What are your top takeaways in Breast Cancer from ASCO 2024?

1. DESTINY-Breast06

This phase 3 trial randomized patients to either Trastuzumab deruxtecan (T-DXd) vs. physician’s choice chemotherapy (capecitabine, nab-paclitaxel, paclitaxel) in hormone receptor positive HER2 low or HER2 ultralow (any membrane staining) metastatic breast cancer after prior endocrine therapy (ET). Patients had to have >2 lines or 1 line if progression occurred <6 months on first line ET+ CDK4/6 inhibitor OR had recurrence <24 months after starting adjuvant ET. Thirty percent of patients had de-novo metastatic disease, ~30% had primary endocrine resistance, ~86% had visceral disease, ~88% had prior CDKi, and ~30% had prior other targeted therapy. The most common physician's choice chemotherapy was mainly capecitabine (59%) or Nab-paclitaxel (24%).

T-Dxd showed a 5.1 month (mo median progression free survival (mPFS) benefit (13.2mo vs. 8.1 mo, HR 0.62) in the HER2 low and 4.9 mo mPFS benefit (13.2 mo vs. 8.3 mo, HR 0.78) in the HER2 ultralow population compared to physician’s choice chemotherapy (TPC). Overall response rate (ORR) was also improved from 31% to 57% in the intent-to-treat population with numerically higher improvements in the HER2-ultralow group compared to the Her2-low group. All subgroups benefited with some suggestions that the HER2 2+ benefited more than the HER2 1+ subgroup. Median treatment duration was 11 months (mos) for the T-DXd vs 5.6 mos for TPC. 5.3% of patients discontinued T-Dxd for pneumonitis, and 11% had any grade. Ejection fraction was decreased by 8% compared to 2.9%, mostly grade 2.

In HR+ metastatic breast cancer (mBC) patients, ~60-65% have HER2 low disease and 20-25% of patients have HER2 ultralow disease. Post CDK 4/6 inhibitor, median progression free survival (mPFS) is ~7-8 months. Therefore, the results of this trial now move up T-DXd as a 1st line chemotherapy option for those patients with endocrine refractory disease. It also expands the use of T-DXd now to include a larger population who are eligible (the HER2 ultralow) to benefit from this drug. However, the T-Dxd arm had more treatment related adverse events (TRAE), more grade >3 AEs, more serious TRAE, and resulted in more treatment discontinuation or dose interruptions vs. TPC. Hence, while an effective option, patient selection will be important in determining those patients who may benefit from upfront (especially those with symptomatic or rapidly progressive disease) vs. subsequent treatment with T-DXd ( patients with more limited asymptomatic disease).

2. RxPONDER and serum Anti-Mullerian Hormone (AMH)

In the RxPONDER trial, premenopausal women [patients <55 who had last menstrual period (LMP) <6 mo or <50 without prior BSO and who had LMP <12 mo] with HR+/HER2 negative early stage breast cancer with 1-3 lymph nodes involved and recurrence score <25 benefited from the addition of chemotherapy. In this analysis, patients on the trial who were premenopausal and who had low AMH (<10) levels did not benefit from chemotherapy (21% of the study population). AMH predicted chemotherapy benefits more than age, menopausal status based on history, or other serum hormone levels.

Therefore, we now have evidence that AMH can be used to potentially spare some “premenopausal” women with early-stage node positive (1-3) breast cancer from having to receive chemotherapy. Enrollment in the OFSET (BR009) trial will help further elucidate who may benefit from chemotherapy in this population.

3. INAVO120 update

This trial looked at first-line palbociclib+ fulvestrant +/- inavolisib in patients with PIK3CA Mutated HR+/HER2 negative advanced breast cancer patients who had progressed within 12 months of being on adjuvant endocrine therapy. The addition of Inavolisib improved ORR (58% vs. 25%), PFS (15 months vs. 7.3 months, HR 0.43), delayed time to subsequent therapy including chemotherapy (~8.9 mo), and worsening pain (~12 mo). The addition of inavolisib was associated with hyperglycemia, stomatitis, diarrhea, and rash usually within the first month with the majority being grade 1-2 and it was discontinued in 6.2% due to AEs.

