Conleth G. Murphy

Current or recent pregnancy is associated with adverse pathologic features but not impaired survival in early breast cancer

Pregnancy‐associated breast cancer (PABC) may be defined as breast cancer diagnosed during pregnancy or within 1 year of giving birth. Conflicting data exist regarding the impact of pregnancy on clinical features and prognosis of breast cancer.

Recent advances in novel targeted therapies for HER2-positive breast cancer.

The monoclonal antibody trastuzumab has improved the outcomes of patients with breast cancer that overexpresses the human epidermal growth factor receptor 2 (HER2). However, despite this advancement, many tumors develop resistance and novel approaches are needed. Recently, a greater understanding of cellular biology has translated into the development of novel anti-HER2 agents with varying mechanisms of action. The small molecule tyrosine kinase inhibitor lapatinib has demonstrated activity in HER2-positive metastatic breast cancer (MBC) and in the preoperative setting. Pertuzumab is a monoclonal antibody with a distinct binding site from trastuzumab, which inhibits receptor dimerization. In recent studies, the addition of pertuzumab to combination therapy has led to improvements in progression-free survival in patients with HER2-positive MBC and higher response rates in the preoperative setting. An alternative approach is the use of novel antibody–drug conjugates such as trastuzumab–emtansine, which recently demonstrated activity in MBC. Neratinib, a pan-HER tyrosine kinase inhibitor, which irreversibly inhibits HER1 and HER2, also has proven activity in MBC. A range of compounds is being developed to attempt to overcome trastuzumab resistance by targeting heat shock protein 90, a molecular chaperone required for the stabilization of cellular proteins. Furthermore, agents are being developed to inhibit the mammalian target of rapamycin, a downstream component of the PTEN/PI3K pathway, which has been implicated in trastuzumab resistance. Finally, there are emerging data indicating that combinations of anti-HER2 agents may circumvent resistance mechanisms and improve patient outcomes. In this review, recent data on these emerging agents and novel combinations for HER2-positive breast cancer are discussed.

BRCA gene structure and function in tumor suppression: a repair-centric perspective.

Germline mutations in the BRCA1 and BRCA2 genes are characterized by deficient repair of DNA double-strand breaks by homologous recombination. Defective DNA double-strand break repair has been not only implicated as a key contributor to tumorigenesis in mutation carriers but also represents a potential target for therapy. The transcriptional similarities between BRCA1-deficient tumors and sporadic tumors of the basal-like subtype have led to the investigation of homologous recombination repair-directed therapy in triple-negative tumors, which demonstrates overlap with the basal-like subtype. We broaden the scope of this topic by addressing a “repair-defective” rather than “BRCA1-like” phenotype. We discuss structural and functional aspects of key repair proteins including BRCA1, BRCA2, BRCA1 interacting protein C-terminal helicase 1, and partner and localizer of BRCA2 and describe the phenotypic consequences of their loss at the cellular, tissue, and organism level. We review potential mechanisms of repair pathway dysfunction in sporadic tumors and address how the identification of such defects may guide the application of repair-directed therapies.

The Role of CDK4/6 Inhibition in Breast Cancer

Imbalance of the cyclin D and cyclin-dependent kinase (CDK) pathway in cancer cells may result in diversion away from a pathway to senescence and toward a more proliferative phenotype. Cancer cells may increase cyclin D-dependent activity through a variety of mechanisms. Therapeutic inhibition of CDKs in tumors to negate their evasion of growth suppressors has been identified as a key anticancer strategy. In this review, we outline the development of CDK inhibitory therapy in breast cancer, including the initial experience with the pan-CDK inhibitor flavopiridol and the next generation of oral highly selective CDK4 and CDK6 inhibitors PD0332991 (palbociclib), LEE011 (ribociclib), and LY2835219 (abemaciclib). Data from phase I and II studies in estrogen receptor-positive (ER+) breast cancer demonstrate promising efficacy with manageable toxic effects, chiefly neutropenia. We discuss these studies and the phase III studies that are accruing or nearing completion. We describe the application of such therapy to other breast cancer settings, including HER2-positive breast cancer and the adjuvant treatment of early breast cancer. We also discuss potential concerns surrounding the combination of CDK inhibitors with chemotherapy and their effects on repair of double-strand DNA breaks in cancer cells. Oral highly selective CDK inhibitors show great promise in improving the outcomes of patients with ER+ breast cancer, although caution must apply to their combination with other agents and in the early breast cancer setting.

