemotherapy in HER2-negative breast cancer--a substudy of the neoadjuvant GeparQuinto trial. PLoS One. 2013;8:e79775.

 Ladoire S, Arnould L, Apetoh L, et al. Pathologic complete response to neoadjuvant chemotherapy of breast carcinoma is associated with the disappearance of tumor-infiltrating foxp3+ regulatory T cells. Clin Cancer Res. 2008;14:2413-20.

 Ladoire S, Mignot G, Dabakuyo S, et al. In situ immune response after neoadjuvant chemotherapy for breast cancer predicts survival. J Pathol. 2011;224:389-400.

 Aruga T, Suzuki E, Saji S, et al. A low number of tumor-infiltrating FOXP3-positive cells during primary systemic chemotherapy correlates with favorable anti-tumor response in patients with breast cancer. Oncol Rep. 2009;22:273-8.

This commentary addresses our perspectives from a regulatory standpoint, as well as some controversies related to the use of neoadjuvant therapy as a platform for drug development. 

Neoadjuvant Therapy As a Platform for Drug Development: Current Controversies and Regulatory Perspectives

A Paradigm Shift From a Dogma of the Cytotoxic Era

The primary goals when treating patients with metastatic breast cancer are to improve both duration and quality of life. With cytotoxic chemotherapy, this is typically achieved by using single agents sequentially (rather than combination regimens), switching therapies in the face of disease progression or prohibitive toxicity. This approach is supported by clinical trial data showing that chemotherapy doublets enhance neither the duration nor the quality of life compared with sequential single agents.[1,2] Combination therapy is more likely to be associated with drug toxicity, without clear evidence of benefit.

We argue that the same principle does not hold true when using targeted agents for advanced human epidermal growth factor receptor (HER) 2–positive breast cancer. Rather, there is often a strong case for combining the anti-HER2 antibody trastuzumab with another HER2-directed therapy. Unlike with chemotherapy, the efficacy-vs-toxicity trade-off often favors combination approaches in the setting of HER2-positive disease.

The notion that combining anti-HER2 therapies might be particularly effective stems from the fact that each of these agents targets the HER2 signaling pathway differently. Trastuzumab interferes with ligand-independent HER2-HER3 interactions and prevents cleavage of HER2 at the membrane, whereas pertuzumab prevents ligand-dependent HER2-HER3 interactions. In contrast, lapatinib inhibits the function of the epidermal growth factor receptor (EGFR) and HER2 kinases.[3] Both antibodies, but not lapatinib, also invoke antibody-dependent cell-mediated cytotoxicity (ADCC) against tumor cells.

Striking preclinical and clinical data support use of the trastuzumab + pertuzumab combination. HER2-HER3 heterodimers are the dominant mediators of signaling in HER2-positive breast cancers[4]; through enhanced prevention of HER2-HER3 interactions, trastuzumab and pertuzumab act synergistically against tumor cells in vitro.[5]

In keeping with laboratory data, results of the BO17929 clinical trial suggest synergistic antitumor activity when trastuzumab and pertuzumab are combined. In this nonrandomized study, one cohort of patients whose metastatic disease was progressing on trastuzumab was treated with pertuzumab alone, yielding an overall response rate (ORR) of only 3%. When these patients then switched to the trastuzumab + pertuzumab combination (ie, after their disease had progressed on both trastuzumab and pertuzumab used individually), an ORR of 18% was observed.[6] The notable ORR with trastuzumab + pertuzumab in patients in whom each agent used individually had failed speaks to the benefit of using these agents in combination.

Further data supporting use of the trastuzumab + pertuzumab combination has come from the randomized phase III Clinical Evaluation of Pertuzumab and Trastuzumab (CLEOPATRA) study.[7] Although this first-line metastatic trial did not specifically compare combination vs sequential anti-HER2 therapy, the addition of pertuzumab to a docetaxel/trastuzumab backbone yielded an unprecedented 15-month improvement in overall survival (OS). This improvement came at the cost of extra toxicity (diarrhea, mucositis, rash, and febrile neutropenia), but the magnitude of the benefit and relatively modest toxicity have cemented the position of trastuzumab + pertuzumab as an integral component of first-line therapy for advanced HER2-positive breast cancer.