The addition of inavolisib does result in additional disease control benefits at a cost of increased, but manageable toxicities for most patients. While PFS2 was also improved, only 25% of patients received PI3K inhibitors in the second line setting. Its approval process is being fast-tracked by the FDA.  

1. DB06 - T-DxD has benefit in ultralow HER2 as first line chemo-like option.
2. postMONARCH - abemaciclib has benefit after CDK46i progression
3. A-BRAVE - adjuvant avelumab may have benefit in TNBC
4. AMH in RxPONDER - benefit may be limited to those patients not in ovarian failure, suggesting that chemo benefit may largely be due to ovarian ablation in patients with RS <25.

1. Abemaciclib plus fulvestrant vs fulvestrant alone for HR+, HER2- advanced breast cancer following progression on a prior CDK4/6 inhibitor plus endocrine therapy: Primary outcome of the phase 3 postMONARCH trial.
   This is the first phase 3 randomized trial that demonstrated that the CDK4/6 inhibitor abemaciclib in combination with fulvestrant led to significantly longer PFS of 6.0 months (95% CI, 5.6-8.6) compared to fulvestrant alone of 5.3 months (95% CI, 3.7-5.6) in patients who experienced disease progression from prior CDK4/6 inhibitor. The benefit was observed regardless of ESR1 or PI3K pathway gene mutation status. This study provides another option for patients with hormone receptor-positive/HER2-negative advanced breast cancer, post disease progression on CDK4/6 inhibitors, regardless of mutation status of ESR1 or PIK3CA/AKT/PTEN alterations.
   
   
2. Trastuzumab deruxtecan (T-DXd) vs physician’s choice of chemotherapy (TPC) in patients (pts) with hormone receptor-positive (HR+), human epidermal growth factor receptor 2 (HER2)-low or HER2-ultralow metastatic breast cancer (mBC) with prior endocrine therapy (ET): Primary results from DESTINY-Breast06 (DB-06).
   This randomized phase 3 trial demonstrated that T-DXd is more effective than traditional chemotherapy as first-line chemotherapy regimen for patients with advanced HR+ breast cancer that is either HER2-low or HER2-ultra low post progression on endocrine therapy and CDK4/6 inhibitor. The mPFS was 13.2 months vs 8.1 months in the HER2-low population and similar results in the HER2-ultra low population. Interstitial lung disease occurred in 11% of participants. This study provides evidence for patients to receive T-DXd as a first line chemotherapy option, especially when the need of efficacy outweighs the potential toxicities of this agent. 
   
   
3. ECOG-ACRIN EAZ171: Prospective validation trial of germline predictors of taxane-induced peripheral neuropathy (TIPN) in Black women with early-stage breast cancer.
   In the prospective phase 2 trial, Black patients with early-stage breast cancer received physician’s choice of either docetaxel every 3 weeks or weekly paclitaxel. The study did not meet the primary endpoint of germline predictors of TIPN. However, analysis of secondary outcomes demonstrated that Black patients who received docetaxel experienced less TIPN and fewer dose reductions than Black patients who received paclitaxel. Although future study is needed before drawing the conclusion that docetaxel should be preferred than paclitaxel in Black patients, the data highlights the need to optimize taxane regimen in Black patients and the need to enroll minority patient population to clinical trials.

1. DESTINY-Breast06: Two big shifts here in this trial for T-DXd, 1) 1st line cytotoxic for HR+ breast instead of 2nd line, and 2) included “ultra-low” HER-2 expression, aka IHC 0 that have some membrane expression. This will include another 20-25% of HR+ patients, so now about 85 or 90% of patients eligible for T-DXd. Among HER-2 low, PFS improved 5.1 months (8.1 to 13.2 months), among ultra-low specifically PFS improved 4.9 months (8.3 to 13.2 months). Remember, that this is 1st line cytotoxic, and DOES NOT come before endocrine therapy.
   
   
2. DESTINY-Breast03: We previously heard this 2nd line HER-2 positive trial had significant OS, but medians were reached. We see that OS is improved by 9.9 months (42.7 mo with T-DM1 to 52.6 mo T-DXd). This is a big deal as it is the longest OS seen in HER-2 positive breast cancer and is in the 2nd line – so at 2nd line, our patients are living on average at least 4.3 more years!
   
