Genomic Testing, New Treatments, and Biomarkers Advance HR-Positive Breast Cancer Treatment

About 13% of American women will develop breast cancer at some point in their lives, according to the American Cancer Society.¹ Its prevalence keeps it at the front of many patients’ and physicians’ minds, and breast cancer is the most changing treatment in an ever-evolving landscape.

Targeted therapies in HR-positive advanced breast cancers were the focus of a poster discussion at the 2020 San Antonio Breast Cancer Symposium moderated by Hope Rugo, MD, FASCO, director of Breast Oncology and Clinical Trials Education at the University of California San Francisco Helen Diller Family Comprehensive Cancer Center.

Next-generation sequencing (NGS) and evolving treatment algorithms

Maria Dieci, MD, of the University of Padova, Italy, kicked off with issues in next-generation sequencing (NGS), drawing on the SOLAR-1 trial, which used NGS to assess the clinical outcomes of alpelisib plus fulvestrant in HR-positive, HER2-negative advanced breast cancer with PIK3CA alterations.² The study showed alpelisib and fulvestrant to have a significant effect on progression-free survival (PFS) and overall survival (OS), leading to FDA approval of the combination.

Patients were assessed for eligibility with PIK3CA mutation testing on tumor tissue with PCR-based assays for 11 mutations in exons 7, 9, and 20. But questions remain in optimal testing strategy for PIK3CA mutations, including whether tissue or circulating tumor DNA (ctDNA) samples are sufficient, PCR vs NGS, and when testing is appropriate, Dieci said.

Plasma samples from the population were retrospectively analyzed for PIK3CA status by PCR on ctDNA, and the benefits of the combination treatment were maintained in patients whose mutations were detected by PCR on ctDNA. However, the ctDNA PCR assay had low sensitivity, detecting 26% fewer mutations than the same assay performed on tissue samples.

“When ctDNA is analyzed for PIK3CA mutation status to identify patients eligible for alpelisib, a tissue reflex test is needed in case of negative results on the ctDNA, especially when the assay sensitivity is known to be low,” Dieci said.

Where timing is concerned, Dieci suggested testing ctDNA following first-line endocrine therapy (ET) and CDK4/6 inhibitor treatment to maximize the pool of patients potentially eligible for fulvestrant and alpelisib. If no mutations are found, then a reflex tissue test is warranted.

But testing is only the beginning after first-line treatment. In 2 further posters, Dieci discussed the current treatment landscape of HR-positive breast cancer in the post-CDK4/6 inhibitor setting.

Based on results from the BYLieve study, a combination of alpelisib and fulvestrant led to a PFS of 5.7 months, favorable compared with the 3.6-month median PFS in general that PIK3CA-mutated patients tend to have in the post-CDK4/6 inhibitor setting, she noted.³

“After the standard first line of endocrine therapy and CDK4/6 inhibitor, patients with a PIK3CA mutation might benefit from alpelisib combined with endocrine therapy,” Dieci said. The companion ET could be either an aromatase inhibitor or fulvestrant depending on prior exposure in the CDK4/6 inhibitor-based line, she said.

A selective aurora kinase inhibitor, alisertib, might also emerge as a new potential treatment option in the post-CDK4/6 inhibitor setting, Dieci said. In the TBCRC041 study, alisertib monotherapy demonstrated promising efficacy and a 5.6-month median PFS.⁴ The monotherapy arm outperformed an alisertib plus fulvestrant arm.

The results of the TBCRC041 study need to be confirmed in larger trials, and the predictive biomarkers for its efficacy need to be evaluated further. Its place in the treatment algorithm of other therapies is also uncertain, Dieci noted.

CDK4/6 inhibitors in early and late stage disease

Amy Clark, MD, of the University of Pennsylvania, discussed the potential of abemaciclib and palbociclib as options in high-risk early stage breast cancer, as well as ribociclib in metastatic breast cancer.

Beginning with abemaciclib, Clark briefly reviewed the MonarchE study, which randomized HR-positive, HER2-negative breast cancer patients with 4 or more positive axillary lymph nodes or 1-3 positive axillary lymph nodes with a high tumor grade, a tumor size 5 cm or greater, or tumor Ki-67 of greater than or equal to 20% were randomized to receive abemaciclib with standard ET or standard ET alone.⁵

An second interim analysis presented at SABCS 2020 showed significant improvements over ET alone in invasive disease-free survival (IDFS) and in IDFS in the Ki-67 high population specifically. At a 2-year follow-up, the IDSF rate in patients in the abemaciclib arm was 91.3%, compared with 86.1% in the ET monotherapy arm. Low Ki-67 patients did not see a significant statistical difference but did see a lower number of IDFS events.

