Merkel cell carcinoma (MCC) is a rare but potentially lethal skin cancer that has traditionally been treated with surgery, radiation, and in advanced cases, chemotherapy. Patients with even localized disease have a high risk of recurrence and those who develop metastatic disease have had a poor overall survival. Several factors have been associated with the development of MCC including immunosuppression, ultraviolet (UV) exposure, and infection with the Merkel cell polyomavirus (MCPyV). Randomized-controlled trials are a paucity in this disease; therefore, historic treatment algorithms are mostly based on retrospective case series. Historically, the National Comprehensive Cancer Network guidelines have recommended participation in a clinical trial for patients with metastatic disease. If patients were not able to participate in or access a trial, then they would often receive a combination of platinum and etoposide chemotherapy. However, recent years have seen trials of immunotherapies showing benefit for patients with stage IV disease. In 2017, avelumab became the first immunotherapy to be approved for advanced stage MCC. This paper will summarize the basis of the current standard of care for this disease as well as review the new data for biomarkers and immunotherapy in advanced MCC.

Merkel cell carcinoma (MCC) is a rare and aggressive cutaneous malignancy with an estimated incidence in the United States of approximately 1600 cases per year. Unfortunately, the number of cases has been steadily increasing over the last few decades. Patients with stage I or II disease have a 5-year disease specific survival of 78% while those with stage III disease have only a 54%.

The 5-year overall survival (OS) for patients with metastatic disease has historically averaged between 0% to 18%.

There is a higher incidence of MCC in men and it predominantly affects those with lighter skin. MCC typically affects older individuals with the mean age for diagnosis of 74 years for men and 76 years for women.

The risk of MCC is higher in immunosuppressed individuals such as those with a history of organ transplant, HIV, or other malignancy.

Due to the rarity of this disease, the data on natural history and treatment of MCC are lacking in quality; also, there are sparse data from clinical trials. The data are gathered primarily from retrospective case series, although a handful of randomized trials are available. This should be taken into account while reading this review.

Primary lesions of MCC generally appear as painless, rapidly growing, and nontender lesions. The color can vary from flesh colored to red or bluish. The most common sites are in sun-exposed areas with 43% occurring in the head and neck area.

Diagnosis of MCC requires a high index of suspicion. The acronym AEIOU was developed to help identify clinical characteristics of lesions suggestive of MCC: asymptomatic, expanding rapidly, immune suppression, older than 50 years of age, and UV-exposed area in a fair-skinned individual.8 Traditionally, MCC is thought to arise from Merkel cells located in the basal layer of the dermis. However, there are alternative hypotheses regarding the cell of origin. On immunohistochemistry examination, MCC expresses both epithelial and neuroendocrine markers. CK20 is consistently positive with a paranuclear staining pattern.

Several factors have been associated with the development of MCC including immunosuppression, UV exposure, and infection with the Merkel cell polyomavirus (MCPyV). MCPyV is a ubiquitous double stranded DNA virus. Approximately 88% of older individuals with MCC will have positive antibody titers specific to the capsid viral protein 1.9 The virus is present at tumor initiation and the viral proteins are felt to be oncogenic drivers. There is a subset of MCCs with low or absent MCPyV antigen expression. These tumors are felt to be related more to UV exposure and have higher rates of mutations in tumor suppressor genes such as TP53 and RB1.

The increase in mutational burden is felt to increase expression of neoantigens and immunogenicity.

Historically, the National Comprehensive Cancer Network guidelines have recommended participation in a clinical trial for patients with metastatic disease. If patients were not able to participate in or access a trial, then they would often receive a combination of platinum-based chemotherapy and etoposide in the first-line setting. MCC is a chemosensitive disease with response rates of 51% to 63% with chemotherapy.

However, these responses are short in duration with a median progression-free survival (PFS) of 94 days. Additionally, chemotherapy has not demonstrated an improvement in OS.

Given the older age of many patients and their comorbidities, the toxicity of treatment could severely impact quality of life. However, until recently the majority of patients were treated with chemotherapy.

In March 2017, the FDA approved avelumab, a programmed death receptor ligand 1 (PD-L1) inhibitor. Approval was based on the results of a phase II study that enrolled 88 patients. All patients had progressed on first-line chemotherapy. They were treated with avelumab 10 mg/kg every 2 weeks. The objective response rate (ORR) was 32% with a complete response rate (CRC) of 9%. Ten percent of patients had stable disease. Median PFS was 2.7 months and median OS was 11.3 months. The duration of response was greater than or equal to 6 months in 86% of patients. Treatment was overall well tolerated with no grade 4 or 5 toxicities and only 4.5% of the patients experienced grade 3 toxicities. Most common toxicities included fatigue and infusion reactions. Additionally, responses were seen regardless of PD-L1 expression or polyomavirus status.

Although not yet approved at the writing of this article, the PD-1 inhibitor pembrolizumab has shown promise in clinical trials. A phase II study of pembrolizumab enrolled 25 patients. Patients had distant metastatic or recurrent locoregional disease that was not amenable to surgery or radiation. Patients could not have received prior systemic therapy for advanced disease. An objective response rate was 56% with 4 patients achieving a CR and 10 patients out of 25 achieving a partial response. Twelve of the 14 patients with a response had an ongoing response at follow-up with a median follow-up of 33 weeks. Toxicity was similar to other trials and disease types with pembrolizumab; 4 of 25 patients had grade 3-4 toxicity, including 1 case of myocarditis from supplement of this article.

The approval of avelumab and promising results seen in a clinical trial with pembrolizumab will dramatically shift the way patients are treated as part of standard of care. Although it is still too early for long- term survival data, the information available demonstrates that these responses are more durable than those obtained with chemotherapy. Additionally, responses are seen in both virus positive and negative tumors with expected rates of toxicity. Although not yet approved in the first-line setting immunotherapy is poised to replace chemotherapy as standard treatment.

Surgery is the primary treatment modality for localized disease. Surgical margins of 1 to 2 cm are the standard of care for excision of the primary lesion. Sentinel lymph node biopsy (SLNB) is recommended prior to excision and is important in staging patients. One third of early stage patients have been documented to have sentinel lymph node (SLN) micrometasteses.

In patients with SLNB, the nodal basin can be observed or radiation can be considered in high-risk patients. If a positive SLN has been identified, patients are recommended to be discussed in a multidisciplinary tumor board about both nodal dissection and adjuvant radiation. MCC is notable for a high-risk of recurrence of up to 56% in SLNB-positive patients and 39% on SLNB-negative patients. Radiation is often used in the adjuvant setting to minimize locoregional recurrence. A meta-analysis showed a lowered rate of regional recurrence with radiotherapy (RT) when compared with surgery alone.

In patients with no lymph node involvement there is an improvement in OS. However, this has not been demonstrated in lymph node-positive disease.

