This month, I will be covering some of the data from this year’s American Society of Clinical Oncology^® (ASCO) meeting. In this edition, I will review a number of the abstracts in melanoma, gynecologic oncology, genitourinary cancers, and breast cancers.

Presentations from the Breast Cancer Session at The Annual Oncology Meeting

There are 4 main themes in the breast cancer abstracts that I am highlighting from ASCO 2009. These include the treatment of triple-negative breast cancer, newer HER-2 targeted agents in trastuzumab-resistant metastatic breast cancer, bevacizumab for metastatic breast cancer, and CYP2D6 inhibitors when given with tamoxifen.

With regards to triple-negative breast cancer, these cancers share some but not all pathologic features with BRCA 1 related breast cancer including mutant p53 status, basal-like gene expression profiles, poor differentiation, and chemosensitivity to DNA-damaging agents. Poly ADP-ribose polymerase (PARP) is a regulator of DNA damage repair processes in the cell. It binds directly to DNA damage and is involved in the DNA base-excision repair. BRCA 1 and 2 are also involved in DNA base-excision repair. If PARP is inhibited, then there is a disabling of this base-excision repair leading to replication fork collapse and double strand DNA breaks. Chemotherapy such as the platinum compounds inflict DNA damage via adducts and DNA cross-linking. Thus, there is a potential for synergy if using a platinum compound with a PARP inhibitor, or using a PARP inhibitor in a patient with mutations in BRCA 1 and 2.

Abstract 3: Efficacy of BSI-201, a poly (ADP-ribose) polymerase-1 (PARP1) inhibitor, in combination with gemcitabine/carboplatin (G/C) in patients with metastatic triple-negative breast cancer (TNBC): Results of a randomized phase II trial.

O’Shaughnessy et al presented the results of a randomized phase II study in women with triple-negative metastatic breast cancer. Patients randomly were assigned to either gemcitabine-carboplatin or the same chemotherapy with the IV PARP inhibitor BSI-201. The primary statistical outcome of the trial was the clinical benefit rate. In addition, crossover to the experimental arm was permitted at the time of progression. Preliminary efficacy results were available on 86 of the 120 patients accrued to the trial. The ORR comparing chemotherapy alone versus chemotherapy with the PARP inhibitor was 16% versus 48%. Clinical benefit rate (CBR) was also improved from 21% to 62%. Most of the patients on the trial were receiving chemotherapy in the front-line. The investigators concluded that BSI-201 + gemcitabine-carboplatin was well tolerated and that the addition of the PARP inhibitor did not potentiate the chemotherapy-related toxicity. A phase III study will be initiated in 2009. Unfortunately, BRCA testing was not performed on any of the patients in this trial. Thus the contribution of the PARP inhibitor in BRCA-negative patients is still unknown.

Abstract CRA501: Phase II trial of the oral PARP inhibitor olaparib in BRCA-deficient advanced breast cancer.

Complementing the trial by O’Shaughnessy et al was a phase II trial of an oral PARP inhibitor, olaparib. Tutt et al presented data on 54 patients with a confirmed BRCA1 or 2 mutation, with advanced refractory breast cancer who had received at least 1 prior chemotherapy regimen in the advanced setting. Two sequential patient cohorts were accrued: those receiving 100mg BID, and those receiving 400 mg BID. The median number of prior chemotherapy regimens was 3. The overall response rate for this single agent was 41% in the 400 mg BID dose level, and 22% in the lower dose cohort. The median PFS was 5.7 months for patients at the higher dose. There were few episodes of grade 3/4 toxicity at the lower dose, and grade 3 fatigue, nausea and vomiting were seen in 15%, 19% and 11%, respectively, at the higher dose. The authors stated that the represented clinical proof-of-concept for targeting BRCA 1/BRCA 2 mutations in breast cancer.

Abstract 502: Neoadjuvant therapy with cisplatin in BRCA1-positive breast cancer patients.

Gronwald et al sought to confirm the sensitivity of BRCA 1/2 mutant cancers to cisplatin. Garber et al had previously published a neo-adjuvant clinical trial of cisplatin single agent chemotherapy in 28 women with triple-negative breast cancer. There was a 22% pathologic complete response (pCR) rate that included the 2 women with BRCA 1 mutations. This trial was initiated to evaluate the frequency of pCR after neoadjuvant cisplatin chemotherapy in women with breast cancer and a BRCA 1 mutation. Twenty-five women with stage I-III breast cancer and a BRCA mutation were given primary chemotherapy with cisplatin 75 mg/m² IV every 3 weeks for 4 cycles. Pathologic complete response was defined as no residual invasive disease in breast or lymph nodes. Residual ductal carcinoma in situ (DCIS) was permitted. Complete pathologic response was seen in18/25 patients (72%). The remainder of the patients was found to have a partial pathologic response. The investigators suggested that clinical trials were needed to more fully explore the optimal treatment for women with BRCA 1 breast cancer.

