Jordan Hill, PharmD BCOP
Ambulatory Oncology Pharmacy Specialist, Solid Tumors
WVU Cancer Institute
Morgantown, WV

The 41st Annual San Antonio Breast Cancer Symposium took place December 4–8, 2018, in San Antonio, TX. Approximately 7,500 people from more than 90 countries attended the 5-day program. The conference provided insights into recent trials and therapeutic advances in the management of breast cancer.

T-DM1 After Neoadjuvant Therapy Among Women with HER2-Positive Cancer and Residual Disease

KATHERINE is an international phase 3 open-label study of 1,486 patients with residual breast or axillary disease after neoadjuvant chemotherapy and HER2-targeted therapy that randomized patients to receive 14 cycles of adjuvant ado-trastuzumab emtansine (T-DM1) or trastuzumab. The median duration of follow-up was 40.9 months in the trastuzumab group and 41.4 months in the T-DM1 group with similar baseline characteristics. Five hundred sixty-four women in the trastuzumab group (75.9%) and 579 women in the T-DM1 group (77.9%) had received prior anthracyclines. T-DM1 was associated with a total of 91 invasive disease-free (IDF) events, such as distant recurrence or contralateral breast cancer, versus 165 for trastuzumab (hazard ratio [HR] = 0.5, 95% confidence interval [CI], 0.39–0.64; p < .0001). Three-year invasive disease-free survival (IDFS) was 88% with T-DM1 and 77% with trastuzumab; however, 133 patients (18%) discontinued T-DM1 because of adverse effects (AEs) such as decreased platelet count or increased bilirubin, compared with only 15 (2.1%) patients discontinuing trastuzumab. In a discussion following the trial presentation, Eric P. Winer, MD, of the Dana-Farber Cancer Institute stated that “the standard of care has changed, and T-DM1 should be recommended to the vast majority of patients with residual disease after a taxane-based neoadjuvant regimen.”¹

Immune Biomarker Subgroups of IMpassion130

The IMpassion130 trial randomized 451 patients with untreated triple negative breast cancer (TNBC) to receive nab-paclitaxel plus either atezolizumab or placebo in a 1:1 randomized, double-blind design. Results of a biomarker subgroup analysis including tumor programmed death-ligand 1 (PD-L1) expression, intratumoral CD8+ T cells, and stromal tumor-infiltrating lymphocytes were reported at the symposium. For PD-L1-positive tumors, the combination regimen was associated with a median overall survival (OS) of 25 months versus 15.5 months for those receiving nab-paclitaxel and placebo; progression-free survival (PFS) was 7.5 months versus 5 months. Alternatively, for PD-L1-negative tumors, the median OS and PFS were essentially equal in both arms. Other biomarkers were not predictive of differences in outcomes. These results may help clinicians better identify patients most likely to benefit from the addition of atezolizumab.²

Adjuvant Capecitabine to Standard Chemotherapy in Early Triple Negative Breast Cancer

The randomized phase 3 GEICAM/CIBOMA trial evaluated the benefit of adjuvant capecitabine to standard neoadjuvant or adjuvant chemotherapy in 876 patients with early-stage TNBC. The addition of capecitabine to anthracycline-based chemotherapy (with or without a taxane) did not significantly increase disease-free survival (DFS) or OS. The 5-year DFS in the capecitabine arm was 79.6%, versus 76.8% in the observation arm. Similarly, OS in the capecitabine arm was 86.2% versus 85.9%, respectively. As expected, the most common AE was hand-foot syndrome, followed by diarrhea, nausea, and fatigue. In contrast to the CREATE-X trial, the patients included in this trial did not have residual disease after initial chemotherapy.^3,4

Low-Dose Tamoxifen Reduces Breast Cancer Recurrence

The phase 3 TAM01 trial took place in 14 centers in Italy, where a total of 500 women were randomized to either 5 mg/day of tamoxifen or placebo for 3 years. Women less than 75 years old with atypical ductal carcinoma or lobular carcinoma in situ and estrogen receptor (ER)–positive or ductal carcinoma in situ of unknown origin were included in the study. With a median follow-up of 5.1 years, investigators observed a 52% decrease in the risk for recurrence with tamoxifen 5 mg. There were 14 breast cancer events in the low-dose tamoxifen arm and 28 among those receiving placebo. There was also a significant decrease in contralateral breast cancer events in the low-dose tamoxifen arm (12 vs. 3). With regard to AEs, no difference in vaginal dryness, dyspareunia, or musculoskeletal pain was seen in the two groups. There was also no difference in the rates of endometrial cancer or venous thromboembolism with the 5-mg dose of tamoxifen and placebo, and the rates observed were 2.5 times lower than what would be expected with the 20-mg dose over the same duration. These results are promising for patients unable to tolerate full-dose tamoxifen.⁵