MCC is a chemosensitive disease in the metastatic setting. However, there are no prospective trials showing a benefit of adjuvant chemotherapy. A retrospective review of 4815 patients with MCC of the head and neck showed an improvement in survival with adjuvant RT and chemo-radiotherapy. However, adjuvant chemotherapy alone had a worse OS compared with surgery alone.

Given the retrospective nature of this paper, it is difficult to make conclusions as treating physicians likely would choose to give adjuvant chemotherapy in the younger, healthier patients. National Cancer Database review of 6908 patients did not show an improvement or worsening of OS with chemotherapy or chemoradiotherapy.

It should be noted that there are no high-quality randomized studies with chemotherapy and/or radiation in this disease. Neither has been prospectively shown to improve survival. Because of this fact, it is very difficult to know the true benefit or lack of benefit these interventions have on MCC.

Given the high risk of recurrent disease and the promise of immune checkpoint blockade in the metastatic setting, several trials are ongoing looking at both neoadjuvant and adjuvant treatment for MCC. NCT02196961 is an adjuvant trial for resected Merkel cell that administers 4 doses of ipilimumab at 3 mg/kg vs. observation. Additionally, nivolumab is being given in the neoadjuvant setting prior to resection (NCT02488759). Studies with avelumab are currently in development as well. Results are not yet available, but are anxiously awaited given the high risk of recurrence in patients.

The prognosis of patients diagnosed with MCC is currently based on TNM staging. Intratumoral CD8 positivity may play an additional role in determining prognosis at diagnosis for this immunogenic malignancy. CD8+ lymphocytes mediate antiviral immune responses. One hundred and thirty-seven MCC cases were classified based on the presence of intra-tumoral CD8. Samples were categorized as having absent, low, or moderate/strong CD8 expression. Intra-tumoral CD8+ presence was found to have a direct correlation with MCC-specific survival. A similar trend was found for OS, but was not statistically significant.

Patients who undergo resection of MCC have a high risk of recurrence. Current surveillance recommendations are for periodic imaging with no clear scientifically defined frequency. However, in patients who have developed a positive antibody titer to the MCPyV oncoprotein, recent research has shown promise for detecting recurrence based on monitoring of the antibody titers. In a cohort of 219 prospectively followed patients, an increase in oncoprotein antibody titers were associated with an increase in disease recurrence. Among seropositive patients, an increase in oncoprotein titer had a positive predictive value of 66% while a decrease had a negative predictive value of 97%.21 This represents a promising new tool for monitoring recurrence in high-risk patients. It should be noted that is a single institution study and much additional research is needed to define the optimal screening using both a combination of imaging and antibody titers.

Although immunotherapy represents an improvement in treatment options for patients with metastatic disease, not everybody responds to therapy. Several exploratory biomarker analyses have investigated patterns of response. An exploratory biomarker analysis of the phase II trial that led to the approval of avelumab looked at the role of tumor PD-L1 expression. An ORR of 34.5% was found in PD-L1positive versus only 18.8% in PDL-1&ndash;negative patients at the 1% expression level cutoff. At the 5% expression level cutoff 52.6% of PD-L1 positive patients and 23.6% of PD-L1 negative patients had an overall response. Additionally, 26.1% of patients with MCPyV&ndash;positive tumors compared with 35.5% in MCPyV&ndash;negative tumors had a response. When high versus low CD8+ baseline T cell density at the margin was compared, the ORR was 44.4% versus 19.2% respectively.22 In the trial of patients receiving first-line treatment with pembrolizumab, 62% of patients who responded had virus-positive tumors while 44% had virus-negative tumors.

MCC is a rare and aggressive malignancy. Patients with localized disease have a high risk of recurrence and those who develop metastatic disease have a poor OS. In recent years much has been learned about the roles that MCPyV and mutational burden play in the pathogenesis of the disease. This has translated into potential options for monitoring high-risk patients with antibody titers though further study is needed.

Fitzgerald TL, Dennis S, Kachare SD, Vohra NA, Wong JH, Zervos EE. Dramatic increase in the incidence and mortality from Merkel cell carcinoma in the United States. Am Surg. 2015;81(8):802-806.

Allen PJ, Bowne WB, Jaques DP, Brennan MF, Busam K, Coit DG. Merkel cell carcinoma: prognosis and treatment of patients from a single institution. J Clin Oncol. 2005;23(10):2300-2309. doi: 10.1200/JCO.2005.02.329.

Tai PT, Yu E, Winquist E, et al. Chemotherapy in neuroendocrine/Merkel cell carcinoma of the skin: case series and review of 204 cases. J Clin Oncol. 2000;18(12):2493-2499. doi: 10.1200/JCO.2000.18.12.2493.

Santamaria-Barria JA, Boland GM, Yeap BY, Nardi V, Dias-Santagata D, Cusack JC Jr. Merkel cell carcinoma: 30-year experience from a single institution. Ann Surg Oncol. 2013;20(4):1365-1373. doi: 10.1245/s10434- 012-2779-3.

Voog E, Biron P, Martin JP, Blay JY. Chemotherapy for patients with locally advanced or metastatic Merkel cell carcinoma. Cancer. 1999;85(12):2589-2595.

Albores-Saavedra J, Batich K, Chable-Montero F, Sagy N, Schwartz AM, Henson DE. Merkel cell carcinoma demographics, morphology, and survival based on 3870 cases: a population based study. J Cutan Pathol. 2010;37(1):20-27. doi: 10.1111/j.1600-0560.2009.01370.x.

Harms KL, Healy MA, Nghiem P, et al. Analysis of prognostic factors from 9387 Merkel cell carcinoma cases forms the basis for the new 8th edition AJCC staging system. Ann Surg Oncol. 2016;23(11):3564-3571. doi: 10.1245/ s10434-016-5266-4.

Heath M, Jaimes N, Lemos B, et al. Clinical characteristics of Merkel cell carcinoma at diagnosis in 195 patients: the &ldquo;AEIOU&rdquo; features. J Am Acad Dermatol. 2008;58(3):375-381. doi: 10.1016/j.jaad.2007.11.020.

Carter JJ, Paulson KG, Wipf GC, et al. Association of Merkel cell polyomavirus-specific antibodies with Merkel cell carcinoma. J Natl Cancer Inst. 2009;101(21):1510-1522. doi: 10.1093/jnci/djp332.

Harms PW, Patel RM, Verhaegen ME, et al. Distinct gene expression profiles of viral- and nonviral-associated merkel cell carcinoma revealed by transcriptome analysis. J Invest Dermatol. 2013;133(4):936-945. doi: 10.1038/jid.2012.445.

Erstad DJ, Jr JC. Mutational analysis of merkel cell carcinoma. Cancers (Basel). 2014;6(4):2116-2136. doi: 10.3390/cancers6042116.