Two experimental agents targeting the HER-2 gene were presented in patients with trastuzumab-resistant advanced disease.

Abstract 1004: Neratinib in combination with trastuzumab for the treatment of advanced breast cancer: A phase I/II study.

Swaby et al presented data on neratinib (HKI-272), an oral, irreversible, pan-ErbB receptor tyrosine kinase inhibitor. A prior phase II study of neratinib alone had shown a preliminary ORR of 26% in patients with advanced HER2–positive breast cancer with prior exposure to trastuzumab. This study was performed to assess the safety and efficacy of the combination of neratinib plus trastuzumab. Twenty-eight patients were accrued and revealed an ORR of 28.6% and a CBR of 35.7%. The median PFS was 4 months. Diarrhea was the most commonly reported toxicity. We look forward to further data with the use of this compound.

Abstract 1017: A phase II study of trastuzumab-DM1 (T-DM1), a HER2 antibody-drug conjugate (ADC), in patients (pts) with HER2+ metastatic breast cancer (MBC): Final results.

Immunoconjugates are molecules that directly bind to a surface target on a cancer cell. The compound is internalized by the cell and degraded, thus cleaving the bond and releasing the cytotoxic molecule. Trastuzumab-DMI is a trastuzumab molecule linked to maytansine, a naturally occurring anti-tumor antibiotic in the alkylating agent family. Vogel, et al presented the results of a phase II study of 112 women with metastatic HER2-positive breast cancer who had progressed on trastuzumab + chemotherapy. The women received 3.6 mg/kg IV every 3 weeks and the primary objectives of the trial were assessment of ORR and safety. Patients on the trial were heavily pre-treated and had an average 18 month prior trastuzumab exposure, and an average of 6 months of prior lapatinib exposure, and a median of 3 cytotoxic regimens. The investigator ORR was 38.4% with a CBR of 44.6%. The independent review revealed an ORR of 25% with a CBR of 35%. The median PFS was 4.9 months. There were no grade 3 or 4 left ventricular ejection fraction (LVEF) events observed and no discontinuation of study drug due to LVEF decline. The most common adverse events of any grade were fatigue and nausea. Further studies with this fascinating compound are ongoing.

Two trials reported on the use of bevacizumab in the front-line for women with metastatic breast cancer. E-2100 and the AVADO trials previously reported significantly improved PFS when bevacizumab was added to a taxane in the front-line setting. The question remains as to whether this is a class effect with the taxanes, or is suggestive of benefit with bevacizumab in the front-line setting regardless of the chemotherapy used concurrently.

Abstract 1006: Randomized phase II trial of nanoparticle albumin-bound paclitaxel in three dosing schedules with bevacizumab as first-line therapy for HER2-negative metastatic breast cancer (MBC).

Conlin et al reported on the results of this trial in which 209 women were randomly assigned to either nab-paclitaxel 260 mg/m² + bevacizumab 15 mg/kg every 3 weeks, or nab-paclitaxel 260 mg/m² + bevacizumab 10 mg/kg q 2 weeks with filgrastim support, or nab-paclitaxel 130 mg/m² q week + bevacizumab 10 mg/kg q2 weeks. The 2-weekly arm was closed early due to toxicity. The primary endpoint was ORR and safety. The ORR was 44%, 39%, and 46% respectively for the 3 groups with no statistical difference between the groups. The authors suggested that weekly nab-paclitaxel with bevacizumab appeared to have the highest therapeutic index, but with sensory neuropathy being limiting. They suggested a 3 week on and 1 week off schedule should be studied comparatively.

Abstract 1005: RIBBON-1: Randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab (B) for first-line treatment of HER2-negative locally recurrent or metastatic breast cancer (MBC).

Dr Nicholas Robert presented the initial results of the RIBBON-1 trial, a long-awaited trial that was a randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of HER2-negative locally recurrent or metastatic breast cancer. In this trial, 1237 women with previously untreated metastatic breast cancer were given chemotherapy that was chosen by the investigator and then randomized 2:1 to receive bevacizumab or placebo. The choices of chemotherapy were limited and included capecitabine 1000 mg BID x 14 days, taxane (q3 week docetaxel or nab-paclitaxel), or an anthracycline-based chemotherapy including AC, EC, FAC, or FEC. Bevacizumab was given at a dose of 15 mg/kg every 3 weeks. Patients were treated until progressive disease and were subsequently given the option of second-line chemotherapy + bevacizumab at the time of progression. The primary endpoint was investigator-assessed PFS. When evaluating the results, patients were split into 2 cohorts: those who received capecitabine, and those who received a taxane or anthracycline-based regimen. Results: For those patients who received capecitabine, the addition of bevacizumab improved PFS from 6.2 months to 9.8 months (P = .0011), improved ORR from 24% to 35%, and improved OS from 21.2 months to 29 months, although the latter data was non-significant. For those who received either a taxane or anthracycline-based regimen, bevacizumab improved PFS from 8.3 to 10.7 months, ORR from 38% to 51%, and no change in OS. The investigators concluded that the addition of bevacizumab to capecitabine and taxane/anthracycline cohorts led to improved PFS. There was no difference in OS noted, and the incidence of bevacizumab-related adverse events was consistent with prior studies.