Alpelisib and Fulvestrant in PIK3CA-Mutant Estrogen Receptor–Positive Advanced Breast Cancer

Additional analysis of the 572 patients with ER-positive advanced breast cancer randomized to receive alpelisib and fulvestrant or placebo and fulvestrant in the SOLAR-1 trial were presented. The PFS was significantly longer with the addition of alpelisib to fulvestrant (11 months vs. 5.7 months). A retrospective analysis also found that in patients with a PIK3CA mutation, the combination of alpelisib and fulvestrant resulted in a median PFS of 10.9 months vs. 3.7 months with placebo and fulvestrant, whereas alpelisib showed no advantage on median PFS in patients without a PIK3CA mutation. The most common AEs seen with the alpelisib and fulvestrant combination were hyperglycemia, diarrhea, nausea, and rash. Hyperglycemia was reported to usually be apparent by day 15 and was managed with dose interruptions (40.6% of patients), dose adjustments (49.3%), and early initiation of insulin sensitizers, such as metformin (used in 76%). Although high rates of hyperglycemia were not surprising, it is important to note that 60% of patients were considered prediabetic or diabetic at study entry.⁶

Neoadjuvant Chemotherapy De-Escalation in TNBC

The WSG-ADAPT-TN trial enrolled patients with TNBC to receive neoadjuvant chemotherapy with nab-paclitaxel and either carboplatin or gemcitabine. Patients who did not achieve a pathologic complete response (pCR) received adjuvant epirubicin and cyclophosphamide, whereas it was the physician’s choice to give adjuvant chemotherapy to those achieving a pCR. The results of the preplanned translational analysis were presented. Of the 336 trial patients, 306 were included in the translational analysis. Patients who achieved a pCR and also had a high programmed cell death-1 (PD-1) status had a longer event-free survival (EFS) than patients who achieved a pCR and had a low PD-1 status. Additionally, patients with a pCR and a low PD-1 status who received adjuvant chemotherapy had longer EFS than patients who did not receive adjuvant chemotherapy. However, in patients who had a pCR and a high PD-1 status, no difference in EFS was seen between those who received adjuvant chemotherapy and those who did not (98% 3-year EFS). The authors therefore discussed the potential for chemotherapy de-escalation and hence an anthracycline-free chemotherapy regimen for those patients.⁷

Olaparib and Durvalumab in BRCA-Mutated Metastatic Breast Cancer

The phase 2 MEDIOLA trial enrolled patients with HER2-negative, BRCA-mutated locally advanced or metastatic breast cancer (MBC) to receive olaparib 300 mg twice daily for 4 weeks, followed by the combination of olaparib 300 mg twice daily with durvalumab 1,500 mg every 4 weeks. Patients could have received a prior anthracycline and/or taxane treatment but could not have received a prior PARP inhibitor or immunotherapy. Results presented were for 34 patients of the ongoing trial. At 28 weeks, the ORR was 63% (95% CI, 44%–80%), the median duration of response (DOR) was 9.2 months (range, 5.5–13.1), and PFS was 8.2 months (95% CI, 4.6–11.8). Of note, the earlier the combination was used, the better the outcomes were. The median DOR in patients with 0–1 prior line of chemotherapy was 12.9 months, versus 5.5 months in those with two prior lines of chemotherapy, and the median PFS was 11.7 months versus 6.5 months, respectively. Although the numbers are small, the results compared favorably to the results with single-agent olaparib in the OlympiAD trial, in which the median DOR was 6.4 months and the median PFS was 7 months.^8,9

Palbociclib in HER2-Positive Metastatic Breast Cancer

The preliminary results of the combination of palbociclib and trastuzumab from the phase 2 PATRICIA trial included 45 patients with HER2-positive MBC that had received 2–4 prior lines of therapy. Five of 15 patients in the ER-negative cohort, 6 of 15 patients in the ER-positive cohort who received palbociclib without letrozole, and 8 of 15 who received palbociclib and letrozole remained progression free at 6 months (42% total). Interestingly, median PFS was three times higher in patients with luminal disease than in those with nonluminal disease (12 months vs. 4 months, respectively). This particular finding led the investigators to conclude that "identification of the non-luminal subtypes by PAM5 might help identify patients who might not derive a large benefit from the treatment strategy, regardless of hormone receptor status."¹⁰

