Tailoring Therapy for Breast Cancer in 2021: Examining and Applying Clinical Lessons

Article

Personalized medicine has come to the forefront of breast cancer management, with genomic tools being utilized to avoid unnecessary chemotherapy in those with early-stage disease, PARP and PI3K inhibitors improving outcomes for those who harbor select mutations, and the emergence of highly active targeted agents shaking up the HER2-positive paradigm.

Claudine Isaacs, MD, FRCPC

Claudine Isaacs, MD, FRCPC

Personalized medicine has come to the forefront of breast cancer management, with genomic tools being utilized to avoid unnecessary chemotherapy in those with early-stage disease, PARP and PI3K inhibitors improving outcomes for those who harbor select mutations, and the emergence of highly active targeted agents shaking up the HER2-positive paradigm, according to Claudine Isaacs, MD, FRCPC.

“Where are we with tailoring therapy for breast cancer in 2021? We’re building on what we have already been doing. We now have really great genomic tools that allow us to figure out which of our patients with hormone receptor–positive, HER2-negative disease can avoid the toxicity of chemotherapy because there is no additional benefit,” Isaacs said. “We now know the role of PARP inhibitors for germline BRCA1 and BRCA2 carriers, both in the high-risk early-stage setting and the metastatic setting, the [benefit] of alpelisib [Piqray] for patients who have PIK3CA mutations, and we [are excited] about more highly active HER2-directed therapies.”

In her presentation during the 3rd Annual Precision Medicine Symposium, an event hosted by Physicians’ Education Resource®, LLC, Isaacs, a professor of medicine and oncology; associate director of clinical research; and leader of the Breast Cancer Program at Georgetown University, provided a snapshot of pivotal data from key clinical trials that are being used to inform personalized care for patients with breast cancer in clinical practice.1

Tailoring Systemic Therapy in Early-Stage Disease: Which Patients Can Avoid Chemotherapy?

“We first showed the benefit of endocrine therapy for patients with early-stage hormone receptor–positive or –negative disease. At the time, we didn’t know about HER2 status,” Isaacs noted. “We then showed that there was a tiny benefit with the addition of chemotherapy in [those] with node-negative [disease]. After that, we spent a long time figuring out who really needed chemotherapy and who could avoid it.”

Lessons Learned From RxPONDER

The phase 3 RxPONDER trial (NCT01272037) enrolled patients with hormone receptor–positive, HER2-negative breast cancer who had 1 to 3 positive lymph nodes who were able to receive adjuvant taxane and/or anthracycline-based chemotherapy and did not have distant metastases.2 Patients were stratified based on recurrence score (0-13 vs 14-25), menopausal status (pre vs post), and axillary surgery (axillary node dissection vs sentinel node biopsy).

A total of 5000 patients with a recurrence score of 0 to 25 were randomized to arm 1 (n = 2509), where they received chemotherapy followed by endocrine therapy, or arm 2 (n = 2506), where they were given endocrine therapy alone. Notably, half of the patients randomized to chemotherapy received docetaxel plus cyclophosphamide for 4 or 6 cycles.

“I think it is really important to point out that about 16% of the premenopausal group of patients in the endocrine therapy–alone arm and only 3% of those on the chemotherapy plus endocrine therapy arm got ovarian functional suppression [OFS] as part of their adjuvant therapy,” Isaacs said.

Results presented during the 2020 San Antonio Breast Cancer Symposium (SABCS) showed that the 5-year invasive disease-free survival (iDFS) rate in the investigative arm was 92.4% vs 91.0% in the control arm, translating to an absolute difference of just 1.4% between the arms (adjusted HR, 0.81; 95% CI, 0.67-0.98; P = .026).