Iyer JG, Blom A, Doumani R, et al. Response rates and durability of chemotherapy among 62 patients with metastatic Merkel cell carcinoma. Cancer Med. 2016, 10.1002/cam4.815.

Sharma D, Flora G, Grunberg SM. Chemotherapy of metastatic Merkel cell carcinoma: case report and review of the literature. Am J Clin Oncol. 1991;14(2):166-169.

Satpute SR, Ammakkanavar NR, Einhorn LH. Role of platinum-based chemotherapy for Merkel cell tumor in adjuvant and metastatic settings. Proc Am Soc Clin. 2014;32(suppl 5S; abstr 9049).

Kaufman HL, Russell J, Hamid O, et al. Avelumab in patients with chemotherapyrefractory metastatic Merkel cell carcinoma: a multicentre, single-group, openlabel, phase 2 trial. Lancet Oncol. 2016 Oct;17(10):1374-1385

Nghiem P, Bhatia S, Lipson EJ, et al. PD-1 blockade with pembrolizumab in advanced Merkel-cell carcinoma. N Engl J Med. 2016;374(26):2542-2552. doi: 10.1056/NEJMoa1603702.

Lewis KG, Weinstock MA, Weaver AL, Otley CC. Adjuvant local irradiation for Merkel cell carcinoma. Arch Dermatol. 2006;142(6):693-700. doi: 10.1001/ archderm.142.6.693.

Bhatia S, Storer BE, Iyer JG, et al. Adjuvant radiation therapy and chemotherapy in Merkel cell carcinoma: survival analyses of 6908 cases from the National Cancer Data Base. J Natl Cancer Inst. 2016;108(9). doi: 10.1093/jnci/djw042.

Chen MM, Roman SA, Sosa JA, Judson BL. The role of adjuvant therapy in the management of head and neck merkel cell carcinoma: an analysis of 4815 patients. JAMA Otolaryngol Head Neck Surg. 2015;141(2):137-141. doi: 10.1001/jamaoto.2014.3052.

Paulson KG, Iyer JG, Simonson WT, et al. CD8+ lymphocyte intratumoral infiltration as a stage-independent predictor of Merkel cell carcinoma survival. J Clin Oncol. 2017;35(suppl; abstr 9557).

Shapiro I, Grote HJ, D&rsquo;Urso V, et al. Exploratory biomarker analysis in avelumab-treated patients with Merkel cell carcinoma progressed after chemotherapy. J Clin Oncol. 35, 2017 (suppl; abstr 9557).

Articles

Clinical Articles

The authors discuss the current standard of care and review the new data for immunotherapy in advanced merkel cell carcinoma (MCC).

Overview of Merkel Cell Carcinoma

Amultihistology basket study proved the targetability of the

mutation in human cancers by treating patients with various types of cancer harboring an

mutation with AZD5363, an oral pan-AKT inhibitor, according to findings published in the

The PI3K/AKT pathway is one of the most frequently activated pathways across cancers and can be triggered by one of several mutations.

mutation can be found in many cancer types, they nonetheless occur at a relatively low prevalence in individual tumor lineages despite being the most common

mutation. The oncogenic nature of these gain-of-function mutations means they can be targeted with an AKT inhibitor in the hopes of improving patient outcomes.

The safety and efficacy of the AKT inhibitor had previously been investigated in patients with

-mutant estrogen receptor (ER)-positive breast cancer, HER2-positive breast cancer, or gynecologic cancers. Three of 51 patients experienced a partial response, and the optimal dose and schedule for AZD5363 was set.

mutations, 58 heavily pretreated patients were enrolled to receive 480 mg twice daily of AZD5363 on a 21-day cycle for 4 days followed by 3 days off, repeated weekly.

Of the enrolled patients, 52 showed expression of an E17K mutation, 2 patients had an

mutation; one patient had an undetectable mutation. Patients were a median 59 years (range, 31-77) and had received a median of 5 treatment regimens (range, 1-14). A majority of the patients (91.4%) were female and had a WHO performance status of 1 (53.4%); the remainder had a performance status of 0.

Following enrollment, patients were divided into 3 cohorts based on the location of their primary tumor: ER-positive breast cancer (n = 20), gynecologic cancers (n = 18), and other solid tumors (n = 20) (Table).

Table. Primary tumor location of enrolled patients

Once treatment commenced, patient disease was assessed and analyzed at baseline, every 6 weeks for 6 months, then every 12 weeks until any occurrence of a significant change in progression or withdrawal. The primary endpoint of this study was safety; response according to RECIST v1.1 criteria and progression-free survival (PFS) were key secondary endpoints.

Partial responses were confirmed in AKT1 E17K-mutant patients, including in 4 patients with ER-positive breast cancer, 2 with endometrial cancer, and 1 patient each with cervical cancer, triple-negative breast cancer, and lung adenocarcinoma. One patient with ovarian cancer with a Q17K mutation experienced stable disease and tumor regression lasting 14 months.

In treated patients with E17K mutations, the median

PFS was 5.5 months (95% CI, 2.9-6.9) for patients with ER-positive breast cancer, 6.6 months (95% CI, 1.5-8.3) for gynecologic cancers, and 4.2 months (95% CI, 2.1-12.8) for other solid tumor types. Researchers concluded that there was no apparent correlation between tumor type and response.

Grade &ge;3 adverse events (AEs) were observed in 70.7% of patients, and 51.7% were deemed to have a casually related AE, as assessed by the investigator. Hyperglycemia (24.1%), diarrhea (17.2%), and maculopapular rash (15.5%) were the common grade &ge;3 AEs reported. A dose reduction was necessitated in 34% of patients, with the above AEs being the leading causes. Serious AEs were experienced by 15.5% of patients, and the authors, led by David M. Hyman, MD, chief of the Early Drug Development Service at Memorial Sloan Kettering Cancer Center, noted that the toxicity profile was consistent with that of previous studies with AZD5363.

Prior to treatment, researchers collected and sequenced tumor samples and tumor-derived cell-free DNA (cfDNA) for retrospective and comparative analysis purposes and to see whether response could be predicted through examination of biomarkers. Interestingly, in 1 evaluable sample in which the

mutation could not be confirmed in either cfDNA or archival tumor, the patient experienced rapid disease progression.

