Table 2 Drug sensitivity of breast-ovarian cancer syndrome related tumors: clinical evidence
Study | Study design and main findings1 |
|---|---|
Breast cancer | |
15 BRCA1 carriers, 5 BRCA2 carriers and 57 matched controls were treated by anthracycline-based neoadjuvant therapy. Objective responses in 100%, 80%, 63% and pCR in 53%, 0% and 14%, respectively. | |
7 BRCA1 and 4 BRCA2 carriers were treated by 3-4 cycles of anthracycline-based neoadjuvant therapy, 10 (91%) of them achieved cCR; pCR were documented in 4 (44%) out of 9 evaluable cases. 27 patients served as controls: cCR and pCR were detected in 8 (30%) and 1 (4%) patients, respectively. These patients were followed for a median period of 7 years. Among complete clinical responders, only 1 (17%) out 6 BRCA1 carriers but 3 (75%) out of 4 BRCA2 carriers died of breast cancer. | |
Warner et al. [67] | Rapid radiological disappearance and complete pathological response in a BRCA1 carrier treated by neoadjuvant FEC. |
Petit et al. [72] | 55 triple-negative BC treated by neoadjuvant FEC. The subgroup of BRCA1 carriers showed lower pCR rate (2/12, 17%) than overall (23/55, 42%). |
Chrisanthar et al. [94] | 2/3 (67%) CHEK2 mutation carriers as compared to 8/104 (8%) non-carriers progressed on neoadjuvant epirubicin monotherapy for locally advanced breast cancer. |
Hubert et al. [68] | 15 BRCA1 and 7 BRCA2 stage III breast cancers were treated by anthracycline-based neoadjuvant therapy. cCR in 6/15 (40%) and 1/7 (14%), pCR in 2/15 (13%) and 0 patients, respectively. |
Melichar et al. [157] | Case report on 2 related BRCA1 carriers, whose tumor demonstrated pCR upon dose dense AC and sequential weekly paclitaxel. |
Wysocki et al. [75] | 19 non-responders to docetaxel have been analyzed; 5 (26%) of them turned out to be BRCA1 carriers. |
Fong et al. [102] | Phase I study dose escalation study for olaparib. 3 BRCA2-related chemotherapy refractory breast cancer patients were evaluable for the treatment efficacy; 1 OR and 1 SD were observed. No responses in BRCA-mutation-negative cases included in the study. |
Fourquet et al. [69] | Higher rate of cCR to anthracycline-based neoadjuvant therapy in BRCA1/2-carriers (15/33, 46%) vs. non carriers (7/41, 17%) |
Huang et al. [80] | Case report: metastatic breast cancer in a BRCA2-carrier was treated by several regimens of high dose therapy (epirubicin, alkylating agents, cisplatin, other cytotoxic drugs); CR with duration of 11+ years was observed. |
Kriege et al. [73] | 93 BRCA1 and 28 BRCA2 carriers received 1st-line chemotherapy (mainly anthracycline-based or CMF (CMF-like)) for the treatment of metastatic disease. Sporadic cases (n = 121) were used as a control. Marginally improved outcomes in BRCA1 carriers: OR: 66% vs. 50%; median PFS: 7.6 vs. 6.7 months; median OS: 15.0 vs. 13.6 months; significantly improved outcomes in BRCA2 carriers: OR: 89% vs. 50%; median PFS: 11.4 vs. 6.7 months; median OS: 19.3 vs. 13.6 months. |
Rhiem et al. [158] | Case report: major response of heavily pretreated metastatic BRCA1-related cancer to the combination of cisplatin and gemcitabine, with the duration > 6 months. |
Vollebergh et al. [81] | Long term outcome of high dose therapy (carboplatin, thiotepa and cyclophosphamide) is analyzed in 40 patients with metastatic breast cancer. 6 patients remained on complete remission at the time of the analysis (56+ - 150+ months); all these 6 patients demonstrated chromosomal imbalances characteristic for BRCA1-related cancers. Complete long term responders included 1 out of 2 BRCA1- and 1 out of 2 BRCA2-carriers. |
102 BRCA1 carriers treated by neoadjuvant chemotherapy. pCR in 1/14 (7%) women receiving CMF, 2/25 (8%) patients exposed to doxorubicin and docetaxel, 11/51 (22%) cases treated by AC or FAC, 10/12 (83%) women receiving cisplatin. | |
Moiseyenko et al. [74] | Case-report: lack of response of a chemonaive BRCA1-related cancer to the 1st line epirubicin-docetaxel combination, than major response to the 2nd line single-agent cisplatin. |
Silver et al. [78] | 28 stage II or III triple-negative breast cancers were treated by 4 cycles of neoadjuvant cisplatin monotherapy. Two BRCA1-carriers were included in the study, and both achieved pCR. |
Kriege et al. [76] | 32 BRCA1 carriers, 13 BRCA2 carriers and 95 controls treated by taxane monotherapy or taxane-trastuzumab combination. Inferior results in BRCA1 carriers (OR rate = 23% vs. 38%; PD in 60% vs. 19%; median PFS = 2.2 vs. 4.9 months); this difference retained significance only in hormone receptor-negative cases, while hormone receptor-positive tumors showed similar response rates and PFS. BRCA2 carriers: higher OR rate (89% vs. 38%), similar median PFS (7.1 vs. 5.7 months). |
Tutt et al. [82] | BRCA1- and BRCA2-related metastatic breast cancers, with at least 1 prior chemotherapy regimen, treated by high-dose (n = 27) or low-dose (n = 27) olaparib. OR in 41% and 22%; SD in 44% and 44%; median PFS = 5.7 and 3.8 months. |
Sokolenko et al. [104] | 5 BLM-related breast cancers treated by conventional neoadjuvant chemotherapy; 3 patients showed nearly complete pathologic response, and 2 remaining women demonstrated partial response. |
Ovarian cancer | |