The other clinically relevant combination is trastuzumab + lapatinib. Lapatinib is often active against trastuzumab-resistant cell lines,[8] and the trastuzumab + lapatinib combination can act synergistically in vitro.[9] This synergy might arise because lapatinib stabilizes HER2 at the cell membrane, potentiating the effects of trastuzumab and enhancing signal inhibition and apoptosis.[9,10]

Trial data also support use of the trastuzumab + lapatinib combination. In the randomized EGF104900 study, trastuzumab + lapatinib prolonged OS by more than 4 months compared with lapatinib monotherapy in a cohort of heavily pretreated, trastuzumab-resistant patients.[11] Further, trastuzumab + lapatinib was associated with a trend towards improved quality of life,[12] partly reflecting the nonoverlapping toxicities of these agents. Whether the survival benefit seen was due to synergistic inhibition of HER2 signaling or to the persistent influence of trastuzumab-related ADCC in the trastuzumab + lapatinib arm is unknown.

In summary, targeted anti-HER2 agents can act synergistically, and when used in the trastuzumab + pertuzumab or trastuzumab + lapatinib combinations, can improve patient outcomes at the price of manageable toxicity. Indeed, in clinical practice, we would not consider using pertuzumab without concomitant trastuzumab, and would only use lapatinib in conjunction with trastuzumab and/or chemotherapy, but never as a single agent.

We acknowledge that the “more is better” approach may not always hold true. For example, preclinical data provided a rationale for combining pertuzumab with the antibody-drug conjugate ado-trastuzumab emtansine (T-DM1),[13] but recent reports suggest that this strategy may not prove more effective than single-agent T-DM1 therapy in the clinic.[14] This discordance between preclinical and clinical data requires further investigation, and reminds us that each new combination regimen must be assessed on its individual merits.

The authors’ institution has received research funding from Genentech. Neither Dr. Goel nor Dr. Winer has any significant personal financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article

 Sledge GW, Neuberg D, Bernardo P, et al. Phase III trial of doxorubicin, paclitaxel, and the combination of doxorubicin and paclitaxel as front-line chemotherapy for metastatic breast cancer: an intergroup trial (E1193). J Clin Oncol. 2003;21:588-92.

 Miles D, Vukelja S, Moiseyenko V, et al. Survival benefit with capecitabine/docetaxel versus docetaxel alone: analysis of therapy in a randomized phase III trial. Clin Breast Cancer. 2004;5:273-8.

 Stern HM. Improving treatment of HER2-positive cancers: opportunities and challenges. Sci Transl Med. 2012;4:127rv2.

 Lee-Hoeflich ST, Crocker L, Yao E, et al. A central role for HER3 in HER2-amplified breast cancer: implications for targeted therapy. Cancer Res. 2008;68:5878-87.

 Nahta R, Hung MC, Esteva FJ. The HER-2-targeting antibodies trastuzumab and pertuzumab synergistically inhibit the survival of breast cancer cells. Cancer Res. 2004;64:2343-6.

 CortÃ©s J, Fumoleau P, Bianchi GV, et al. Pertuzumab monotherapy after trastuzumab-based treatment and subsequent reintroduction of trastuzumab: activity and tolerability in patients with advanced human epidermal growth factor receptor 2-positive breast cancer. J Clin Oncol. 2012;30:1594-600.

 Swain SM, Baselga J, Kim SB, et al; CLEOPATRA Study Group. Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N Engl J Med. 2015;372:724-34.

 Konecny GE, Pegram MD, Venkatesan N, et al. Activity of the dual kinase inhibitor lapatinib (GW572016) against HER-2-overexpressing and trastuzumab-treated breast cancer cells. Cancer Res. 2006;66:1630-9.

 Scaltriti M, Verma C, Guzman M, et al. Lapatinib, a HER2 tyrosine kinase inhibitor, induces stabilization and accumulation of HER2 and potentiates trastuzumab-dependent cell cytotoxicity. Oncogene. 2009;28:803-14.

 Xia W, Gerard CM, Liu L, et al. Combining lapatinib (GW572016), a small molecule inhibitor of ErbB1 and ErbB2 tyrosine kinases, with therapeutic anti-ErbB2 antibodies enhances apoptosis of ErbB2-overexpressing breast cancer cells. Oncogene. 2005;24:6213-21.

 Blackwell KL, Burstein HJ, Storniolo AM, et al. Overall survival benefit with lapatinib in combination with trastuzumab for patients with human epidermal growth factor receptor 2-positive metastatic breast cancer: final results from the EGF104900 study. J Clin Oncol. 2012;30:2585-92.