   
3. postMONARCH: patients 2nd line after AI + CDK4 randomized to fulvestrant alone vs. fulv + abema. Almost everyone previously saw ribo or palbo. PFS 5.3 vs. 6.0 mo with the addition of abema, interestingly BICR benefit more pronounced (5.6 to 12.9 mo). No real diff with prior CDK duration. Adds another tool to our 2nd line arsenal, probably would be used in patients who don’t have ESR1 or PI3/AKT/PTEN alterations.

1. postMONARCH - First phase III study of fulvestrant with or without abemaciclib in patients who progressed on prior CDK 4/6 inhibitor and endocrine therapy that showed a statistically significant improvement in progression free survival with continued use of a CDK 4/6 inhibitor and switch in endocrine therapy compared to endocrine therapy alone. 
   
   
2. DESTINY-Breast06 - T-DXd led to a statistically significant and clinically meaningful improvement in progression-free survival (PFS) vs investigator’s choice of chemotherapy in pretreated patients with HR+ HER2-low or HR+ HER2-ultralow disease following one or more lines of endocrine therapy. 
   
   
3. S1007 RxPONDER - The update from ASCO 2024 for the RxPONDER study was that patients <55 years of age who are pre/peri-menopausal with a low AMH had no invasive disease-free survival with adjuvant chemotherapy and suggests serum AMH levels may be another tool we can use in pre-/perimenopausal women to better evaluate benefit from adjuvant chemotherapy.

Here are my thoughts:

1. DESTINY-Breast06 late-breaking presentation: While I don’t think it would result in us moving all HER2 low metastatic breast cancer patients to TDXd immediately after exhausting endocrine therapy, this data does give us more flexibility to use TDXd for patients who we feel aren’t good candidates for other chemotherapy drugs like capecitabine following endocrine therapy combinations. Also, the “ultralow” terminology is causing a lot of discussion around how would we identify these patients in our current HER2 testing scheme.
   
   
2. postMONARCH presentation: This data presented by Dr. @Dr. First Last does give us additional information on using abemaciclib with fulvestrant for patients who have progressed on 1st line endocrine therapy + CKD4/6i (largely Palbociclib although there were a minority started on ribociclib).  The data showed there was a PFS advantage so one could envision using this option after patients progress on AI/ribociclib or Palbociclib without other actionable mutations.
   
   
3. A-BRAVE trial provided some information on adjuvant use of avelumab for high-risk TNBC showing that overall it did not improve recurrence free survival although there may have been a signal on overall survival that bears further investigation. We suspect that the use of PD-1/PD-L1 agents may not be as necessary/effective once the primary tumor burden has been removed and as additional adjuvant trials read out like SWOG 1418, it should answer this question for us.

1. Abstract 513 by Choong et al. suggests that ET should still be given to patients with ER-low tumors. There has been a trend to omit ET in these patients. Undoubtedly, the benefit is smaller than in tumors with high ER expression.
   
   
2. Abstract 505 by Kalinsky et al. demonstrated the impact of ovarian function on the benefit of chemotherapy in the RxPONDER trial. Those with preserved ovarian function as measured by anti-Mullerian hormone (AMH) benefitted more from chemotherapy, presumably because chemotherapy would suppress ovarian function, enhancing endocrine therapy.
   
   
3. Abstract 1021 by Tung et al. establishes that germline PALB2 and those with somatic BRCA mutations can benefit from PARP inhibitors. This is practice changing.
   
   
4. LBA1000 by Curigliano et al. adds to the discussion of whether HER2 0 really exists. Ultralow HER2 expression still benefits from trastuzumab deruxtecan.

While not immediately practice-changing; a series of abstracts drew attention to a subset of ER+ breast cancers that could benefit from immunotherapy, in the stage II-III setting.