During cycle 1, a &ge;50% decrease in the

mutant allele in cfDNA was observed in 22 of 23 patients (95.5%) that showed no correlation with response. Observations of an ongoing decrease in mutant alleles going into cycle 2 showed an association with an increase in PFS (median PFS, 5.6 vs 2.6 months in those who did not demonstrate a decline; HR, 0.18;

= .004). Five patients experienced a clearance of

mutant alleles in cfDNA lasting more than 21 days that correlated with objective responses lasting &ge;18 weeks (

Through whole-exome or targeted sequencing in a smaller population of patients (n = 37), researchers tested to see if there was a correlation between the genomic configuration of the mutation and response to AZD5363. An allelic imbalance of

was observed in 57% of the tested patients (n = 21). Further testing revealed that 10 of these patients exhibited a copy-neutral loss of heterozygosity (CN-LOH), whereby 1 patient had acquired 2 copies of a mutant AKT1 E17K allele with no remaining wild-type allele. The authors noted that those patients experienced a longer PFS than those who did not exhibit CN-LOH (median PFS, 8.2 vs 4.1 months, respectively; HR, 0.41;

= .04), and they found this association to be clinically and statistically significant. Furthermore, they concluded that this E17K allelic imbalance was more commonly found in patients with breast or gynecologic cancers (90% vs 10% of other tumor types).

Clonality, or degree of tumor cell presence, of the

mutation may have some type of correlation with respones to AZD5363. Although 92% of patients (34 of 37) had

mutations present in all tumor cells, 2 of the remaining 3 patients with subclonal mutations exhibited a rapid increase in disease progression, and the third patient, who had ovarian granulosa cell cancer, experienced a mixed response. Hyman and his colleagues suspected that the third patient&rsquo;s overall tumor regression of 24% that lasted 253 days was caused by the later acquisition of the

driver mutation, which led to a response from treatment.

Researchers also looked into the influence of commutations and concurrent activation of adjacent signaling pathways on sensitivity to inhibition. Additional mutation and activation of the PI3K/mTOR signaling pathway (Figure

) was found to correlate with longer PFS (median PFS, not reached vs 4.3 months without additional pathway mutations; HR, 0.21;

= .045). Five patients exhibited this coincident mutation in upstream or downstream effectors of signaling of the PI3K/ mTOR pathway. The potential of increased sensitivity to PI3K pathway inhibition due to concomitant pathway mutations is an area worthy of further research, the authors noted.

Other cases include an achievement of durable partial response in 2 of 5 patients with loss-of-function NF1 mutations (cervical and breast cancer), where 1 exhibited a subclonal FGFR3 S249C hotspot mutation; detection of an AZD5363- resistant subclonal KRAS A146T mutation in 1 patient with colorectal cancer; and mutations in the ligand-binding domain of ESR1 in 7 of 20 patients (35%) who experienced a shorter median PFS than those without the mutation (

Overall, the results of this clinical study strongly suggest that AKT1 E17K mutations can be a promising target for cancer therapy. &ldquo;To our knowledge, this study provides the first robust clinical evidence that AKT1 E17K is a targetable oncogene in human cancer,&rdquo; the authors wrote in the study.

The authors also noted that the AZD5363 response in these mutations was greater than that seen with

mutations, which further confirms the efficacy of

inhibition. Yet, they observed that the PFS of these treated patients was disappointingly lower than other therapeutic options targeting

. Thus, they suggested that AZD5363 may be most effective in a combination setting. Studies examining AKT inhibition with antiestrogen therapies are underway in patients with ER-positive,

Hyman and his co-authors feel confident that their study will illuminate further studies and advance the understanding of inhibition in a mutation-specific context. &ldquo;By incorporating comprehensive tissue- and plasma-based correlative studies,&rdquo; they conclude, &ldquo;we elucidate the multifaceted genomic basis of response in a manner that facilitates simultaneous translational genomic discoveries and clinical hypothesis validation to inform future studies."

Hyman D, Smyth LM, Donoghue MTA, et al. AKT1 inhibition in solid tumors with AKT1 mutations. J Clin Oncol. 2017;35(20):2251- 2259. doi: 10.1200/JCO.2017.73.0143

Holmes D. PI3K pathway inhibitors approach junction. Nat Rev Drug Discov. 2011;10(8):563-564. doi: 10.1038/nrd3527.

Amultihistology basket study proved the targetability of the AKT1 E17K mutation in human cancers by treating patients with various types of cancer harboring an AKT1 E17K mutation with AZD5363, an oral pan-AKT inhibitor, according to findings published in the Journal of Clinical Oncology.

Study Shows AKT1 E17K a Targetable Mutation Through AKT Inhibition Across Various Cancer Types

Germline mutations of BRCA 1/2 affect about 5% of patients with breast cancer and are associated with triple-negative breast cancer (TNBC), which has a poor prognosis and has been notoriously resistant to targeted therapies.

After more than a decade of development, poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors may offer these subgroups of patients an option &ldquo;that appears to be better in many ways than conventional chemotherapy,&rdquo; said Mark E. Robson, MD, a medical oncologist and clinical director of the Clinical Genetics Service at Memorial Sloan Kettering Cancer Center.

Robson was lead investigator of the open-label phase III OLYMPIAD trial (NCT02000622) in which olaparib (Lynparza), an oral PARP inhibitor, was associated with a nearly 3-month improvement in median progression-free survival (PFS) compared with physician&rsquo;s choice of conventional single-agent chemotherapy in patients with heavily pretreated HER2-negative metastatic breast cancer and a confirmed or suspected germline BRCA mutation.

The median PFS was 7 months in the olaparib (300 mg twice daily) group and 4.2 months in the group that received 21-day cycles of either capecitabine (Xeloda), eribulin (Halaven), or vinorelbine (hazard ratio [HR], 0.58; 95% CI, 0.43-0.80; P <.001), Robson and his associates reported at the 2017 ASCO Annual Meeting.

The difference in this primary endpoint was slightly more striking among patients with TNBC (HR, 0.43; 95% CI, 0.29-0.63).

&ldquo;Inclusion of patients with TNBC in this study is important, given the limited treatment options for these patients after anthracyclines and taxanes,&rdquo; the investigators wrote when the findings were published simultaneously in the New England Journal of Medicine.

OLYMPIAD is the first of several phase III breast cancer trials of PARP inhibitors that &ldquo;hopefully will lead to FDA approvals and will be a promising option for women with BRCA mutations,&rdquo; Robson said. &ldquo;The question is whether we can improve the effectiveness of treatment in these women as well as in other populations of women with breast cancer, either through better selections or through biomarker analyses.&rdquo;

Results from OLYMPIAD cap more than a decade of work on PARP inhibition in ovarian, breast, and other cancers. Although the PARP enzyme family is involved in many cellular functions,

PARP-1 is the most abundant and best characterized for its vital role in repairing single-strand DNA breaks.

Based on this premise, investigators first developed PARP inhibitors to boost the cytotoxicity of chemotherapy and radiation.

By 2005, researchers found that BRCA 1/2-mutated cells from humans and mice were profoundly sensitive to PARP inhibitors, which triggered chromosomal instability, cell cycle arrest, and apoptosis.

These in vitro findings made sense, considering that the BRCA1 and BRCA2 proteins facilitate double-stranded DNA repair through the homologous recombination pathway, experts noted.

Deleterious BRCA mutations render cells deficient in BRCA proteins and are therefore unable to efficiently activate the homologous recombination apparatus. As a result, they rely on secondary PARP-dependent pathways to repair DNA damage.