 Wu Y, Amonkar MM, Sherrill BH, et al. Impact of lapatinib plus trastuzumab versus single-agent lapatinib on quality of life of patients with trastuzumab-refractory HER2+ metastatic breast cancer. Ann Oncol. 2011;22:2582-90.

 Phillips GD, Fields CT, Li G, et al. Dual targeting of HER2-positive cancer with trastuzumab emtansine and pertuzumab: critical role for neuregulin blockade in antitumor response to combination therapy. Clin Cancer Res. 2014;20:456-68.

 Roche. Roche provides update on phase III MARIANNE study in people with previously untreated advanced HER2-positive breast cancer. 2014.

http://www.roche.com/media/store/releases/med-cor-2014-12-19.htm

We acknowledge that the “more is better” approach may not always hold true. For example, preclinical data provided a rationale for combining pertuzumab with T-DM1, but recent reports suggest that this strategy may not prove more effective than single-agent T-DM1 therapy in the clinic.

POINT: HER2-Targeted Combinations in Advanced HER2-Positive Breast Cancer

Which Agents to Use Together, Which Alone, and When

The Clinical Evaluation of Pertuzumab and Trastuzumab (CLEOPATRA) trial was a phase III, double-blind, randomized, placebo-controlled trial that evaluated dual humanized anti–human epidermal growth factor receptor (HER) 2 antibody blockade with both single-agent pertuzumab and single-agent trastuzumab in combination with docetaxel as first-line therapy in metastatic HER2-positive disease. This trial originally showed that the combination of pertuzumab, trastuzumab, and docetaxel, compared with docetaxel and trastuzumab plus placebo, significantly prolonged progression-free survival (PFS), with an increase of 6.1 months at the median (12.4 vs 18.5 months; hazard ratio [HR], 0.62 [95% confidence interval (CI), 0.51–0.75]).[1] Recently, the final prespecified overall survival (OS) results were reported, with a median follow-up duration of 50 months.[2] The median OS was 56.5 months (95% CI, 49.3 months to not reached [NR]) in the subjects randomized to the pertuzumab combination, compared with 40.8 months (95% CI, 35.8–48.3 months) in the subjects randomized to the placebo combination (HR, 0.68 [95% CI, 0.56–0.84]; 

 < .001), a difference of 15.7 months. This analysis was not adjusted for crossover to the pertuzumab group; therefore, the magnitude of the difference in median OS is likely a conservative value. Moreover, no new safety signals emerged, with long-term cardiac safety maintained in both arms.

Building on the Success of the CLEOPATRA Combination Regimens

Since most of the observed toxicity in both arms of the CLEOPATRA trial resulted from docetaxel, there has subsequently been enthusiasm to investigate pertuzumab and trastuzumab in combination with weekly paclitaxel, which is arguably less toxic than docetaxel. In a phase II trial of pertuzumab and trastuzumab with weekly paclitaxel, patients with metastatic HER2-positive breast cancer who had received up to one prior therapy were treated with paclitaxel, 80 mg/m

 weekly, plus trastuzumab (8 mg/kg loading dose → 6 mg/kg) every 3 weeks plus pertuzumab (840 mg loading dose → 420 mg) every 3 weeks.[3] Altogether 69 patients were treated: 51 (74%) in the first-line metastatic setting and 18 (26%) in the second-line metastatic setting. With a median follow-up of 21 months (range, 3–38 months), 6-month PFS (the primary study endpoint) was 86% (95% CI, 75%–92%). Median PFS was 24.2 months (95% CI, 14 months to NR) and 16.4 months (95% CI, 8.5 months to NR) for those without and with prior treatment, respectively. There was no febrile neutropenia or symptomatic left ventricular systolic dysfunction. These results suggest that paclitaxel given weekly with trastuzumab and pertuzumab is an effective alternative to docetaxel-based combination therapy.[3]

T-DM1 Alone and T-DM1 Combinations: When Superior, When Not

The preferred status of CLEOPATRA-like regimens in the first-line HER2-positive metastatic breast cancer setting has recently been challenged by antibody-drug conjugate regimens based on ado-trastuzumab emtansine (T-DM1). The MARIANNE trial randomly assigned 1,095 patients with locally recurrent unresectable or previously untreated HER2-positive metastatic breast cancer to receive T-DM1 plus pertuzumab (363 patients), T-DM1 plus placebo (367 patients), or trastuzumab plus docetaxel or paclitaxel (365 patients)-with this last regimen being the standard of care for this patient population at the time the trial was initiated.[4] With a median follow-up of 35 months, both T-DM1–containing regimens demonstrated noninferiority, but not superiority, to taxane + trastuzumab. The median PFS was 15.2 months in the T-DM1 + pertuzumab arm (HR, 0.87 [95% CI, 0.69–1.08]; 

