Breast cancer (BC) is the most frequently diagnosed cancer for women, aside from skin cancers, in the US. abs the second leading cause of death of American women after lung cancer. The American Cancer Society estimated that approximately 287,850 new cases of invasive BC have been diagnosed, and 43,250 women have died of BC in the US during 2022.

In 2021, the estimated number of women in the United States living with metastatic breast cancer rose to about 168,000 from 155,000 the year before, according to the Breast Cancer Research Foundation. The good news is that survival rates are also climbing.  Over the last 20 years, advances in HER2 targeting treatments, antibody-drug conjugates (ADCs), immune checkpoint inhibitors (ICIs), and cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6is) have prolonged survival and changed the breast cancer treatment landscape.

New treatment paradigms and advances invariably lead to more questions about optimal drug sequencing, mechanisms of resistance, and how to overcome that resistance

In this episode we attempt to tackle these questions and review advances and trends in MBC. Victoria Goldberg and senior producer Lynda Weatherby have asked Dr. Stephanie Graff, an outstanding clinician, researcher, thought leader, writer and an  exceptional science interpreter, to help us shed some light on these complex issues, new trends and advances in the er+//her2- landscape, the unknowns in the treatment of triple positive MBC, and even the prophylactic MRI for brain mets. The last section of the episode is a 10-minute fragment of a presentation of Dr Hope Rugo at the 2022 OncoAlert Colloquium on the advances in mTNBC.

Highlights

Estrogen receptor-positive (ER+)/HER2-negative (HER2−), the so-called luminal-type breast cancer, is the most frequent subset, accounting for around 70% of all breast cancer cases. Endocrine therapy (ET) combined with cyclin-dependent kinases (CDK) 4/6 inhibitors is the standard first option in the management of advanced luminal breast cancer independently of disease extension. Classically, patients undergo multiple lines of ET ± targeted treatments until endocrine resistance occurs and palliative chemotherapy is proposed. Understanding endocrine resistance mechanisms and development of novel ET options is one of the main challenges in current clinical research. Another area of utmost interest is the improvement of post-endocrine therapeutic approaches. Among others, the development of antibody–drug conjugates (ADCs) is very promising, and some of these drugs will probably soon become a part of the therapeutic arsenal against this incurable disease.

Do all three available CDK4/6 inhibitors behave similarly?

Based on the results of several phase III trials, CDK 4/6 inhibitors (palbociclib, abemaciclib and ribociclib) combined with endocrine treatment [non-steroidal aromatase inhibitors (NSAIs) or fulvestrant] not only became a standard treatment in ER+/HER2 non-amplified advanced breast cancer, but unarguably represents one of the major breakthrough in breast oncology in the past two decades.

 Although some differences can be noticed in the inclusion criteria of pivotal trials mainly regarding prior anticancer treatment, results can be considered overall similar with the three different drugs. One exception might be noticed regarding efficacy data. In the first- and second-line trials using ribociclib (Monaleesa 2, 7 and 3) and in one second-line trial using abemaciclib (Monarch-2), a significant OS benefit was observed (HR 0.72-0.76). On the other hand, the two phase III trials using palbociclib (Paloma-2 and -3) did not report a significant OS benefit in the overall patient population, although both were clearly positive for the primary endpoint, which was PFS.

 This might be due to a less rigorous selection of patients recruited, a weaker potency of this drug to inhibit CDK 4/6 or factors related to post-progression disease on palbociclib.

Does treatment-free interval or prior endocrine sensitivity impact the benefit from CDK 4/6 inhibitors?