By trapping PARP at the site of DNA damage repair, PARP inhibitors stall DNA replication and repair, ultimately leading to cytotoxic double-strand breaks in BRCA-deficient cells.

Inhibitors of PARP were first developed to treat BRCA-associated ovarian cancers, and work progressed rapidly in this setting.

By 2013, multiple phase III studies were enrolling patients, and by 2014, the FDA had approved olaparib as a third-line monotherapy for women with advanced ovarian cancer with confirmed or suspected germline BRCA mutations. Rucaparib (Rubraca) received a similar approval for ovarian cancer in 2016, and in 2017, the FDA approved both niraparib (Zejula) and olaparib oral tablets as maintenance therapies for recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer in patients who had a complete or partial response to platinum-based chemotherapy, regardless of BRCA status.

Olaparib tablets were also approved for the treatment of adult patients with deleterious or suspected germline BRCA-mutated advanced ovarian cancer who have received &ge;3 prior chemotherapy regimens.

BRCA mutations also play an important role in breast cancer, but trials in this setting have been slower to demonstrate the efficacy of PARP inhibition. Consider iniparib, the now-defunct investigational agent that showed promise in a phase II trial of patients with TNBC, but flopped in 3 phase III trials of patients with breast, ovarian, and squamous nonsmall cell lung cancers.

Experts concluded that iniparib did not strongly inhibit PARP and that the crossover design of the phase II trial might have biased the results toward the agent.

Aside from iniparib, the development of PARP inhibitors has been more difficult in breast cancer than in ovarian cancer, said Robson. He explained that most ovarian cancer trials of PARP inhibitors focused on maintenance therapy or enrolled women who had previously responded to a particular platinum-based chemotherapy treatment, which predicts response to PARP inhibition. &ldquo;In breast cancer, we don&rsquo;t usually treat that way,&rdquo; he said. &ldquo;Platinum has not been a commonly used agent, although that is changing. And in the United States, at least, the treatment of breast cancer tends to be ongoing until you move on to the next therapy.&rdquo;

Because the paradigm of maintenance therapy was uncommon in breast cancer, researchers had to compare PARP inhibitors head-to-head with chemotherapy, spurring extensive discussions about how best to do so, according to Robson. Breast cancer also might be more heterogeneous than ovarian cancer, he said. &ldquo;For example, in OLYMPIAD, half of patients were triple-negative and half were HER2-positive.&rdquo;

These challenges made OLYMPIAD&rsquo;s results noteworthy. Olaparib not only met the primary endpoint of PFS, but produced a higher response rate than chemotherapy (59.9% vs 28.8%) with a 36.6% risk of grade 3 or worse adverse events (AEs) compared with a 50.5% rate for chemotherapy.

The trial did not find a difference in overall survival (OS) between the groups, but it was not powered to do so. Moreover, patients in the chemotherapy group were more likely to receive PARP inhibitors, platinum-based treatment, or cytotoxic chemotherapy after disease progression, which could also confound analyses of this endpoint, the investigators noted.

Compared with chemotherapy, olaparib was also associated with a 7.5-point relative improvement (P = .004) in quality of life as measured by the 30-item European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire.

&ldquo;Our formal definition of deterioration of quality of life was a 10-point drop in that instrument, and this was significantly delayed in people who received olaparib,&rdquo; Robson said. &ldquo;Olaparib was associated with fatigue, nausea, and anemia, but these were usually mild and did not lead to treatment discontinuation, whereas individuals who had chemotherapy had low blood cell counts and also developed hand-foot syndrome, or palmar-plantar erythrodysesthesia.&rdquo;

&ldquo;We see an improvement in PFS,&rdquo; said Robson of OLYMPIAD&rsquo;s major takeaways. &ldquo;Whether there&rsquo;s also an improvement in OS remains to be seen, but it did appear that the therapy was less toxic in several ways than conventional chemotherapy and women&rsquo;s quality of life was preserved for a longer period.&rdquo;&nbsp;

Many more trials are underway that should help address remaining questions about PARP inhibitors in breast cancer, Robson said. Ongoing studies are comparing conventional chemotherapy versus combination therapy with PARP inhibitors plus other agents that target DNA damage repair pathways (TABLE).

Moving forward, additional studies are assessing olaparib as maintenance therapy after platinum-based treatment of breast cancer and are also studying PARP inhibitors in combination with immune checkpoint inhibitors.

For the time being, OLYMPIAD provides the most promising data on PARP inhibitors in breast cancer, said Allison W. Kurian, MD, MSc, a medical oncologist and associate professor of oncology and health research and policy at Stanford University Medical Center. Among phase III trials of PARP inhibitors in breast cancer with readouts to date, only OLYMPIAD has met its primary endpoint.

The oral investigational PARP inhibitor veliparib (ABT-888) fell flat in a phase III placebo-controlled trial (NCT02032277) of patients receiving standard neoadjuvant therapy for early-stage TNBC, investigators reported at the 2017 ASCO Annual Meeting. Adding veliparib to carboplatin and paclitaxel did not significantly improve the rate of pathological complete response (53.2% vs 57.5% with placebo; P = .36).

Veliparib also did not significantly improve median PFS when added to paclitaxel and carboplatin in the placebo-controlled phase II BROCADE trial (14.1 vs 12.3 months with placebo; HR, 0.79; 95% CI, 0.54-1.16; P = .231).

Results from the phase III sister trial (BROCADE-3; NCT02163694) in patients with HER2-negative metastatic or locally advanced unresectable BRCA-associated breast cancer are expected in 2018.

Kurian is especially &ldquo;eager to see results of the phase III EMBRACA trial, which is investigating the PARP inhibitor talazoparib in BRCA 1/2 mutation carriers with metastatic breast cancer,&rdquo; she said. EMBRACA (NCT01945775) uses the same study design as OLYMPIAD, comparing the oral investigational PARP inhibitor with physician&rsquo;s choice of capecitabine, eribulin, gemcitabine, or vinorelbine.

&ldquo;Using the same design as OLYMPIAD will be useful because it hopefully will confirm the results of OLYMPIAD with a different drug,&rdquo; said Robson. The trial also has enrolled more patients than OLYMPIAD, which might better power it to detect a difference in OS, he added.

The associated phase II trial (ABRAZO; NCT02034916) evaluated talazoparib (1 mg/day; 21-day cycles) in 70 patients with locally advanced or metastatic breast cancer with BRCA mutations who either had responded to platinum-based treatment or had received at least 2 prior lines of nonplatinum chemotherapy. The objective response rate was 24% in patients with BRCA1 mutations, 34% in patients with BRCA2 mutations, 26% in women with TNBC, and 29% in women with HER2-positive disease.

As with olaparib, the most common AEs included anemia (52%), fatigue (45%), and nausea (42%).