In the June 3rd oral presentations session, the presentation by Dr. @Dr. First Last, “Elucidating the Immune Active State of HR+HER2- MammaPrint High 2 Early Breast Cancer” described early-stage hormone receptor-positive, HER2-negative, MammaPrint H2 (MP High 2) breast cancers are rich in immune cells and exhibit heightened immune active state compared to MammaPrint H1 (MP High 1) tumors. Despite the high immune infiltration, these cancers have poor prognoses with endocrine therapy alone but showed a dramatic increase in pathologic complete response rates (pCR,  24-44%) in 3 different neoadjuvant immunotherapy + chemotherapy arms of the I-SPY2 trial. These observations are consistent with the results of the large, randomized KEYNOTE0-687 and CheckMate 7FL neoadjuvant immunotherapy trials in stage II-III HR+ breast cancer. The clinical relevance of these findings is that since the MammaPrint assay results report MP High 1 and MP High 2 status, MP High 2 patients are eligible for the recently activated SWOG S2206 randomized trial (durvalumab + chemotherapy versus chemotherapy alone) that provides an opportunity for these genomically very high-risk patients to receive immunotherapy.

Two additional presentations informed about the biology and clinical behavior of hormone receptor positive/HER2-negative MammaPrint High 2 cancers. Dr. Rios-Hoyo presented data; “Hormone Receptor Positive HER2-negative/MammaPrint High-2 Breast Cancer Closely Resembles Triple Negative Breast Cancer: Results from Gene Expression Data from the ISPY2 Trial” which indicated close molecular similarity between HR+ MP High 2 and triple negative cancers including shared immune features, high proliferation, and low expression of estrogen receptor co-expressed genes that explain the low endocrine sensitivity and high chemotherapy and immunotherapy sensitivity of this subset of HR+ cancers. Consistent with the molecular phenotype, Dr. @Dr. First Last presented in the rapid oral session “Association of MammaPrint index and 3-year outcome of patients in the FLEX Registry trial with HR+HER2- early-stage breast cancer treated with chemotherapy with or without anthracycline” data that indicated both significantly higher pCR rates in MP High 2 cancers treated with anthracycline + taxane (AC-T) compared to docetaxel/cyclophosphamide (TC) neoadjuvant chemotherapy, and significantly better 3-year recurrence free survival with the more aggressive regimen (RFS, 86% vs 98%). The pCR rates were equally low and 3-year RFS were similar with both regimens in MP High 1 cancers.

In the June 3rd oral presentation session, Dr. Loi provided updates on the “Prognostic utility of ctDNA detection in the monarchE trial of adjuvant abemaciclib plus endocrine therapy (ET) in HR+, HER2-, node-positive, high-risk early breast cancer (EBC)”. This biomarker cohort included 910 patients from across both treatment arms and was enriched for overall invasive disease free survival (IDFS) events. ctDNA was assessed using the Signatera assay at baseline (pre-abemaciclib) and at 3, 6, or 24 months. They found that ctDNA positivity was infrequent (8%) at baseline but patients turned ctDNA positive during follow up and the overall ctDNA positivity rate was 17%. ctDNA detection was highly prognostic for worse outcomes, particularly metastatic recurrence. These data support the prognostic value of ctDNA detection during follow-up but do not inform about what to do with patients who are ctDNA positive. An important currently open multicenter study that addresses the clinical utility question, randomizes Signatera ctDNA+ and imaging negative patients to the continued standard of care versus fulvestrant + palbociclib (NCT04567420).

1. There is an ultralow category that appears to identify patients who benefit from T-DXd. When DB-06 is approved by the FDA, the categorization of HER2 will change again to HER2 3+, negative. For everything else, the question of whether we need to differentiate between ultralow and low categories remains. Based on current knowledge, it seems we probably do not need to make this distinction. We will see where this will go.
   
   
2. For patients with a hormone receptor status of 1-9%, adjuvant endocrine therapy shows an overall survival benefit. This is encouraging because previous data in the neoadjuvant setting has been unclear; the pathological complete response (pCR) rate changes dramatically at 10%. Many of us apply the KEYNOTE-522 regimen to HER2-negative, low HR (1-9%) patients. Does this mean we will now provide adjuvant endocrine therapy post-neoadjuvant chemotherapy (NAC) for low HR triple-negative breast cancer (TNBC)? This is another complicated situation without a definitive answer.
   
   
3. Post non-Abemaciclib CDK inhibitor (CDKi) treatments, Abemaciclib appears effective. However, does the reverse hold true? If a patient receives adjuvant CDKi like Abemaciclib or Ribociclib, what will happen? This is a complex situation that requires further study, especially when genomic changes in tumors influence the choice of regimen.