Oxybutynin for Hot Flashes in Breast Cancer Patients Receiving Endocrine Therapy

The randomized double-blind placebo-controlled SC-1603 trial was designed to evaluate oxybutynin, at two different doses, compared with placebo in treating hot flashes in breast cancer survivors. Patients experiencing 28 or more hot flashes per week for 30 days or longer were randomized to receive either 2.5 mg of oxybutynin twice a day (n = 46); 2.5 mg twice a day for a week, increased to 5 mg twice a day (n = 46); or placebo (n = 44) for 6 weeks. Patients experienced approximately 60% fewer hot flashes with oxybutynin 2.5 mg and an approximate 75% reduction with 5 mg of oxybutynin compared to only a 30% reduction with placebo (p < .01). Although hot flash frequency and severity were significantly reduced, concentration and sexual activity did not improve with either dose, and mood and life enjoyment were improved only with the higher dose. Dry mouth and eyes, abdominal pain, constipation, and difficulty urinating were more common with oxybutynin, but there were no differences in rates of discontinuation because of AEs between the two oxybutynin arms and the placebo arm.¹¹

The 42nd Annual San Antonio Breast Cancer Symposium is scheduled for December 10–14, 2019, in San Antonio, TX. Visit www.sabcs.org for additional details.

References

1. Geyer Jr CE, Huang C-S, Mano MS, et al. Phase III study of trastuzumab emtansine (T-DM1) vs trastuzumab as adjuvant therapy in patients with HER2-positive early breast cancer with residual invasive disease after neoadjuvant chemotherapy and HER2-targeted therapy including trastuzumab: primary results from KATHERINE (NSABP B-50-I, GBG 77 and Roche BO27938). Presented at 2018 San Antonio Breast Cancer Symposium; December 4-8, 2018; San Antonio, TX. Abstract GS1-10.
2. Emens LA, Loi S, Rugo HS, et al. IMpassion130: Efficacy in immune biomarker subgroups from the global, randomized, double-blind, placebo-controlled, phase III study of atezolizumab + nab-paclitaxel in patients with treatment-naïve, locally advanced or metastatic triple-negative breast cancer. Presented at 2018 San Antonio Breast Cancer Symposium; December 4-8, 2018; San Antonio, TX. Abstract GS1-04.
3. Masuda N, Lee SJ, Ohtani S, et al. Adjuvant capecitabine for breast cancer after preoperative chemotherapy. N Engl J Med. 2017; 376:2147-2159.
4. Martín M, Barrios CH, Torrecillas L, et al. Efficacy results from GEICAM/2003-11_CIBOMA/2004-01 study: a randomized phase III trial assessing adjuvant capecitabine after standard chemotherapy for patients with early triple negative breast cancer. Presented at 2018 San Antonio Breast Cancer Symposium; December 4-8, 2018; San Antonio, TX. Abstract LBA_2.
5. De Censi A, Puntoni M, Gonzaga AG, et al. Randomized trial of low dose tamoxifen to prevent recurrence of breast intraepithelial neoplasia. Presented at 2018 San Antonio Breast Cancer Symposium; December 4-8, 2018; San Antonio, TX. Abstract GS03-01.
6. Juric D, Ciruelos EM, Rubovszky G, et al. Alpelisib (ALP) + fulvestrant (FUL) for advanced breast cancer (ABC): Phase 3 SOLAR-1 trial results. Presented at 2018 San Antonio Breast Cancer Symposium; December 4-8; San Antonio, TX. Abstract GS3-08.
7. Gluz O, Nitz U, Liedtke C, et al. No survival benefit of chemotherapy escalation in patients with pCR and “high-immune” triple-negative early breast cancer in the neoadjuvant WSG-ADAPT-TN trial. Presented at 2018 San Antonio Breast Cancer Symposium; December 4-8, 2018; San Antonio, TX. Abstract GS5-06.
8. Robson M, Im, SA, Senkus E, et al. Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. N Engl J Med. 2017;377:523-533.
9. Domchek SM, Postel-Vinay S, Im S-A, et al. An open-label, phase II basket study of olaparib and durvalumab (MEDIOLA): updated results in patients with germline BRCA-mutated (gBRCAm) metastatic breast cancer (MBC). Presented at 2018 San Antonio Breast Cancer Symposium; December 4-8, 2018; San Antonio, TX. Abstract PD5-04.
10. Ciruelos R, Willagrasa P, Pare L, et al. SOLTI-1303 PATRICIA phase II—palbociclib and trastuzumab in postmenopausal patients with HER2-positive metastatic breast cancer. Presented at 2018 San Antonio Breast Cancer Symposium; December 4-8, 2018; San Antonio, TX. Abstract GS1-10.
11. Leon-Ferre RA, Novotny PJ, Faubion SS, et al. A randomized, double-blind, placebo-controlled trial of oxybutynin for hot flashes: ACCRU study SC-1603. Presented at 2018 San Antonio Breast Cancer Symposium; December 4–8, 2018; San Antonio, TX. Abstract GS6-02.