MBBS (Trivandrum), MD (USA), Diplomate of American Board (Med Onc, Hemat, Int Med), MPhil (Cambridge), FACP (USA)
American Board certified (Internal Medicine, Hematology, Med Oncology)
Consultant, Ernakulam Medical Centre & MOSC Medical College, Kolenchery,
Faculty, University of Kentucky Markey Cancer Center, USA
In December of every year the World’s best breast cancer researchers gather in a nondescript city in Texas in the USA. The San Antonio Breast Cancer Symposium (SABCS) is keenly followed by a vast army of oncologists, basic science researchers, patient advocates and stock market analysts (yes!) for insights into the care of a person with breast cancer. As a trainee, I got bit by the SABCS bug around a decade ago. I can never forget the heady experience of seeing the arrival of pertuzumab into the HER2 armamentarium (CLEOPATRA trial). This year, watched SABCS presentations online like everyone else in the World. I also closely followed the #sabcs20 conversations in Twittersphere. In this article, I will share my viewpoint on the movers and shakers in SABCS 2020.
It has been shown beyond an iota of doubt that CDK4/6 inhibitors are life-altering drugs for some patients with hormone receptor-positive and HER2-negative (HR+/HER2-) metastatic breast cancer. Whether it has any curative potential in early and locally-advanced breast cancer is, quite literally, a billion-dollar question. SABCS 2020 provided a glimpse into the answer to this question. Data on abemaciclib (monarchE trial) and palbociclib (PENELOPE-B trial) were presented.
The abemaciclib trial (monarchE) was an adjuvant study in a cohort of patients with HR+/HER2- early-stage breast cancer with a high risk for recurrence (≥4 positive nodes or 1-3 nodes plus grade 3 or large tumour size). The drug was given for 2 years along with the standard-of-care anti-oestrogen therapy. The study noted a 31% reduction in risk for distant relapse with the drug when compared to the control cohort.
The palbociclib trial (PENELOPE-B) was a post-neoadjuvant study in a cohort of patients who were initially treated with chemotherapy followed by surgery. Patients were then given palbociclib along with standard-of-care anti-oestrogen therapy for one year. After nearly 4 years of follow-up, the study did not show any benefit for palbociclib.
The two studies showed contrasting results. Does it have anything to do with the fact that monarchE was not selected for the luminal-A subtype unlike PENELOPE-B which had more patients with an indolent disease biology? Or, to the duration of treatment? Regardless, there definitely is a signal of efficacy for CDK4/6 inhibitors in non-metastatic breast cancer as well. Whether it will cure breast cancer and not just delay distant relapses is a question that will be answered only after overall survival results are read-out. I am grateful to the of women who have consented to participating in these trials, which includes few of my patients (PALLAS trial).
It is one of my favourite catchphrases in oncology. Anatomy is quite easy to define. We can measure the size of the tumour or determine whether the nodes have disease. Defining the biology is tricky. We use various clinicopathological and genomic classification schemes to do just that – eg; Predict, adjuvant online, oncotypeDX (21 gene score), mammaprint (70 gene score). SABCS 2020 had two major presentations that further confirmed the catchphrase.
In the RxPONDER trial, women with early-stage breast cancer with 1-3 positive nodes and having an oncotypeDX score ≤25 were randomized to getting adjuvant chemotherapy or no chemotherapy in addition to standard-of-care anti-oestrogen therapy. Personally, this was a trial I was closely following since I had more than a dozen patients who participated in it. Not surprisingly, the study showed that postmenopausal women who met the inclusion criteria for the RxPONDER trial did not benefit from adjuvant chemotherapy. Premenopausal women benefitted from the adjuvant chemotherapy (nearly 50% reduction in distant recurrences; absolute difference of 3%). The key question that remains is whether the bulk of the benefit in premenopausal women can be attributed to chemotherapy-related ovarian function suppression (OFS). Is OFS an acceptable alternative to adjuvant chemotherapy? We do not know, but it is a question that will intrigue us in our daily clinical practice as we take care of young women with early-stage breast cancer.