Tamoxifen and CYP2D6

Tamoxifen is metabolized to its active form, endoxifen, by the hepatic cytochrome P450 CYP2D6. The function of CYP2D6 can be altered by genetic variations, or by the use of pharmacologic agents that inhibit CYP2D6 concurrently with tamoxifen. Polymorphisms in CYP2D6 alleles have been identified and have classified patients into 4 cohorts based on activity:

1. Poor metabolizer: No CYP2D6 activity
2. Intermediate metabolizer: Reduced activity
3. Extensive metabolizer: Normal activity
4. Ultrarapid metabolizer: Hyperactive CYP2D6.

Although it is controversial, there have been studies that have suggested that there is an association with increased risk of breast cancer recurrence on tamoxifen therapy for patients who are poor metabolizers. This genetic variation can also be mimicked by exposing a patient to a drug that is a potent CYP2D6 inhibitor concurrent with the use of tamoxifen. Many of the selective serotonin reuptake inhibitors (SSRI’s) in use currently either for the treatment of depression or hot flashes are potent inhibitors of this enzyme.

Abstract CRA508: Risk of breast cancer recurrence in women initiating tamoxifen with CYP2D6 inhibitors.

Aubert and colleagues presented data from a large database where pharmacy prescription information, linked to disease, was assessed. The data were derived from the Medco Health Solutions integrated database. They used the data to identify women with breast cancer who were new to tamoxifen therapy in a 30-month period from 2003 – 2005 and investigated the risk of recurrent breast cancer as a function of concurrent use of potent and moderate inhibitors of CYP2D6. To be eligible, women had to have greater than 24 months of follow-up data and had to show adherence to tamoxifen over 2 years. Three study groups were thus identified:

1. CYP2D6-inhibitor weak or without overlap with tamoxifen therapy ( n = 355)
2. No CYP2D6-inhibitor therapy (n = 945)
3. Concomitant moderate or potent CYP2D6 inhibitor overlapping with tamoxifen (n = 359)

Event-free survival (EFS) for no CYP2D6 inhibitor therapy was 7.5% and was 14.0% for any use of a CYP2D6 inhibitor (HR 1.92, P = .0002). Subsequently, the patients who had any exposure to a weak CYP2D6 inhibitor were separated from those with exposure to a potent inhibitor. In this circumstance, those with no inhibitor had an EFS of 7.5%, those with exposure to a weak inhibitor had an EFS of 8.8%, and those with exposure to a potent inhibitor had an EFS of 16%. The authors concluded that these findings add to existing evidence indicating that combined use of tamoxifen and specific moderate-potent CYP2D6 inhibitors can reduce the effectiveness of tamoxifen in preventing breast cancer recurrence.

Abstract CRA509: Concomitant CYP2D6 inhibitor use and tamoxifen adherence in early-stage breast cancer: A pharmacoepidemiologic study.

To contradict the findings of the previous study, Dezentje et al presented a retrospective follow-up study with the objective to relate concomitant CYP2D6 inhibitor use and tamoxifen adherence to breast cancer event-free time. Data were gathered from PHARMO, a pharmacy database, PALGA, a pathology database, and the Dutch Medical Register in the Netherlands. Patients were included in this study if they had breast cancer and were treated with adjuvant tamoxifen between 1994 and 2006. Nine CYP2D6 inhibitors were identified for the purposes of a possible interaction. These included bupropion, paroxetine, fluoxetine, quinidine, duloxetine, terbinafine, amiodarone, cimetidine, and sertraline. In this trail, 1990 breast cancer patients using tamoxifen were identified, among whom 215 used a CYP2D6 inhibitor concomitantly. The study found no association between concomitant CYP2D6 inhibitor use and breast cancer recurrence. However, the study also looked at adherence to tamoxifen and did find an association between poor adherence and an increased risk of a breast cancer recurrence.

Putting these 2 studies together, it appears that the jury is still out regarding CYP2D6 genetic alleles and concomitant inhibitor therapy for patients receiving adjuvant tamoxifen.

OncoFacts™ Editor:

Christy Russell, MD

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