 = .14) and 14.1 months with T-DM1 alone (HR, 0.91 [95% CI, 0.73–1.13]; 

 = .31), compared with 13.7 months for the taxane + trastuzumab control.[4] Thus, T-DM1 + pertuzumab is insufficient to replace CLEOPATRA-like regimens in the first-line HER2-positive metastatic breast cancer setting, based on efficacy considerations. For HER2-positive metastatic breast cancer patients with disease progression following prior treatment with a taxane and trastuzumab (or relapsed within 6 months of completion of an adjuvant trastuzumab regimen), T-DM1 has been shown to be significantly superior to lapatinib + capecitabine, for both PFS and OS, and is arguably better tolerated.[5] Therefore, under the assumption that T-DM1 remains superior to lapatinib + capecitabine following a taxane, trastuzumab, and pertuzumab, T-DM1 is the logical treatment choice for consideration as next in sequence in the second-line setting.

Upon further disease progression following a prior pertuzumab/trastuzumab–containing regimen and T-DM1, lapatinib-based regimens (either lapatinib + capecitabine or lapatinib + trastuzumab) are a logical next choice.[6,7] However, neither of these regimens has efficacy data available in the setting of prior progression after multiple HER2-targeting antibody–based strategies. In later lines of treatment, clinicians regularly default to sequential salvage chemotherapeutics given in combination with trastuzumab in multiple lines, although this practice is not based on randomized trial evidence beyond the second line.[8]

Dr. Pegram serves as a consultant for Genentech

Baselga J, CortÃ©s J, Kim SB, et al; CLEOPATRA Study Group. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med. 2012;366:109-19.

Swain SM, Baselga J, Kim SB, et al; CLEOPATRA Study Group. Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N Engl J Med. 2015;372:724-34.

Dang C, Iyengar N, Datko F, et al. Phase II study of paclitaxel given once per week along with trastuzumab and pertuzumab in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer. J Clin Oncol. 2015;33:442-7.

Ellis PA, Barrios CH, Eiermann W, et al. Phase III, randomized study of trastuzumab emtansine (T-DM1) ± pertuzumab (P) vs trastuzumab + taxane (HT) for first-line treatment of HER2-positive MBC: primary results from the MARIANNE study. J Clin Oncol. 2015;33(suppl):abstr 507.

Verma S, Miles D, Gianni L, et al; EMILIA Study Group. Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med. 2012;367:1783-91.

Geyer CE, Forster J, Lindquist D, et al. Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med. 2006; 355:2733-43.

Blackwell KL, Burstein HJ, Storniolo AM, et al. Overall survival benefit with lapatinib in combination with trastuzumab for patients with human epidermal growth factor receptor 2-positive metastatic breast cancer: final results from the EGF104900 study. J Clin Oncol. 2012;30:2585-92.

von Minckwitz G, Schwedler K, Schmidt M, et al; GBG 26/BIG 03-05 study group and participating investigators. Trastuzumab beyond progression: overall survival analysis of the GBG 26/BIG 3-05 phase III study in HER2-positive breast cancer. Eur J Cancer. 2011;47:2273-81.

The preferred status of CLEOPATRA-like regimens in the first-line HER2-positive metastatic breast cancer setting has recently been challenged by antibody-drug conjugate regimens based on ado-trastuzumab emtansine (T-DM1). 

COUNTERPOINT: HER2-Targeted Combinations in Advanced HER2-Positive Breast Cancer

You are a real advocate for cancer patients when it comes to discussing topics that may not be part of an oncologist-patient conversation after a cancer diagnosis; for example, sexual health during cancer treatment. How and when do you think this type of discussion should happen? Is it relevant for all cancer patients?

 I think the topic should be discussed at the beginning, when cancer is first diagnosed. What I’m hoping is that it becomes a part of the comprehensive initial history and physical we all take when we first meet our new patients. It’s as important as any other aspect of the review of systems. In fact, we typically address issues of employment, marital status, children, to name a few. We go beyond the scope of physiology quite readily, so why not also cover sexual health history? This conversation doesn’t have to be scary and it doesn’t have to be lengthy, but the important part is that it sends the message to our patients that even if it isn’t something important right now, or something you don’t want to discuss, that “door” is open, and I am willing to engage you in that discussion. So when the patient feels like he/she needs to bring something up, they know that you’re okay about having that discussion.