Robson and Kurian are both anticipating the results of the phase III placebo-controlled OlympiA trial (NCT02032823), which is evaluating olaparib as adjuvant therapy for patients with early-stage germline BRCA 1/2-mutated HER2-negative breast cancer. Study investigators are still enrolling participants and intend to finish collecting data on the primary endpoint of invasive disease-free survival by 2020. Meanwhile, the phase II/ III PARTNER (NCT03150576) trial is evaluating whether adding olaparib to platinum-based therapy in the neoadjuvant setting is safe and improves the likelihood of complete pathological response at surgery in patients with TNBC or germline BRCA-mutated breast cancer.

Additionally, a phase I study determined that the combination of olaparib and cyclophosphamide was tolerable and produced antitumor activity in individuals with germline BRCA mutations and set a phase II recommended dose for the combination for further study.

Niraparib is also the subject of several studies. The phase III BRAVO trial (NCT01905592) is comparing this oral PARP inhibitor with physician&rsquo;s choice of chemotherapy in patients with HER2-negative, germline BRCA-mutated breast cancer. Earlier this year, the sponsor reported that enough patients had dropped out of the chemotherapy control arm that the trial would probably not support a registration.20 However, a phase I/II trial (NCT02657889) is recruiting patients with TNBC or ovarian cancer to study treatment with niraparib plus the antiPD-1 antibody pembrolizumab (Keytruda). Additional trials of niraparib in breast cancer are planned, but are not yet recruiting.&nbsp;

Work also continues on rucaparib, which is currently approved for the treatment of ovarian cancer in patients with somatic or germline BRCA mutations. The phase II RUBY trial (NCT02505048) is evaluating rucaparib monotherapy (600 mg twice daily in 21-day cycles) in patients with HER2-negative breast cancer and mutations of BRCA 1/2 or other genes involved in the homologous recombination repair pathway.

Topline results are expected in December 2017.

For now, it&rsquo;s too soon to say which PARP inhibitors or combinations will provide the most benefit in breast cancer, or in which patient subgroups, Robson said. &ldquo;Even in ovarian cancer, this is not clear, and it would be difficult to extrapolate from ovarian cancer to breast cancer anyway. There are material differences between the drugs, and I&rsquo;m not sure there&rsquo;s a winner to pick in terms of the best agent.&rdquo;

He emphasized that increasing numbers of patients with breast cancer are being found to have either germline or somatic BRCA mutations or mutations in other genes in the homologous recombination pathway. For example, in a recent study of 560 patients with breast cancer, investigators identified all possible mutations and developed a weighted computer model called HRDetect that detected &ldquo;mutational signatures&rdquo;somatic substitutions and patterns of DNA insertions, deletions, and rearrangement corresponding with BRCA 1/2 mutations.

Only 22 patients (4%) in the cohort had known germline BRCA 1/2 mutations, which echoes the prevalence in other studies. Strikingly, HRDetect identified 22 additional tumors with somatic BRCA mutations and 47 tumors with a functional BRCA1/BRCA2 deficiency. None of these patients had detectible BRCA germline mutations. The researchers validated HRDetect in separate groups of patients with breast, ovarian, and pancreatic cancers, where it again detected tumors with &ldquo;BRCAness&rdquo; in patients who lacked the classic germline mutations.

Testing for these mutational signatures could help physicians identify patients whose breast cancer might be sensitive to PARP inhibition even though they lack BRCA 1/2 germline mutations, the researchers concluded. Editors of the September 2017 issue of Cancer agreed, noting that up to 20% of breast cancers might be treatable with PARP inhibitors if these findings hold up in other studies.

Kurian looks even further ahead. Five to 10 years from now, she hopes that additional trials will have spurred FDA approvals of PARP inhibitors that effectively treat BRCA 1/2-associated breast cancer, both in the metastatic and early-stage, curable settings, she said. &ldquo;I also hope that we will see efficacy of PARP inhibitors among patients whose breast cancers are the result of DNA repair gene mutations other than BRCA 1/2, such as ATM [ataxia telangiectasia mutated], for which we now routinely test in clinical practice.&rdquo;

Bianchini G, Balko JM, Mayer IA, Sanders ME, Gianni L. Triple-negative breast cancer: challenges and opportunities of a heterogeneous disease. Nat Rev Clin Oncol. 2016;13(11):674-690. doi: 10.1038/nrclinonc.2016.66.

Robson M, Im S-A, Senkus E, et al. Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. New Engl J Med. 2017;377(6):523-533. doi: 10.1056/NEJMoa1706450.

Robson ME, IM S-A, Senkus E, et al. OlympiAD: Phase III trial of olaparib monotherapy versus chemotherapy for patients (pts) with HER2-negative metastatic breast cancer (mBC) and a germline BRCA mutation (gBRCAm). J Clin Oncol. 2017;35(suppl 18; abstr LBA4). ascopubs.org/doi/ abs/10.1200/JCO.2017.35.18_suppl.LBA4.

Livraghi L, Garber JE. PARP inhibitors in the management of breast cancer: current data and future prospects. BMC Med. 2015;13:188. doi: 10.1186/s12916-015-0425-1.

Benanif S, Hall M. An update on PARP inhibitors for the treatment of cancer. Onco Targets Ther. 2015;8:519-528. doi: 10.2147/OTT.S30793.

Calabrese CR, Almassy R, Barton S, et al. Anticancer chemosensitization and radiosensitization by the novel poly(ADP-ribose) polymerase-1 inhibitor AG14361. J Natl Cancer Inst. 2004;96(1):56-67. doi: 10.1093/jnci/djh005.

Farmer H, McCabe N, Lord CJ, et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature. 2005;434(7035):917-921. doi: 10.1038/nature03445.

Liu JF, Konstantinopoulos PA, Matulonis UA. PARP inhibitors in ovarian cancer: current status and future promise. Gynecol Oncol. 2014;133(2):362-369. doi: 10.1016/j.ygyno.2014.02.039.

Ali R, Rakha EA, Madhusudan S, Bryant HE. DNA damage repair in breast cancer and its therapeutic implications. Pathology. 2017;49(2):156-165. doi: 10.1016/j.pathol.2016.11.002.

Lim JSJ, Tan DSP. Understanding resistance mechanisms and expanding the therapeutic utility of PARP inhibitors. Cancers (Basel). 2017;9(8). pii: E109. doi: 10.3390/cancers9080109.

FDA approves maintenance treatment for recurrent epithelial ovarian, fallopian tube or primary peritoneal cancers [press release]. Silver Spring, MD: FDA; March 29, 2017. www.fda.gov/newsevents/ newsroom/pressannouncements/ucm548948.htm. Accessed September 14, 2017.

FDA approves olaparib tablets for maintenance treatment in ovarian cancer [press release]. Silver Spring, MD: FDA; August 17, 2017. www.fda.gov/drugs/informationondrugs/approveddrugs/ ucm572143.htm. Accessed September 14, 2017.