The second major study in this field was also published in the Journal of Clinical Oncology. The investigators attempted to overcome a deficit of the oncotypeDX score in not incorporating a clinicopathological risk stratification. Using data from two trials (NSABP B-14 and TAILORx), they devised an RSClin tool which incorporates both the recurrence score obtained from the oncotypeDX test as well as the clinicopathological factors (age, tumour size and grade). The RSClin tool (accessible via Guardant Health’s website) was able to improve the prognostic ability of either of these when used alone. For most of us in India, we will still rely on clinicopathological factors to help us take a decision on adjuvant chemotherapy due to the exorbitant cost of genomic assays.
Here’s another one of my favourite catchphrases. I am so glad to use it in connection with the PRIME-2 trial. Most of us may have already made 'paternalistic' decisions for our elderly patients with low-risk HR+ breast cancer who have undergone local excision. Like me, you may have omitted adjuvant radiation and just used adjuvant endocrine therapy. Now here’s some data to back-up your decision. Ten-year follow-up of PRIME-2 trial confirms that such a strategy does not result in increased risk for death or distant relapse.
The ADAPT HR+/HER2- trial investigated two questions: first, is weekly nab-paclitaxel better than dose-dense paclitaxel (yes – slightly higher pathologic complete responses), and second, does dynamic monitoring of Ki67 response to neoadjuvant endocrine therapy (significant reduction) correlates with lack of benefit from intensive chemotherapy (yes). Ki67 response assessment after a few weeks of neoadjuvant endocrine therapy maybe a reasonable surrogate for a hormone-responsive biology (ALTERNATE trial presented at SABCS 2020 provides a similar signal). One major downside is that the patient must commit to a second core needle biopsy after a few weeks of therapy. Of course, I must also mention the rather poor inter-observer concordance with Ki67 assessment (big spoiler). Clearly, this emerging biomarker is not ready for primetime use in our clinics.
Twelve-year follow-up data of the IBIS-2 trial in patients with high-risk DCIS/atypical hyperplasia/LCIS showed that anastrozole and tamoxifen are equal in efficacy, but differs in side effect profile. The data will help guide our discussion in the clinic for patients who may benefit from a pharmacological breast cancer risk reduction strategy.
A pooled analysis from the MONALEESA trials of ribociclib showed that HR+/HER2- tumours are a heterogenous group. Intrinsic subtyping of these tumours showed that around one in ten tumours are molecularly HER2-enriched; a handful maybe basal-like (haven’t we all seen HR+/HER2- disease that behaves like a TNBC!). In any case, the benefit of ribociclib was seen in luminal A and B, and HER2-enriched cohorts.
Epigenetic changes have been proposed as one of the aetiologies for endocrine resistance in HR+/HER2- metastatic breast cancer. A phase II trial of an HDAC inhibitor (entinostat) found PFS benefit suggesting that targeting epigenetic changes in cancer may provide a way to control cancer. The phase III trial of entinostat (E2112 trial) in combination with endocrine therapy was negative. I remember how hard it was to accrue patients into the study at my centre. But the negative result of the phase III trial reminds us how important it is to complete the full circle of trial development and not just rely on early positive results, especially the surrogate endpoints.
Sacituzumab govitecan continued its ascent in the treatment of metastatic TNBC. Biomarker study from the ASCENT trial showed that the efficacy of the drug was independent of the degree of Trop-2 expression. In the CONTESSA trial, a new oral taxane (tesetaxel) showed PFS benefit when combined with capecitabine (compared to capecitabine monotherapy). And, was left on the sidelines of the conference, showing once again the tremendous challenge in developing checkpoint inhibitor therapy in breast cancer. Progress in the management of breast cancer is incremental in nature. The last two decades of the 20 th century saw big leaps in survival rates with the advent of effective chemotherapy, hormonal therapy, radiation therapy and surgery. Further progress may look less dramatic, but nonetheless remains significant for the thousands of women diagnosed with breast cancer every year.
I have no conflicts of interest to disclose in connection with this article.
Courtesy - Indian Journal of Medical and Paediatric Oncology (IJMPO)
Editor-in-Chief - Dr. Padmaj Kulkarni