However, when looking at these rates according to menopausal status, it was found that for premenopausal patients with recurrence scores between 0 and 25, there was an absolute difference of 5.2% with the addition of chemotherapy to endocrine therapy. The 5-year iDFS rate in the investigative arm was 94.2% vs 89.0% in the control arm (adjusted HR, 0.54; 95% CI, 0.38-0.76; P = .0004). In this subgroup, the absolute difference in distant recurrence as first site was 2.9%. Moreover, a 53% decrease in deaths was observed (HR, 0.47; 95% CI, 0.24-0.94), which resulted in a 5-year OS absolute improvement of 1.3%.

In postmenopausal patients, no statistically significant difference in 5-year iDFS (adjusted HR, 0.97; 95% CI, 0.78-1.22; P = .082) or OS (adjusted HR, 0.96; 95% CI, 0.70-1.31; P = .79) was observed between the arms.

“RxPONDER was definitely practice-changing. I think one of the things that has left us scratching our heads still is: Is it chemotherapy? Or is it simply that chemotherapy is a relatively ‘nasty’ way to make a patient postmenopausal?” Isaacs questioned. “If we had given [OFS plus] endocrine therapy, would it have resulted in the same benefit, or at least a chunk of the benefit that was seen in these premenopausal women with 1 to 3 positive nodes?”

Chemotherapy Tips

For postmenopausal patients who are node negative or have up to 3 positive nodes, there is no benefit to adding chemotherapy to endocrine therapy, according to Isaacs. However, those within this subset who have tumors with recurrence scores of greater than 26, chemotherapy plus endocrine therapy might be considered.

“In the premenopausal group, it’s a little bit more confusing. In the lymph node–positive group, based on results from RxPONDER, we know there was a benefit for chemotherapy for [those with] a recurrence score [up to] 25. In individual cases, I think you can discuss OFS plus an aromatase inhibitor [AI] as an alternative,” Isaacs explained. “However, the data do suggest that you need to do something more than tamoxifen alone. Based on the data that now stand, it’s chemotherapy that we have clear data on, but there is certainly a question about OFS.”

Among premenopausal patients who are lymph node negative, both recurrence score and tumor characteristics should influence decision making, according to Isaacs. In those with recurrence scores 15 and under, endocrine therapy is the optimal approach, Isaacs said. In those with scores that are 26 and higher, chemotherapy should be recommended.

“For recurrence scores that fall in between, that’s when [decisions should be] based on incorporation of the data, the clinical factors related to the tumor itself, and also speaking with the patient about OFS with an AI vs chemotherapy,” Isaacs added.

Leveraging PARP Inhibitors in BRCA1/2 Carriers and Beyond

Patients with HER2-negative metastatic breast cancer are recommended to undergo germline testing to determine whether their tumors may harbor BRCA1 or BRCA2 mutations based on the benefits observed with PARP inhibitors like olaparib (Lynparza) and talazoparib (Talzenna) in the population.

To further understand the benefit of these agents, investigators launched the phase 2 TBRC 048 trial (NCT03344965), which set out to evaluate whether olaparib had efficacy in other mutations in the homologous recombination deficiency (HRD) pathway.3

Results indicated that among 13 patients with metastatic breast cancer who harbored germline PALB2 mutations, the partial response (PR) rate was 82%, with a clinical benefit rate (CBR) of 100% with the PARP inhibitor. In 16 patients with somatic BRCA1/BRCA2 mutations, these rates were 50% and 66%, respectively. Olaparib did not elicit any responses in 7 patients whose tumors harbored ATM or CHEK2 mutations.

“The numbers are small, but they are encouraging. The study has an expansion group [focused on those with] germline PALB2 and somatic BRCA1 and BRCA2 [alterations],” Isaacs said. “So, if you do have patients [who can enroll], it would be great to [see] a bit of a stronger signal. [Then,] we [can really] know whether this carries true in these other [sub]groups.”

Taking Notes From OlympiA

The phase 3 OlympiA trial (NCT02032823) set out to evaluate olaparib as an adjuvant treatment in patients with germline BRCA-mutated, high-risk, HER2-negative primary breast cancer.