The question remains whether Ki-67 measurement should be used in treatment decisions, Clark said. Ki-67 measurement in itself is controversial, with inter-reader variability and varying definitions of high (14% vs 20%). The American Society of Clinical Oncology specifically recommends against using Ki-67 in treatment decision making.

Despite cautioning against using it to make treatment decisions due to potentially unreliable results, Clark noted the potential utility of Ki-67 testing. “I do think that we can conclude that Ki-67 adds prognostic information to those with high clinical pathologic risk factors,” Clark said. “However, I would also say that patients benefit from the addition of abemaciclib regardless of Ki-67 with 2 years of follow up.”

Clark also discussed the PALLAS study, which randomized stage II-III HR-positive, HER2-negative breast cancer patients to either receive palbociclib plus ET or ET alone with a primary end point of IDFS after 2 years.⁶ But the results at an interim analysis were less promising than those of the MonarchE trial. In the palbociclib arm, 55% of patients required dose reductions at some point during treatment and 42% of patients discontinued early (27.2% due to adverse events).

Overall, there was no significant improvement in 2-year IDFS with combination palbociclib treatment vs ET alone, although a final analysis will take place once the data are mature at 469 events. She points out the fact that PALLAS is negative while MonarchE is positive despite both drugs inhibiting CDK4/6.

“I think we need to await final analysis of PALLAS to definitively understand what the role of palbociclib will be in the adjuvant space,” Clark said. “I do think an outstanding question is whether either trial will show a decrease in late recurrence.”

Results of the MONALEESA-7 trial of ribociclib in the advanced HR-positive, HER2-negative setting were last up for discussion.⁷ Pre- or perimenopausal women with HR-positive, HER2-negative metastatic breast cancer who had received 0 or 1 lines of chemotherapy and no lines of ET for advanced breast cancer were randomized to receive ovarian suppression with either a non-steroidal aromatase inhibitor (NSAI) or tamoxifen, plus ribociclib or a placebo. PFS and OS were primary end points.

Preliminary OS analysis found that adding ribociclib to endocrine therapy resulted in a 10-month increase in OS (median 58.7 months vs 48 months), and there was no difference whether the ET partner was a NSAI or tamoxifen. Ribociclib also lengthened the time to chemotherapy and chemotherapy-free survival.

“I think we all know that CDK4/6 inhibitors are here to stay,” Clark concluded. “And I think that this this last analysis of MONALEESA-7 really just underscores the fact that all patients with ER-positive metastatic disease should be receiving CDK4/6 inhibitors.”

The big question, she said, is whether any of these CDK4/6 inhibitors will help with late relapse—but only time will tell.

Predictive biomarkers in hormone receptor positive breast cancer

Women with HR-positive breast cancer are more prone to late recurrence, explained Luca Malorni, MD, PhD, of the Hospital of Prato, Italy, in a discussion of predictive biomarkers in HR-positive breast cancer. Extended ET may benefit node-positive patients, albeit with side effects, he said.

The estimated benefits of extended hormonal therapy currently rely largely on tumor stage and node status, but gene expression assays can provide more information on the chances of late recurrence, although they are not currently indicated for clinical use, Malorni explained.

The Breast Cancer Index (BCI) gene expression assay includes effective prognostic and predictive indexes, and data presented in the discussion indicated that it is effective independent from clinical risk factors, pointing to its utility in the clinical setting.⁸

“Clinical risk is not sufficient for predicting benefits from extended endocrine therapy, but indications on tumor biology might be important,” he said, adding that more research is needed to inform treatment strategy.

Malorni also discussed the common occurrence of early discontinuation of adjuvant endocrine therapy in younger patients and the possible prognostic implications of early discontinuation.⁹ Using patient-reported data from women under 40 years of age the Women’s Breast Cancer Study, another abstract assessed the effects of discontinuation.

Surprisingly, women who reported staying consistent with therapy had higher rates of recurrence than those who discontinued therapy at less than 5 years and did not restart. The major limitation is the self-reported data pulled from voluntary surveys.

The CYP2D6 genotype is another potential predictive marker that was examined in a substudy of the SOFT trial, which randomized patients to receive either tamoxifen, tamoxifen and ovarian suppression, or exemestane plus ovarian suppression.¹⁰ Previous research regarding CYP2D6 status has been inconsistent, and in this case, there was no difference observed in outcomes based on CYP2D6 status.