Cass et al. [83] | 34 BRCA carriers (22 BRCA1 and 12 BRCA2) vs. 37 non-carriers were included in the study; 29 vs. 25 had stage III-IV disease and were therefore considered for the analysis of treatment outcome; 22 vs. 18 received paclitaxel plus carboplatin, and 7 vs. 7 were treated by cyclophosphamide plus carboplatin. BRCA1/2 carriers demonstrated higher OR rate (21/24 (88%) vs. 9/19 (47%)) and longer median OS (91 vs. 54 months) than non-carriers. |
Tan et al. [84] | Therapy response was compared in 22 BRCA carriers (17 BRCA1 and 5 BRCA2) vs. 44 non carriers matched by stage, histological subtype, age at diagnosis and year at diagnosis. Higher sensitivity to platinum-based therapy in the 1st line (OR: 96% vs. 59%; CR: 82% vs. 43%), 2nd line (92% vs. 41%) and 3rd line treatment (100% vs. 14%); longer median OS (8.4 vs. 2.9 years). |
Fong et al. [102] | Phase I study dose escalation study for olaparib. 15 BRCA-related (14 BRCA1 and 1 BRCA2) chemotherapy refractory ovarian cancer patients were evaluable for treatment efficacy; 8 (53%) OR and 1 (7%) SD were observed. No responses in BRCA-mutation-negative cases included in the study. |
Leunen et al. [161] | 6 patients with relapsed BRCA-related ovarian cancer, treated by multiple lines of therapy including dose-dense paclitaxel-carboplatin; all patients responded to the therapy; median OS = 37 months as compared to 18 months in the historical control. |
Melichar et al. [86] | Case report on a BRCA1-related ovarian cancer relapsed after prolonged post-surgical paclitaxel-carboplatin therapy; each of 4 consequent relapses showed complete response to paclitaxel-cisplatin combination. |
Audeh et al. [87] | BRCA1- and BRCA2-related recurrent ovarian cancers, with at least 1 prior chemotherapy regimen, treated by high-dose (n = 33) or low-dose (n = 24) olaparib. OR in 33% and 15%; SD in 36% and 29%; median duration of response = 290 and 269 days. |
Fong et al. [88] | Phase I dose escalation and single-stage expansion trial for olaparib, given to 50 patients (including 41 BRCA1 and 7 BRCA2 carriers) with advanced ovarian cancer, previously treated by platinum based therapy. OR in 20 (40%) and SD in 3 (6%) patients. Median duration of response = 28 weeks. Strong correlation with platinum sensitivity of the disease. |
Moiseyenko et al. [74] | Complete clinical response and nearly-complete pathological response of bulky tumor treated by 5 cycles of single-agent cisplatin. |
Vencken et al. [85] | 93 BRCA1-related, 13 BRCA2-related and 222 sporadic cancers analyzed for response to the 1st line chemotherapy. CR or no evidence for disease: 87%, 92% and 71%, respectively; PD: 2%, 0% and 15%; median PFS: 2.1, 5.6 and 1.3 years; median OS: 5.9, > 10 and 2.9 years. Similar response rates in patients receiving combination of platinum and paclitaxel vs. those treated by platinum-based therapy without paclitaxel. |
Pancreatic cancer | |
Chalasani et al. [98] | Case report on a BRCA2-related pancreatic adenocarcinoma. 1st line therapy included combination of gemcitabine with experimental alkylating agent, and resulted in a major tumor response. Then alkylating agent was discontinued due to toxicity, and PD was observed on single-agent gemcitabine. Experimental antiangiogenic drug was given in the 2nd line without any effect. 3rd line therapy included mitomycin C plus capecitabine, and again led to a major tumor response. |
James et al. [99] | Case report on a BRCA2-related, KRAS wild-type pancreatic adenocarcinoma. Prolonged SD (56+ months) upon multiple lines of chemotherapy (combination of docetaxel, capecitabine and gemcitabine; then irinotecan monotherapy; then irinotecan plus cetuximab; then mitomycin C plus oxaliplatin; then mitomycin C plus irinotecan). |
Villarroel et al. [97] | Case report on a PALB2-related pancreatic adenocarcinoma, which progressed under 1st line single-agent gemcitabine, but showed major response after mitomycin C administration. Later mitomycin C was replaced by cisplatin due to toxicity of the former. The patient remains asymptomatic for 36+ months. |
Fogelman et al. [100] | Case report on a BRCA2-related relapsed pancreatic adenocarcinoma, which rapidly regressed upon the combination of gemcitabine and iniparib. Subsequent surgery revealed a complete pathologic response. |
Other cancers | |
Fong et al. [102] | Phase I study dose escalation study for olaparib. 1 BRCA2-related castration-resistant prostate cancer patient was included in the study; he demonstrated significant, durable marker response as well as resolution of bone metastases. No responses in BRCA-mutation-negative cases. |
Moule et al. [101] | Case report: complete response lasting for 10+ years in a BRCA2 carrier, whose advanced non-small cell lung cancer was treated by the combination of mitomycin C, cisplatin and vincristine. |
Vesprini et al. [103] | Case report describing a patient with metastatic BRCA2-related prostate cancer, who was treated by cisplatin after becoming insensitive to androgen ablation. Cisplatin therapy resulted in normalization of prostate-specific antigen level and symptomatic relief for period of 8 months; docetaxel was administered after the disease progression, and also led to an evident tumor response. |