Treatment-free interval (TFI) was measured as the time elapsed between the end of adjuvant treatment and relapse.Roughly, one-third of patients treated with CDK 4/6 inhibitors and fulvestrant in the three pivotal trials (Paloma-3, Monaleesa-3 and Monarch-2) received previous endocrine treatment for advanced breast cancer and all of them were resistant to ET (e.g. relapsed within 12 months after adjuvant treatment or progressed during ET in the setting of advanced breast cancer) except a group of patients in Monaleesa-3 who were treatment naïve (n = 367). In patients with primary endocrine resistance numerically stronger effect (HR) was seen with fulvestrant and abemaciclib for both PFS and OS (PFS: HR 0.454 in primary resistance, HR 0.591 in secondary resistance; OS: HR 0.686 in primary resistance, HR 0.787 in secondary resistance).This is in contrast with OS data of Paloma-3, where only patients who showed prior sensitivity to ET derived significant benefit from combination therapy [median OS (mOS) 39.7 months with fulvestrant + palbociclib versus 29.7 months with fulvestrant + placebo, HR 0.72], whereas no significant difference in OS was observed in the intention-to treat population.These data are reassuring regarding the use of abemaciclib in an endocrine-resistant setting or in cases of early relapse after adjuvant treatment, but it should be interpreted in the light of a slightly different patient population included in these trials. Paloma-3 patients were more heavily pre-treated (30.8% received chemotherapy and 37.8% had ≥2 lines of treatment in a metastatic setting), whereas Monarch-2 recruited a mixed population of first- and second-line patients without prior chemotherapy.

Re-challenge with CDK 4/6 inhibitors after previous exposure

Cross-resistance between CDK 4/6 inhibitors is unknown. Retrospective data suggest potential clinical activity with abemaciclib in patients who had prior exposure to palbociclib. The first prospective phase II randomized trial (MAINTAIN) exploring this hypothesis showed a significant PFS benefit using ribociclib + switching ET versus placebo + switching ET in patients progressing on ET + CDK 4/6 inhibitor (mPFS 5.29 months versus 2.76 months, HR 0.57, 95% CI 0.39-0.95, P = 0.006). The previous CDK 4/6 inhibitor was palbociclib in 87% of cases and the switching ET was mainly fulvestrant. Benefit seems to be limited to the ESR1wt group.

The efficacy of pursuing CDK 4/6 inhibitors beyond progression is currently assessed in other phase II trials having as primary endpoint PFS or CBR at 24 months. Those patients who were exposed to CDK 4/6 inhibitors in the adjuvant setting can be probably re-challenged when relapse occurs later than 1 year after stopping adjuvant treatment. However, no data exist so far to confirm the efficacy of CDK 4/6 inhibitor re-challenge in this particular situation.

New oral selective estrogen receptor down-regulators (SERDs)

Mutations of ESR-1 are typically more frequent in advanced breast cancer (30%). Retrospective analysis in two phase III trials (SoFEA and EFECT) showed a significantly worse PFS and OS in patients treated with exemestane compared to fulvestrant when ESR-1 mutation was detected.

Oral SERDs show promising activity even after CDK 4/6 inhibitors in early-phase trials. According to available data, response rate with new oral SERDs (elacestrant, AZD-9833, GDC-9545, LSZ102, LY3484356, G1T48, SAR439859) in patients progressing on previous ET ± CDK 4/5 inhibitors is around 13%-20% and the median PFS ranges between 4.5 and 7.8 months.

 Combining these drugs with CDK 4/6 inhibitors seems feasible.

The first phase III trial comparing elacestrant with ET alone (n = 477) in patients pre-treated with CDK 4/6 inhibitors showed a statistically significant albeit limited PFS benefit (HR 0.70 in all-comers and 0.55 in ESR-1mut patients). However, the activity of ET alone in this post-CDK 4/6 inhibitor setting seems to be very limited (mPFS 2.8 months with elacestrant and only 1.9 months with fulvestrant), highlighting the need to develop novel combinations and potent drugs.

 Two other trials in the same setting investigating giredestrant and amcenestrant were recently reported as negatives.

Poodle Mixes Mentioned

There are currently over 40 different types of Poodle mixes—or doodles, as they're lovingly called. These dogs are born from Poodles with other purebreds like pugs, Labradors, or Cocker Spaniels. Since the 1980s, doodle dogs have increased in their popularity.

Referenced Works of Art

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