Within the neoadjuvant group, if patients had triple-negative breast cancer (TNBC), they could not have achieved a pCR.4 Those with hormone receptor–positive disease could not have had a pCR and they had to have a clinical and pathologic stage plus estrogen receptor status and histologic grade score of 3 or higher. To be in the neoadjuvant group, patients needed to have received 6 or more cycles of neoadjuvant chemotherapy followed by surgery with or without radiotherapy.

Within the adjuvant group, patients with TNBC had to have pT2 or more or pN1 or more. If patients had hormone receptor–positive disease, they had to have 4 or more positive lymph nodes. Those in the adjuvant group must have underwent surgery and received 6 or more cycles of adjuvant chemotherapy with or without radiotherapy.

A total of 1836 patients were randomized 1:1 to receive either olaparib at 300 mg twice daily for 1 year or placebo for the same schedule. The primary end point of the trial was iDFS by STEEP system.

Approximately 70% had germline BRCA1 mutations, about 30% had germline BRCA2 mutations, about 81% had TNBC, about half received prior adjuvant chemotherapy, and about half received prior neoadjuvant chemotherapy. Of those who previously had neoadjuvant chemotherapy, approximately 93% had an anthracycline/taxane and about 26% received platinum. Sixty-one percent of patients were premenopausal.

Results indicated that olaparib improved iDFS over placebo (stratified HR, 0.58; 95% CI, 0.41-0.82; P < .001).

“This is a practice-changing trial because when they looked at iDFS at 3 years, the absolute difference was 8.8 percentage points, so a huge benefit for this very select and very well-defined group of patients,” Isaacs noted. “This is what has caused the recommendation for us to check for mutation status in our patients with high-risk, early-stage, HER2-negative breast cancer so we can determine whether they are candidates for this therapy, which clearly has a significant impact in terms of outcome”

PI3K Inhibition With Alpelisib in HR+/HER2– Metastatic Breast Cancer

The phase 3 SOLAR-1 trial (NCT02437318), which examined the safety and efficacy of the PI3K inhibitor alpelisib plus fulvestrant in men and postmenopausal women with advanced breast cancer which progressed on or after an AI.5,6

Results showed that among 341 patients whose tumors harbored PIK3CA mutations, the median progression-free survival (PFS) with alpelisib was 11.0 months vs 5.7 months with placebo (HR, 0.65; 95% CI, 0.50-0.85; P < .001). In 231 patients without PIK3CA mutations, the median PFS was 7.4 months and 5.6 months, respectively (HR, 0.85; 95% CI, 0.58-1.25). “The bottom line is that there was no difference in patients who did not have PIK3CA mutations in their tumor,” Isaacs noted.

Knowing this, the phase 2 BYLieve trial (NCT03056755) selected patients based on their PIK3CA mutational status in their tumor and all patients had to have progressed on a prior CDK4/6 inhibitor.7 If the partner that they received with their CDK4/6 inhibitor was an AI, then they were given fulvestrant (Faslodex) plus alpelisib. If they had fulvestrant with a prior CDK4/6 inhibitor, they received letrozole plus alpelisib.

The primary end point was the percentage of patients who were alive without progressive disease at 6 months. Of those who received fulvestrant/alpelisib, 50.4% were alive vs 46.1% of those who received letrozole/alpelisib. The median PFS was 7.3 months and 5.7 months, respectively.

“This trial showed us that if [a patient] has progression on a CDK4/6 inhibitor, look for whether the patient has a PIK3CA mutation, and then give them alpelisib with the appropriate endocrine therapy partner; [it] has benefit,” Isaacs said.

Agents Shaking Up HER2+ Metastatic Paradigm

One targeted agent that has generated excitement in the HER2-positive treatment paradigm is tucatinib (Tukysa). “Lapatinib [Tykerb] and neratinib [Nerlynx] inhibit EGFR and HER2 with similar potencies, whereas tucatinib is highly selective for HER2,” Isaacs noted.