Sinha G. Downfall of iniparib: a PARP inhibitor that doesn&rsquo;t inhibit PARP after all. J Natl Cancer Inst. 2014;106(1):djt447. doi: 10.1093/jnci/djt447.

Robert M, Frenel JS, Gourmelon C, Patsouris A, Augereau P, Campone M. Olaparib for the treatment of breast cancer. Expert Opin Investig Drugs. 2017;26(6):751-759. doi: 10.1080/13543784.2017.1318847. 15. Geyer CE, O&rsquo;Shaughnessy J, Untch M, et al. Phase 3 study evaluating efficacy and safety of veliparib (V) plus carboplatin (Cb) or Cb in combination with standard neoadjuvant chemotherapy (NAC) in patients (pts) with early stage triple-negative breast cancer (TNBC). J Clin Oncol. 2017;35(suppl 15; abstr 520). ascopubs.org/doi/abs/10.1200/JCO.2017.35.15_suppl.520.

Geyer CE, O&rsquo;Shaughnessy J, Untch M, et al. Phase 3 study evaluating efficacy and safety of veliparib (V) plus carboplatin (Cb) or Cb in combination with standard neoadjuvant chemotherapy (NAC) in patients (pts) with early stage triple-negative breast cancer (TNBC). J Clin Oncol. 2017;35(suppl 15; abstr 520). ascopubs.org/doi/abs/10.1200/JCO.2017.35.15_suppl.520.

Gampenrieder SP, Rinnerthaler G, Greil R. SABCS 2016: systemic therapy for metastatic breast cancer. Memo. 2017;10(2):86-89. doi: 10.1007/s12254-017-0326-4.

Turner NC, Telli ML, Rugo HS, et al. Final results of a phase 2 study of talazoparib (TALA) following platinum or multiple cytotoxic regimens in advanced breast cancer patients (pts) with germline BRCA 1/2 mutations (ABRAZO). J Clin Oncol. 2017;35(suppl 15; abstr 1007). ascopubs.org/doi/ abs/10.1200/JCO.2017.35.15_suppl.1007.

Earl HM, Vallier A-L, Qian W, et al. PARTNER: Randomised, phase II/III trial to evaluate the safety and efficacy of the addition of olaparib to platinum-based neoadjuvant chemotherapy in triple negative and/or germline BRCA mutated breast cancer patients. J Clin Oncol. 2017;35(suppl 15; abstr TPS591). ascopubs.org/doi/abs/10.1200/JCO.2017.35.15_suppl.TPS591.

Lee CK, Scott CL, Lindeman GJ, et al; Australia and New Zealand Breast Cancer Trials Group. Phase I study of olaparib (O), in combination with oral cyclophosphamide (C), in patients (pts) with metastatic triple negative breast cancer (TNBC) and recurrent high grade serous ovarian cancer (OVCA). J Clin Oncol. 2017;35(suppl 15; abstr 1104). ascopubs.org/doi/abs/10.1200/ JCO.2017.35.15_suppl.1104.

TESARO announces expanded development program for niraparib focused on the treatment of front-line metastatic ovarian and lung cancers and metastatic breast cancer [press release]. Waltham, MA: Tesaro; March 27, 2017. globenewswire.com/news-release/2017/03/27/945563/0/ en/TESARO-Announces-Expanded-Development-Program-for-Niraparib-Focused-on-the-Treatment- of-Front-Line-Metastatic-Ovarian-and-Lung-Cancers-and-Metastatic-Breast-Cancer.html. Accessed September 11, 2017.

Patsouris A, Vicier C, Campion L, et al. An open-label, phase II study of rucaparib, a PARP inhibitor, in HER2- metastatic breast cancer patients with high genomic loss of heterozygosity: RUBY. J Clin Oncol. 2017;35(suppl 15; abstr TPS1117). ascopubs.org/doi/abs/10.1200/JCO.2017.35.15_ suppl.TPS1117.

Davies H, Glodzik D, Morganella S, et al. HRDetect is a predictor of BRCA1 and BRCA2 deficiency based on mutational signatures. Nat Med. 2017;23(4):517-525. doi: 10.1038/nm.4292.

More breast cancer patients could benefit from PARP inhibitors. Cancer. 2017;123(18):3433. doi: 10.1002/cncr.30962.

Mark E. Robson, MD, discusses the progress that has been seen in breast cancer care with the use of PARP inhibitors.

Select Ongoing Clinical Trials of PARP Inhibitors in Breast Cancer

&trade;, Jonathan E. Rosenberg, MD, discussed the guidelines and their significance for the treatment of patients with muscle-invasive bladder cancer (MIBC).

Rosenberg, a medical oncologist at Memorial Sloan Kettering Cancer Center, emphasized that one of the effects of these new guidelines is that cisplatin-based neoadjuvant chemotherapy prior to cystectomy is now being established among urologists as a standard of care for eligible patients. This treatment approach received a strong grade B recommendation in the guidelines and will improve survival for these patients.

Can you discuss these guidelines for bladder cancer and their significance?

Traditionally, MIBC has been managed purely by urologists in the United States with radical cystectomy being the only treatment often offered. However, there have been several large, randomized trials that show a benefit with cisplatin-based neoadjuvant chemotherapy prior to cystectomy.

There&rsquo;s been a large educational effort over the years, and this is an outgrowth of that effort to implement appropriate therapy for patients who are candidates for cisplatin-based neoadjuvant chemotherapy. We know that it reduces the risk of death from bladder cancer by one-third and improves the survival by 5% to 10%, depending on the clinical trial.

We have worked on these guidelines to establish this as a standard of care in conjunction with other organizations, such as ASCO. These guidelines now incorporate cisplatin-based chemotherapy for patients who have adequate kidney function, no significant neuropathy, no significant hearing loss, and who are otherwise healthy enough to undergo this type of treatment.

Is immunotherapy mentioned in these guidelines?

Not yet. Immunotherapy for these patients remains experimental, and there are multiple clinical trials that are testing this. There is a focus on adjuvant immunotherapy in large randomized phase III trials that are currently accruing patients. These trials are testing whether PD-1/PD-L1 inhibition versus observation or placebo, depending on the study, will improve survival for high-risk patients after cystectomy.

Postoperative treatment is generally adjuvant cisplatin-based chemotherapy for patients with high-risk disease who have not received neoadjuvant chemotherapy. In my opinion, if they have received neoadjuvant therapy, these patients should consider enrolling in one of these trials if their cancer is still high risk after cystectomy.

There are many patients who can&rsquo;t receive cisplatin-based chemotherapy for a variety of medical reasons, in which case they are not receiving neoadjuvant chemotherapy and could consider enrolling in one of the adjuvant therapy trials. To date, there are no results from these studies and we are looking for evidence that these patients would benefit from this approach.

