Hereditary Cancer & Genetics

Post by Zsofia K. Stadler, MD:

Today’s ASCO presentations in hereditary cancer and genetics continued with the theme of targeted BRCA-associated cancer treatment. At the Clinical Science Symposium in Gynecologic Cancer, Audeh et al (Abstract #5500) presented the results of a Phase II trial of the oral PARP inhibitor, olaparib, in germline BRCA mutation carriers with advanced ovarian cancer. Similar to the abstract presented by Tutt et al yesterday (Abstract #501) on BRCA-associated breast cancer, this was a proof-of-concept single-arm study again using sequential cohorts receiving 400mg BID (33 patients) or 100mg BID (24 patients) dosing of olaparib. Patient characteristics included median age of 54-56, a median of 3 prior lines of chemotherapy, with about three-fourths of the combined cohort consisting of BRCA1 carriers. Overall response rate, the primary endpoint, was 33% in the higher and 13% in the lower dose cohort. Progression free survival, the secondary endpoint, was 5.8 months in the higher dose cohort. Response was seen in both BRCA1 and BRCA2 carriers as well as in platinum sensitive and resistant disease. Toxicities were largely limited to nausea, vomiting, fatigue, abdominal pain and diarrhea with 12% of patients discontinued from treatment secondary to toxicities. In comparison to prior studies of PARP inhibitors in more heterogeneous populations, the toxicity profile in BRCA mutation carriers versus non-carriers was similar.

In summary, this year’s ASCO meeting has provided much awaited clinical data on the use of PARP inhibitors in BRCA-associated cancers and demonstrates the possibility of utilizing underlying genetic defects to develop targeted therapies for such patients.

Hereditary Cancer & Genetics

Post by Zsofia K. Stadler, MD:

This afternoon’s Clinical Science Symposium focused on basal-like and triple-negative breast cancers with two of the abstracts presented specifically addressing treatment of BRCA-associated breast cancers. The long awaited initial evaluation of Poly-(ADP-ribose) polymerase-1 (PARP) inhibitors in BRCA-associated breast cancers were presented by Tutt et al (Abstract 501). As a prelude, earlier in the day at the Plenary Session, O’Shaughnessy et al (Abstract #3) reported on the efficacy of BSI-201, in combination with gemcitabine and carboplatin in metastatic triple-negative breast cancer, but data specific to BRCA-associated breast cancers was not reported. PARP, an enzyme involved in base excision repair, plays a key role in the repair of DNA single-strand breaks. In BRCA mutant cells, with impaired ability to repair DNA double-strand breaks by homologous recombination, the inhibition of PARP leads to the persistence of DNA lesions that are normally repaired by homologous recombination. Ever since the demonstration of the exquisite sensitivity of BRCA mutant cells to PARP inhibitors by Farmer et al in Nature 2005, there has been excitement regarding the potential usefulness of PARP inhibitors in BRCA-associated cancers. In this proof-of–concept Phase II single-arm trial with a sequential cohort design, patients with metastatic breast cancer with an identified germline BRCA1 or BRCA2 mutation, received olaparib, an oral PARP inhibitor, either at 400mg BID or 100mg BID dosing. Overall response rate in a total of 54 patients, with a median of three prior chemotherapies, was 41% in patients receiving 400mg and 22% in patients receiving the 100mg dosing. Progression free survival was 5.7 months in the higher dose cohort. Responses were seen in both BRCA1 and BRCA2 carriers and were not exclusive to patients with triple negative breast cancer. This promising study is the first report of the use of targeted therapies specifically for BRCA-associated breast cancer. Tomorrow, additional data on PARP inhibitors in BRCA-deficient advanced ovarian cancer are to be presented.

Additionally, Gronwald et al (Abstract #502) presented their data on the use of neoadjuvant cisplatin in early-stage BRCA1-associated breast cancer. With a sample size of 25, a pathologic complete response was observed in 72% of patients. The role of platinum drugs in triple-negative breast cancer is already an area of active investigation and determining whether the use of these agents provides a selective advantage in breast cancer in BRCA1 carriers needs to be further explored.

Hereditary Cancer & Genetics

Post by : Zsofia K. Stadler, MD:

Presentations on hereditary cancer and genetics at ASCO are usually dispersed between the Cancer Prevention and the Tumor Biology/Human Genetics tracks. In addition, cancer-specific treatment related topics, such as advances in BRCA-associated breast cancer treatments, a major focus of this year’s meeting, are usually found under the specific cancer track. While this can make navigating the meeting a bit of a challenge, in many ways, this precisely reflects the broad impact that cancer genetics is beginning to have on all aspects of cancer care.

Although the majority of abstracts in hereditary cancer & genetics this year will be presented Sunday and Monday, including the eagerly awaited presentation of the initial studies of PARP inhibitors in BRCA-associated breast cancers, a few relevant topics were covered at the meeting on Saturday. At the Cancer Prevention oral presentations, a number of preliminary biomarker modulation prevention studies in BRCA mutation carriers and women at high-risk for breast cancer were presented. Klifa et al (Abst #1506) used breast MRI to quantify breast density in BRCA mutation carriers pre- and post-treatment with an intranasal GnRH agonist. Their results of decreased breast density in response to GnRH agonist were previously reported with use of mammographic breast density, but now the authors report on a novel technique to assess breast density using volumetric “MR density,” measured as the ratio of fibroglandular tissue volume to total volume of breast. In another early-phase prevention study, Fabian et al (Abst #1507) evaluated Ki-67, a proliferation marker, in the benign breast tissue of women at high-risk for breast cancer, pre- and post-treatment with flaxseed derivative, using random periareolar fine needle aspiration. Although reduction in Ki-67 was observed in response to flaxseed derivative, an agent previously implicated in reducing breast cancer cell proliferation, a placebo-controlled trial will be needed to confirm results, especially given possible technical and physiologic variation in measurement of Ki-67 levels. Importantly, while the feasibility of using breast density and markers of proliferation as potential biomarkers of response in early-phase prevention trials has been demonstrated, the appropriateness of these measures as surrogate endpoint biomarkers in the oncogenic pathway is yet to be proven.

Colon Cancer and Microsatellite Instability – While only ~15% of colorectal tumors demonstrate microsatellite instability (MSI), nearly all patients with Lynch syndrome associated colon cancer have MSI tumors, thereby bringing our attention to abstract #4001. Tejpar et al assessed MSI status in the PETACC 3 trial consisting of Stage II and III colon cancer patients treated with adjuvant 5FU/LV alone versus 5FU/LV and irinotecan. As with previous studies, the value of MSI as a strong prognostic factor was conferred, with an especially beneficial effect demonstrated in Stage II patients. On the other hand, the predictive impact of MSI remains controversial with continued discordance between results. Whether the prognostic or predictive impact of MSI varies between MSI associated with Lynch syndrome (patients with germline mismatch repair gene mutations) or sporadic MSI remains to be determined.