Endocrine resistance in hormone-responsive breast cancer: mechanisms and therapeutic strategies.

The majority of breast cancers may be considered hormone responsive due to expression of hormone receptors (HR+). Although endocrine therapy is always considered for advanced HR+ breast cancer, the emergence of resistance is inevitable over time and is present from the start in a proportion of patients. In this review, we explore the mechanisms underlying de novo and acquired resistance to endocrine therapy. We comprehensively review newly approved and emerging therapies that have been developed to counteract specific mechanisms of resistance. We discuss the challenges pertinent to this therapeutic arena including the potential relief of negative regulatory feedback inhibition with compensatory pathway activation and the evolution of molecular changes in HR+ breast cancers during treatment. We discuss strategies to address these challenges in order to develop rational therapy approaches for patients with advanced HR+ breast cancer.

Cystoid Macular Edema Secondary tonab-Paclitaxel Therapy

Patient 1 is a 65-year-old woman with a diagnosis of breast cancer metastatic to bone, pleura, pericardium, and lymph nodes. She received adjuvant chemotherapy with cyclophosphamide, methotrexate, and fluorouracil following her original diagnosis in 1990. In 1998, she progressed systemically and was treated with multiple lines of endocrine therapy. She subsequently received sequential single-agent chemotherapy with capecitabine, gemcitabine, vinorelbine, paclitaxel, and weekly anthracycline therapy with conventional doxorubicin. Her past medical history included hypertension, obesity, and stable chronic renal impairment with symptomatic fluid overload responding to diuretic therapy. In July 2008 she started weekly nanoparticle albumin bound (nab) –paclitaxel (Abraxane; Abraxis Bioscience, Bridgewater, NJ) and bevacizumab; the bevacizumab was discontinued after a single dose because of proteinuria. In October 2008, she complained of deterioration in her vision over a period of 6 weeks that prevented her from reading the newspaper. Visual acuity was 20/60 in both eyes and color vision was intact. Fundoscopy was normal. Two weeks later, her visual acuity had deteriorated to 20/80 on the right. Fundoscopic examination was suggestive of macular edema bilaterally. Ocular coherence tomography (OCT) showed cystic spaces in the retina, confirming cystoid macular edema (CME), with no leakage of dye evident on angiography. The nab-paclitaxel was discontinued and she was treated with topical steroids and nonsteroidal antiinflammatory drugs. She experienced rapid recovery of her visual function, such that she could read newspapers comfortably on review 3 weeks after stopping nab-paclitaxel. Her visual acuity had recovered to 20/60 on the right and 20/40 on the left at the time of this review. Patient 2 is a 58-year-old woman who was diagnosed with a T2N0 left breast cancer at the age of 38 years in 1988. She was treated with wide local excision and axillary lymph node dissection, followed by adjuvant radiotherapy. She did not receive adjuvant chemotherapy or endocrine therapy. She developed bone, liver, and pleural metastases 10 years after her original diagnosis. She was treated with sequential endocrine therapies from January 1999 to May 2006. At that time she was switched to the oral antimetabolite chemotherapy drug capecitabine, and bevacizumab was added in March 2007. She was switched to nab-paclitaxel plus bevacizumab in August 2007. In January 2008 she complained of increased tear production, which was relieved by lubricant eye drops. An eye examination by her local ophthalmologist showed no evidence of canalicular stenosis. She continued to receive nab-paclitaxel and bevacizumab, although the bevacizumab was held from August 2008, in anticipation of possible cataract surgery. She experienced deterioration of her vision despite discontinuation of bevacizumab. On examination in September 2008, 11 months after commencing nab-paclitaxel, her best corrected visual acuity was 20/70 in both eyes. On dilated fundus examination there was evidence of bilateral cystoid macular edema (Fig 1). OCT confirmed bilateral cystic retinal changes (Fig 2, white arrows). Fluorescein angiography showed no evidence of leakage. The nab-paclitaxel was discontinued. On review 2 months later, her visual acuity had improved to 20/50 on the right and 20/30 on the left. Follow-up OCT performed 3 months after discontinuation of nab-paclitaxel confirmed marked decrease in macular edema (Fig 3, white arrows). Paclitaxel is a member of the taxane family of microtubule stabilizing agents that has demonstrated clinical efficacy in multiple human malignancies. Because of its hydrophobic nature, paclitaxel is poorly soluble. The first licensed formulation of paclitaxel (CrEL-paclitaxel or Taxol, Bristol-Myers Squibb, Princeton, NJ) used polyethylated castor oil (Cremophor EL) and ethanol to emulsify paclitaxel. The CrEL formulation can cause hypersensitivity reactions, requiring a prolonged infusion time and premedication with steroids and antihistamines. In addition, special infusion tubing and inline filters must be used when administering CrEL-paclitaxel. A newer formulation of paclitaxel, nab-paclitaxel, uses albumin bound nanoparticles to enhance the solubility of the drug. This formulation has been shown in pharmacokinetic studies to result in a higher paclitaxel clearance and volume of distribution than the CrEL formulation. A pivotal phase III trial in patients with metastatic breast cancer randomly assigned 454 patients to the standard arm of CrEL-paclitaxel 175 mg/m versus nab-paclitaxel 260 mg/m, with both drugs given every 3 weeks. The nab formulation was superior in terms of overall response rate (33% v 19%; P .001) and time to progression (23.0 v 16.9 weeks; hazard ratio, 0.75; P .006). Macular edema is a condition characterized by abnormal thickening of the retina associated with the accumulation of excess fluid in the extracellular space of the neurosensory retina. It can occur in Fig 1. JOURNAL OF CLINICAL ONCOLOGY D I A G N O S I S I N O N C O L O G Y VOLUME 28 NUMBER 33 NOVEMBER 2