: Have any recent advancements in the field affected these guidelines?

One of the questions that always arises is whether there are any molecular or clinical predictors about who would benefit from neoadjuvant chemotherapy. There are multiple intriguing technologies that are investigating this. My own opinion is that none of them are ready for primetime.

One methodology is looking at DNA damage-repair mutations, which is essentially the mechanism of action for cisplatin-based chemotherapy. It damages the DNA; the cells that have defective DNA repair are unable to recover, and we see better outcomes in those patients. However, the data thus far have been retrospective and it requires prospective validation.

There is also evidence for RNA-expression profiling. There is one subtype of bladder cancer, the basal subtype, that might benefit more from chemotherapy, although it doesn&rsquo;t mean that the other subtypes don&rsquo;t derive benefit. Work still needs to be done to better understand if that classifier can be used to select patients for chemotherapy, but it&rsquo;s not clear that they can tell someone that they don&rsquo;t need chemotherapy or that they wouldn&rsquo;t benefit from it.

That is all very exciting and interesting. There is a lot of intersection between that data, the outcomes of patients treated with immunotherapy, and advanced disease because many of the things that predict good responses to chemotherapy also predict good responses to immunotherapy. We are trying to integrate all of this knowledge to understand the potential novel targets that are responsible for these differences.

: How does having these guidelines benefit the treatment decisions for these patients?

Setting standards as to what is appropriate care is important in medicine and the care of patients with bladder cancer. We have a long history of failure to accrue to clinical trials, as well as a failure to follow guidelines for the treatment of these patients. Therefore, setting standards and guidelines will help to ensure that the recommendations are out there about how these matters should be handled.

An important area is bladder preservation, which is something that is involved in these guidelines with chemoradiation. There are 2 types of bladder preservation. The first is selective bladder preservation for people who could be cystectomy candidates but might do well with chemotherapy, radiation therapy, and radical transurethral resection. Or there are patients who also aren&rsquo;t candidates for cystectomy and need treatment for their MIBC. Those patients are also well served by chemoradiation as opposed to no treatment, which unfortunately often happens for many patients.

: What should the main takeaways be from these guidelines?

From a medical oncologist&rsquo;s perspective, the strong recommendation for perioperative systemic therapy is important because we know it cures patients. The problem is that we don&rsquo;t have a way to figure out who those patients are in advance. We need to select them so that we aren&rsquo;t treating everybody. We would rather only treat the patients who will benefit. At the moment, the data do support the use of these treatments. It is a major step forward to say that this is what is suggested as optimal therapy for these patients.

In an interview, Jonathan E. Rosenberg, MD, discusses the guidelines and their significance for the treatment of patients with muscle-invasive bladder cancer.

The Impact of the New Muscle-Invasive Bladder Cancer Guidelines

A multidisciplinary set of guidelines for the treatment of patients with nonmetastatic muscle-invasive bladder cancer (MIBC) has been created as a result of a new collaboration between the American Urological Association (AUA) and several other prominent urological groups.

The new guidelines provide a risk-stratified clinical framework to better diagnose, treat, and manage the disease.

The guideline statements included input from the AUA, American Society of Clinical Oncology, the Society of Urologic Oncology, the American Society for Radiation Oncology, and the Bladder Cancer Advocacy Network. This first-of-its-kind collaboration offers clinicians evidence-based recommendations of 3 levels (A, B, and C); clinical principle statements that all clinicians or urologists generally agree upon; and expert opinions that express the unanimous conclusions of the panelists.

There is a clinical need for improved management of patients with MIBC, as 79,030 new cases of bladder cancer and 16,870 deaths from the disease are predicted for 2017 in the United States.

&ldquo;Approximately 25% of newly diagnosed patients have muscle-invasive disease, and that rate hasn&rsquo;t changed over the past 25 years. In addition, the overall prognosis of patients with muscle-invasive disease has not changed in the last 30 years and is primarily based on stage,&rdquo; said Jeffrey M. Holzbeierlein, MD, a member of the panel that put together the guidelines, and director of urologic oncology at the University of Kansas Medical Center, in his presentation of the new guidelines during the 2017 American Urological Association Annual Meeting.

The first series of guidelines includes statements regarding the need for staging evaluation during physical examination of patients under anesthesia. &ldquo;The panel felt that this was an important component of identifying patients [whose tumors] might be resectable, and, of course, you would do this if you suspect MIBC at the time of [transurethral resection of bladder tumor (TURBT)]. Also, since there are a lot of comorbidities, this is a critical component to assess patients to determine what they might be candidates for in terms of treatment,&rdquo; Holzbeierlein said.

Although imaging and lab evaluation are critical components of staging patients with MIBC, the panel did not recommend any specific imaging modalities. The panel, however, did agree that cross-section imaging of the abdomen and pelvis should be done with intravenous contrast, as well as recognized that there are no data to support any single imaging modality over another. The guidelines do not recommend PET scans, as the panel said there was insufficient evidence to support their superiority over CT scans.

They did note that PET imaging should be reserved for patients with abnormal chest, abdominal, or pelvic images that require further evaluation or in cases where a lymph node biopsy is not feasible.

Although chest imaging is somewhat controversial, the new guidelines recommend a chest CT scan if the patient has a history of smoking. &ldquo;We do recognize that we are seeing increased amounts of variant histology, and when that is suspected, we recommended a review by a dedicated GU pathologist, as the definitive histology can change treatment in up to one-third of patients,&rdquo; Holzbeierlein commented.

The guidelines recommend that patients receive an explanation of all treatment options that are available, including surgery, chemotherapy, and radiotherapy. &ldquo;We recognize that not all clinicians have the ability to provide 3 different disciplines, but certainly 1 clinician can provide an explanation of the multidisciplinary approaches to treatment options that are available,&rdquo; he said.

The implications of various treatments on quality of life should also be discussed with the patient, and this is expressed as a clinical principle in the guidelines.

A multidisciplinary set of guidelines for the treatment of patients with nonmetastatic muscle-invasive bladder cancer has been created as a result of a new collaboration between the American Urological Association and several other prominent urological groups.&nbsp;The new guidelines provide a risk-stratified clinical framework to better diagnose, treat, and manage the disease.&nbsp;

October 2017 | Targeted Therapies in Oncology

Overview of Merkel Cell Carcinoma

Study Shows AKT1 E17K a Targetable Mutation Through AKT Inhibition Across Various Cancer Types

Select Ongoing Clinical Trials of PARP Inhibitors in Breast Cancer

The Impact of the New Muscle-Invasive Bladder Cancer Guidelines

Multidisciplinary Guidelines for Diagnosis and Treatment of MIBC

FGFR4 Inhibitor Demonstrates Promising Activity in HCC Subgroup

Predictive and Prognostic Biomarkers Sought in HCC