I think it’s very important to bring up sexual health when we think intimacy is going to be impacted by our treatment, but it’s my sense that we often do this more readily with men than we do with women. For example, with men who have prostate cancer, doctors are really great about going into issues regarding impotence and erectile dysfunction with regard to the surgical or androgen deprivation therapies. But we don’t readily do that when we’re discussing the role of aromatase inhibitors (AIs) for women with breast cancer. That is, clinicians don’t usually discuss that these drugs can cause sexual side effects such as pain with penetration and vaginal dryness, which are experienced by a lot of women on AIs, and even if we do, I think most of the time it’s just cursory. In summary, I think the conversations about sexual health are important for all cancer patients. It’s not all about intercourse. It’s also about intimacy, and it’s also about experiences of pleasure, which are universally acknowledged concerns and part of the human experience that needs to be acknowledged as such.

 Maintaining fertility in younger patients with cancer is an issue that seems to have come more into focus over the last few years. Do you think oncologists are doing enough when it comes to preserving fertility in those patients who may wish to have children after cancer treatment?

I think doctors are more cognizant that fertility is an issue, but there’s still a lot of subconscious bias around whether we actually do discuss fertility with our patients. For example, we think the issue might not be relevant because a patient is single, or because she’s 38, or even because the prognosis of her cancer is so terrible. As a result of these biases, I don’t think everyone who should have a discussion about fertility is necessarily having one.

One of my colleagues here at Mass General, Mary Sabatini, oftentimes makes a point of saying to her patients, “If you’re having trouble having a child, I will help you with that. But make sure you enjoy the pleasure of each other’s company. Make sure the sexuality is not impacted even as fertility becomes challenging.” Because sometimes, in women who are dealing with infertility, where their sole purpose is to have a child, the pleasure that comes with a sexual encounter can go away because the goal has shifted, and it becomes work. Clinicians don’t necessarily need to be skilled in terms of discussing the gamut of all the sexual complications of cancer treatments, but to assume the issue of fertility was discussed just because the topic of sexual health was raised would be incorrect.

 There has been a lot of excitement and press around the developments in precision medicine and targeted therapy for cancer in recent years. However, you recently wrote a blog post with Lecia Sequist in which you talked about the disappointments of precision medicine. Can you talk a little about those disappointments, and how clinicians should address them with their patients?

 When I contacted Lecia Sequist to write the blog with me, I thought we would probably have a very similar experience of talking about precision therapy with our patients; that is, we receive the results [of molecular testing] and see that no mutation is targetable with a drug. It was very eye-opening to hear Lecia’s perspective on the issue of the hype around targeted therapies, because she practices thoracic oncology, where there’s often an expectation that patients with a targetable mutation will respond 

 to the treatment directed at that mutation-but that isn’t always the case. It’s like there is an expectation for some patients that because they have a targetable mutation that they’ve won the cancer “lottery,” so to speak. But just because they have a mutation doesn’t automatically guarantee a durable response. Lecia’s viewpoint was just so revelatory for me, because she essentially says that even if patients have a targetable mutation, they can still die of their cancer. In contrast, I am not finding mutations with the available testing in my own clinic-a disappointment of a different kind.

My hope as a clinician is that I will see more and more people shift from being poor prognostic to good prognostic in my lifetime. We saw it with HER2-directed therapies in breast cancers, and I hope to see it with other tumors in the future. But for now we are not in the situation where a specific mutation can predict with 100% certainty that a treatment will be successful. We certainly don’t yet have it for ovarian cancer; we don’t have it in triple-negative breast cancer, either. We have it to some degree for a few types of lung cancer, but not all. We have to remember that right now, a lot of our patients are not going to experience the fruits of precision medicine.

One of the ways we’re working toward that goal is to try to heighten our understanding of tumor biology. Right now, we have access to tumor genomics, but my sense is that the key may lie beyond that; it might be in functional proteomics, evaluation of epigenetic mechanisms, or copy number alterations. Right now, unfortunately, I’m not finding useful genomic information for the vast majority of my own patients [women with gynecologic and breast cancers].

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

In this interview we discuss sexual health during cancer treatment and some of the disappointments of precision medicine.