Evolving Approaches to Metastatic Breast Cancer Previously Treated with Anthracyclines and Taxanes

Despite major advances in the adjuvant treatment of breast cancer, many women will develop metastatic disease, either de novo or following optimal adjuvant therapy. Further effective therapeutic options are needed for women who progress following anthracycline- and taxane-containing regimens. Capecitabine is approved by the US Food and Drug Administration as monotherapy in this setting. Other agents such as gemcitabine or vinorelbine might be considered based on multiple phase II studies. Combination therapies generally increase response rates but with a concomitant increase in toxicity. Other agents that have been studied in this setting include etoposide, irinotecan, and pemetrexed. Novel agents undergoing testing include the fluorinated vinca alkaloid vinflunine and the halichondrin B analogue eribulin. Responses have been seen in taxane-pretreated patients with the use of another conventional taxane, novel formulations, or alternative schedules. Pegylated liposomal doxorubicin might be considered in some patients for whom there is a concern regarding cardiac toxicity with the conventional preparation. The epothilones are a novel group of microtubule-stabilizing agents. Ixabepilone is a member of this class that has been approved as monotherapy in patients whose tumors are resistant or refractory to anthracyclines, taxanes, and capecitabine. It is also approved with capecitabine in patients whose cancer is resistant to treatment with anthracyclines and taxanes. Decision-making regarding treatment selection must take into account multiple patient and tumor factors. The therapeutic indices of the available treatments should be considered in the context of the individual patient.

CDK4/6 inhibitors in breast cancer.

Deregulation of the cyclin-dependent kinase (CDK) 4/6-retinoblastoma (RB) axis can occur through a number of mechanisms and contributes towards the unrestrained growth witnessed in a variety of cancers including breast cancers. Recent years have seen the development of selective CDK4/6 inhibitors, which have delivered promising preclinical and clinical results in breast cancer and other tumours. A number of trials assessing antitumour efficacy in various disease settings and combinations are ongoing. The cyclin D1-CDK-Rb axis and its role in the cell cycle of normal and cancer cells are delineated. The early pan-CDK inhibitor flavopiridol and subsequent preclinical and clinical development of selective CDK4/6 inhibitors are described. Ongoing studies in breast cancer with novel CDK4/6 inhibitors (palbociclib, abemaciclib and ribociclib) are explored. A literature search of these topics was performed through PubMed. Abstracts from major oncology meetings were also reviewed. Selective CDK4/6 inhibitors, as represented by the competing compounds currently in clinical development, comprise a novel, safe and, thus far, promisingly efficacious group of drugs. Considerable resources are being devoted towards exploring the efficacy of these drugs in combination with endocrine therapies, an approach that has yielded encouraging results and accelerated approval by the US Food and Drugs Administration for one of these agents (palbociclib). The results of confirmatory phase 3 trials are, however, awaited. We discuss further therapy combinations in development and highlight potential areas for caution including the potential for antagonistic interactions with cytotoxic chemotherapies.

Abstract P5-18-20: Phase II study of pertuzumab, trastuzumab, and weekly paclitaxel in patients with metastatic HER2-overexpressing metastatic breast cancer.