In April 2020, the FDA approved tucatinib for use in combination with trastuzumab and capecitabine for use in patients with unresectable locally advanced or metastatic HER2-positive breast cancer, including those with brain metastases, following at least 1 previous anti–HER2-based regimen in the metastatic setting.8

The decision was based on findings from the phase 2 HER2CLIMB trial, which were originally presented at the 2019 SABCS.9,10 Here, the tucatinib triplet reduced the risk of death by 34% compared with trastuzumab/capecitabine alone in heavily pretreated patients with unresectable locally advanced or metastatic HER2-positive disease. The median overall survival (OS) in the investigative and control arms was 21.9 months (95% CI, 18.3-31.0) vs 17.4 months (95% CI, 13.6-19.9), respectively (HR, 0.66; 95% CI, 0.50-0.88; P = .0048).

The triplet also resulted in a 46% reduction in the risk of disease progression or death vs trastuzumab/capecitabine alone. The median PFS with the triplet was 7.8 months (95% CI, 7.5-9.6) vs 5.6 months (95% CI, 4.2-7.1) with the doublet (HR, 0.54; 95% CI, 0.42-0.71; P < .001).

Among patients with brain metastases, the median OS with tucatinib was 18.1 months vs 12.0 months with the control.11 The median PFS in this subset was 7.5 months with the tucatinib regimen vs 4.1 months with the placebo regimen.

Fam-trastuzumab deruxtecan-nxki (Enhertu) is another agent that has emerged in the treatment landscape. The antibody-drug conjugate (ADC) has a novel payload, high potency, bystander effect, a short systemic half-life payload, a stable linker payload, a tumor-selective cleavable linker, and a high drug-to-antibody ratio.

Data from the phase 2 DESTINY-Breast01 trial (NCT03248492) showed that the ADC elicited an overall response rate of 60.9% (95% CI, 53.4%-68.0%) per independent central review, with a CR of 6.0% among 184 patients with previously treated HER2-positive breast cancer who received the agent at a dose of 5.4 mg/kg.12

Moreover, disease control rate with trastuzumab deruxtecan was 97.3% (95% CI, 93.8%-99.1%), the CBR at 6 months was 76.1% (95% CI, 69.3%-82.1%), and the median duration of response was 14.8 months (95% CI, 13.8-16.9).

These data resulted in the December 2019 FDA approval of trastuzumab deruxtecan for use in adult patients with unresectable or metastatic HER2-positive breast cancer who have received 2 or more prior anti–HER2-based regimens in the metastatic setting.13

Data from the phase 3 DESTINY-Breast03 trial (NCT03529110), were presented during the 2021 ESMO Congress, showing that the ADC resulted in a clinically meaningful and statistically significant improvement in PFS vs standard-of-care ado-trastuzumab emtansine (T-DM1; Kadcyla) in previously treated patients with HER2-positive metastatic disease.14 The median PFS with trastuzumab deruxtecan was not reached (95% CI, 18.5–not estimable) vs 6.8 months (95% CI, 5.6-8.2) with T-DM1 (HR, 0.28; 95% CI, 0.22-0.37; P = 7.8 x 10-22). In the 261 patients who received trastuzumab deruxtecan, the 12-month PFS rate was 75.8% (95% CI, 69.8%-80.7%) vs 34.1% (95% CI, 27.7%-40.5%) in the 263 patients who were given T-DM1.

“We have 2 very active drugs and the data from tucatinib indicate that this drug is particularly active in patients with brain metastases, [which is very exciting],” Isaacs concluded.