Malorni pointed to a final abstract validating a predictive model for patient responsiveness to neoadjuvant endocrine therapy (NET) in postmenopausal women with clinical stage II or III ER-positive, HER2-negative breast cancer.

The “Dowsett” algorithm, which uses ER, progesterone receptor (PR), and Ki-67 levels to stratify patients with primary ER+/HER2- into 3 groups for appropriateness for NET, was shown to be predictive of ET outcome in postmenopausal women, but a simplified model was just as effective in a simplified model, according to the abstract.¹¹ A 4-week biopsy was also recommended if Ki-67 was greater than 15% at baseline. But high confidence in Ki-67 is necessary for it to be effective, and there is not enough evidence to support the method in premenopausal women.

In all, the topics discussed over the course of the panel point to a dynamic field in the treatment of HR-positive breast cancer across stages. From predictive and prognostic testing to treatment in the early and late stages of the disease, there is no shortage of paths being investigated.

References

1. How Common Is Breast Cancer? American Cancer Society. Updated January 8, 2020. Accessed December 10, 2020. https://www.cancer.org/cancer/breast-cancer/about/how-common-is-breast-cancer.html

2. 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 8-11, 2020. Abstract PD2-06.

3. Rugo HS, Lerebours F, Juric D, et al. Alpelisib + letrozole in patients with PIK3CA-mutated, hormone-receptor positive (HR+), human epidermal growth factor receptor-2-negative (HER2-) advanced breast cancer (ABC) previously treated with a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) + fulvestrant: BYLieve study results. Presented at: 2020 San Antonio Breast Cancer Symposium; December 8-11, 2020. Abstract PD2-07.

4. Haddad T, D'Assoro A, Suman V, et al. Randomized phaseII trial to evaluate alisertib alone or combined with fulvestrant for advanced, endocrine-resistant breast cancer (TBCRC 041). Presented at: 2020 San Antonio Breast Cancer Symposium; December 8-11, 2020. Abstract PD2-05.

5. Harbeck N, Johnston S, Fasching P, et al. High Ki-67 as a biomarker for identifying patients with high risk early breast cancer treated in monarchE. Presented at: 2020 San Antonio Breast Cancer Symposium; December 8-11, 2020. Abstract PD2-01.

6. Mayer EL, Fesl C, Dueck A, et al. Treatment exposure and discontinuation in the PALLAS trial: PALbociclib CoLlaborative Adjuvant Study of palbociclib with adjuvant endocrine therapy for HR+/HER2- early breast cancer. Presented at: 2020 San Antonio Breast Cancer Symposium; December 8-11, 2020. Abstract PD2-03

7. Tripathy D, Im S-A, Colleoni M, et al. Updated overall survival (OS) results from the phase III MONALEESA-7 trial of pre- or perimenopausal patients with hormone receptor positive/human epidermal growth factor receptor 2 negative (HR+/HER2−) advanced breast cancer (ABC) treated with endocrine therapy (ET) ± ribociclib. Presented at: 2020 San Antonio Breast Cancer Symposium; December 8-11, 2020. Abstract PD2-04

8. Liefers G-J, Noordhoek I, Treuner K, at al. Breast cancer index is a molecular signature of endocrine responsiveness that determines extended endocrine benefit independent of prognostic risk. Presented at: 2020 San Antonio Breast Cancer Symposium; December 8-11, 2020. Abstract PD2-11.

9. Rosenberg SM, Zheng Y, Poorvu P, et al. Endocrine therapy non-persistence and recurrence in young women with early stage breast cancer. Presented at: 2020 San Antonio Breast Cancer Symposium; December 8-11, 2020. Abstract PD2-08.

10. Goetz MP, Fleming GF, Kuffel M, et al. The role of CYP2D6 mediated tamoxifen metabolism in the suppression of ovarian function trial (SOFT). Presented at: 2020 San Antonio Breast Cancer Symposium; December 8-11, 2020. Abstract PD2-09.

11. Ellis MJ, Suman V, Leitch AM, et al. Validation of a predictive model for potential response to neoadjuvant endocrine therapy (NET) in postmenopausal women with clinical stage II or III Estrogen Receptor positive (ER+) and HER2 negative (HER2-) breast cancer (BC): an ALTERNATE trial analysis (Alliance A011106). Presented at: 2020 San Antonio Breast Cancer Symposium; December 8-11, 2020. Abstract PD2-10.