Background: Pertuzumab (P) is a monoclonal antibody which binds to extracellular domain II of HER2 distally from trastuzumab (H), disrupting HER2 dimerization and signaling. The CLEOPATRA phase III trial showed that HP + docetaxel in HER2+ metastatic breast cancer (MBC) prolonged progression-free survival (PFS) compared to placebo + H + docetaxel. We report preliminary results of a phase II study to evaluate the safety and efficacy of weekly paclitaxel with HP (THP). Methods: Patients (pts) with HER2+ MBC with 0–1 prior treatment (Rx) are eligible. Pts receive weekly (w) paclitaxel (80mg/m2), q3w trastuzumab (loading dose 8mg/kg → 6mg/kg), and q3w pertuzumab (flat loading dose 840mg → flat dose 420mg). The primary endpoint is PFS at 6 months (mo). Secondary endpoints include response, safety (including cardiac events), and tolerability. Evaluable pts are those who have started study Rx and are assessed at 6 mo for PFS. Left ventricular ejection fraction (LVEF) is monitored by echocardiogram every 3 mo. Cardiac events are defined as symptomatic LV systolic dysfunction (LVSD), non-LVSD cardiac death, or probable cardiac death. Results: As of 6–1-12, 38 of the planned 69 pts were enrolled and 20 pts were evaluable at 6 mo. Median age is 52 years (range 32 to 72). A total of 11 pts (55%) previously received trastuzumab in the adjuvant or metastatic setting, and 8 pts (40%) were being treated in the second-line metastatic setting. Of the 20 evaluable pts, G 3/4 toxicities were sepsis (1 pt, 5%), cholecystitis (1 pt, 5%), fatigue (1 pt, 5%), skin ulceration (1 pt, 5%) and cystic macular degeneration (1 pt with prior prolonged Rx with paclitaxel, 5%). Common G 1/2 toxicities included alopecia (20 pts, 100%), peripheral neuropathy (20 pts, 100%), fatigue (18 pts, 90%), ALT/AST elevation (17 pts, 85%), diarrhea (15 pts, 75%), rash (13 pts, 65%), nail changes (10 pts, 50%), mucositis (9 pts, 45%), dry skin (8 pts, 40%), and nausea (8 pts, 40%). Median LVEF was 64% at baseline (range 50% to 69%), 60% at 3mo (range 50% to 73%), and 60% at 6mo (range 49% to 67%). There were no cardiac events. At 6 mo, 15/20 pts (75%) were progression-free (2 CR, 8 PR and 5 SD); 5 pts had progressed. The 6 mo PFS results for all 38 enrolled patients will be updated. Conclusions: Our single-center phase II study continues to accrue, with no clinically significant diarrhea or signal of increased cardiac toxicity to date. Pertuzumab was recently FDA-approved in combination with trastuzumab and docetaxel. If the estimate of safety and activity is similar to results with docetaxel in CLEOPATRA, this study will provide support for weekly paclitaxel as an alternative option in combination with trastuzumab and pertuzumab in this setting. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-18-20.

Phase II trial of patupilone in patients with brain metastases from breast cancer

BACKGROUND For patients with progressive breast cancer brain metastasis (BCBM) after whole brain radiotherapy (WBRT), few options exist. Patupilone is an epothilone that crosses the blood-brain barrier. We hypothesized that patupilone would produce a 35% 3-month CNS progression-free survival in women with BCBM after WBRT. METHODS This multicenter phase II trial included 2 cohorts. Group A included women with progressive BCBM after WBRT. Group B was an exploratory cohort of patients with either leptomeningeal metastases or untreated brain metastases. The primary goal was to observe a 35% 3-month CNS progression-free survival in Group A. The sample size was 45 for Group A and 10 for Group B. Patients received patupilone 10 mg/m(2) once every 3 weeks until progression. Responses were scored according to the Macdonald criteria. RESULTS Fifty-five patients (45 in Group A, 10 in Group B) enrolled. In Group A, the 3-month CNS progression-free survival was 27%, the median overall survival was 12.7 months, and the overall response rate was 9%. In Group B, which enrolled 5 patients with leptomeningeal disease and 5 with no prior WBRT, no responses occurred and 8 patients had CNS progression before 3 months. Systemic responses occurred in 15% of patients, including a complete response in liver metastases. Diarrhea occurred in 87% of patients; 25% had grade 3 and 4 adverse events. CONCLUSIONS Patupilone in patients with BCBM did not meet the efficacy criteria and had significant gastrointestinal toxicity. Further study of brain-penetrant agents is warranted for patients with CNS metastases from breast cancer.