References

  1. Issacs C. Tailoring breast cancer therapy. Presented at: 3rd Annual Precision Medicine Symposium; September 17-18, 2021; virtual.
  2. Kalinsky K, Barlow WE, Meric-Bernstam F, et al. First results from a phase III randomized clinical trial of standard adjuvant endocrine therapy (ET) +/- chemotherapy (CT) in patients (pts) with 1-3 positive nodes, hormone receptor-positive (HR+) and HER2-negative (HER2-) breast cancer (BC) with recurrent score (RS) ≤25: SWOG S1007 (RxPonder). Presented at: 2020 San Antonio Breast Cancer Symposium; December 8-12, 2020; virtual. Abstract GS3-00.
  3. Tung NM, Robson ME, Ventz S, et al. TBRC 048: phase II study of olaparib for metastatic breast cancer and mutations in homologous recombination-related genes. J Clin Oncol. 2020;38(36):4274-4282. doi:10.1200/JCO.20.02151
  4. Tutt ANJ, Garber JE, Kaufman B, et al. Adjuvant olaparib for patients with BRCA- or BRCA-2 mutated breast cancer. N Engl J Med. 2021;384(25):2394-2405. doi:10.1056/NEJMoa2105215
  5. André F, Ciruelos EM, Juric D, et al. Alpelisib plus fulvestrant for PIK3CA-mutated, hormone receptor-positive, human epidermal growth factor receptor-2-negative advanced breast cancer: final overall survival results from SOLAR-1. Ann Oncol. 2021;32(2):208-217. doi:10.1016/j.annonc.2020.11.011
  6. Ciruelos EM, Loibl S, Mayer IA, et al. Clinical outcomes of alpelisib plus fulvestrant in hormone receptor-positive, human epidermal growth factor receptor-2-negative advanced breast cancer with PIK3CA alterations detected in plasma ctDNA by next-generation sequencing: biomarker analysis from the SOLAR-1 study. Presented at: 2020 San Antonio Breast Cancer Symposium; December 8-12, 2020; virtual. Abstract PD2-06.
  7. Rugo HS, Lerebours F, Ciruelos E, et al. Alpelisib (ALP) + fulvestrant (FUL) in patients (pts) with PIK3CA-mutated (mut) hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC) previously treated with cyclin-dependent kinase 4/6 inhibitor (CDKi) + aromatase inhibitor (AI): BYLieve study results. J Clin Oncol. 2021;38(suppl 15):1006-1006. doi:10.1200/JCO.2020.38.15_suppl.1006
  8. FDA approves first new drug under international collaboration, a treatment option for patients with HER2-positive metastatic breast cancer. News release. FDA. April 17, 2020. Accessed September 21, 2021. https://bit.ly/2RKhVwv
  9. Murthy R, Loi S, Okines A, et al. Tucatinib vs placebo, both combined with capecitabine and trastuzumab, for patients with pretreated HER2-positive metastatic breast cancer with and without brain metastases (HER2CLIMB). Presented at: 2019 San Antonio Breast Cancer Symposium; December 10-14, 2019; San Antonio, TX. Abstract GS1-01.
  10. Murthy RK, Loi S, Okines A, et al. Tucatinib, trastuzumab, and capecitabine for HER2-positive metastatic breast cancer. N Engl J Med. 2020;382(6):597-609. doi:10.1056/NEJMoa1914609
  11. Bachelot T, Lin NU, Murthy RK, et al. Impact of tucatinib on progression free survival in patients with HER2+ metastatic breast cancer and stable or active brain metastases. Ann Oncol. 2020;31(suppl 4):S359-S360. doi:10.1016/j.annonc.2020.08.395
  12. Modi M, Saura C, Yamashita T, et al. Trastuzumab deruxtecan in previously treated HER2-positive breast cancer. N Engl J Med. 2020;382(7):610-621. doi:10.1056/NEJMoa1914510
  13. FDA approves new treatment option for patients with HER2-positive breast cancer who have progressed on available therapies. New release. FDA. Published December 20, 2019. Accessed September 21, 2021. https://bit.ly/2tzcabv
  14. Cortés J, Kim SB, Chung WP, et al. Trastuzumab deruxtecan (T-DXd) vs trastuzumab emtansine (T-DM) in patients (Pts) with HER2+ metastatic breast cancer (mBC): results of the randomized phase III DESTINY-Breast03 study. Presented at: 2021 ESMO Congress; September 16-21, 2021; virtual. Abstract LBA1.
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