Current advance of nanotechnology in diagnosis and treatment for malignant tumors
Advancing Neoadjuvant Therapy For HER2+ Breast Cancer Through CtDNA Monitoring
In an interview with Targeted Oncology, Adrienne Waks, MD, provided insights into the significance of the findings from the DAPHNe trial and their clinical implications for patients with HER2-positive breast cancer.
The DAPHNe trial (NCT03716180) showed that circulating tumor DNA (ctDNA) is a promising biomarker for monitoring treatment response and minimal residual disease (MRD) in early-stage HER2-positive breast cancer, with neoadjuvant paclitaxel, trastuzumab (Herceptin), and pertuzumab (Perjeta) therapy showing high efficacy in clearing ctDNA.1
Among the 98 patients enrolled in the DAPHNe trial, 50 had at least 1 plasma sample sequenced for ctDNA analysis. The median age of these patients was 50 years, and 92% had clinical stage II disease. A total of 64% of patients had hormone receptor–positive tumors. Residual cancer burden (RCB) scores were classified as RCB 0 in 66% of patients, RCB I in 4%, RCB II in 28%, and RCB III in 2%.
At baseline, 92% of patients had detectable ctDNA, with a median detected level of 210 parts per million. The detection rate varied based on tumor stage: 100% of patients with T3/T4 tumors or positive nodes had detectable ctDNA at baseline, while 91% of patients with T1/T2 or node-negative tumors also had detectable ctDNA.
After 12 weeks of neoadjuvant therapy, most patients had cleared their ctDNA, and 4% had detectable ctDNA at pre-operative and post-operative timepoints. At later follow-up points, more than 90% of patients had sustained clearance of ctDNA.
In an interview with Targeted OncologyTM, Adrienne Waks, MD, senior physician and the associate director of breast oncology clinical research at Dana-Farber Cancer Institute and an assistant professor of medicine at Harvard Medical School, provided insights into the significance of these findings and their clinical implications for patients with HER2-positive breast cancer.
Breast cancer cells: © LASZLO- stock.Adobe.Com
Targeted Oncology: What are the unmet needs in this patient population?
Waks: We were looking at patients with early stage, stage II, and stage III HER2-positive breast cancer. And I think in that space, the biggest unmet need at the moment is that we have this expanding set of options for how we treat them. We can give a lot of chemotherapy, we can give a lot of anti-HER2 drugs. We can give a little chemotherapy. We could give no chemotherapy and only anti-HER2 drugs. So, it's a good problem to have. In some ways, we have all these different options, but a big issue at the moment is we don't know how to customize them. We don't know how to figure out which patient needs the most that we can give them, which patient could get away with a lot less and obviously be spared unnecessary toxicity.
What were the overall goals of the DAPHNe trial?
This was a study where we took this patient set of about 100 patients with stage II and III, HER2-positive breast cancer, and we treated them with neoadjuvant chemotherapy, single-agent taxol for 12 weeks, and then 2 anti-HER2 drugs: trastuzumab and pertuzumab. We then brought all those patients to surgery and looked at how good or bad of a response they had to those 12 weeks of therapy. That was the sort of parent trial itself. What we were doing in this poster is diving into the circulating tumor DNA on a subset of those patients. Looking at when they were first diagnosed with breast cancer and enrolled on the trial, could we detect circulating tumor DNA using this novel assay called next personnel? And then as they went through their treatment for their surgery after their surgery, and then a later follow up time point? Could we detect circulating tumor DNA for them?
What were the main findings from the trial?
What we found was that at baseline, the patients who had not yet had surgery for breast cancer still had a breast tumor in place. At baseline, we could detect circulating tumor DNA in 92% of them. We were happy with that number. Ideally, you would want it to be 100%, since they have a tumor in place, so detecting circulating tumor DNA in all of them would be reassuring. But compared with other assays and datasets out there, 92% is a good, high number. At baseline, with the tumor in place, the detectability rate was good, and that was one important finding for us.
Over the 12 weeks of therapy, when we retested their circulating tumor DNA before surgery, we found that almost all of them had cleared their circulating tumor DNA—though not quite all, but almost all. Then, postoperatively, when we looked at their adjuvant therapy about a year later, the large majority—over 90% to 95%—had persistent clearance of circulating tumor DNA at those later time points.
Based on these findings, what are the implications for clinicians?
Circulating tumor DNA is a promising technology, particularly in the neoadjuvant setting, although it can be applied to almost any scenario in breast cancer. Specifically, in the neoadjuvant setting, I think it holds potential for identifying who might need more chemotherapy or additional drugs before surgery and who could safely receive an abbreviated course and proceed to surgery earlier.
I believe our study aligns with that hypothesis, though our cohort is too small to draw definitive conclusions. That said, it does suggest that circulating tumor DNA is a dynamic marker that we can monitor to better understand how well treatments are working—potentially even earlier than traditional methods like taking someone to surgery and analyzing their pathology under a microscope.
Do you find that ctDNA is predictive of long-term outcomes?
If you are wondering if circulating tumor DNA, a positive vs a negative result, has some correlation with whether a patient will recur or not recur in the future? I think the answer to that is yes. It is clear that the positive predictive value—meaning the likelihood that if you have a positive result, you will ultimately experience a recurrence—is much stronger than the negative predictive value. In other words, if you have a negative result and undetectable ctDNA, it is not as reassuring that you won't experience a recurrence in the future, although it's still a good sign.
I think we are increasingly aware that we need to improve the sensitivity of these assays to make both the positive and negative predictive values more reliable. Additionally, if we measure circulating tumor DNA at multiple time points—especially if it remains negative over time—that can give higher confidence that the long-term risk of recurrence is lower. So, while I believe these correlations exist, they are far from a one-to-one relationship. At this point, I do not think ctDNA is a tool we can routinely use in clinical practice to guide decisions.
REFERENCE: 1. Waks AG, Tarantino P, Li T, et al. Prevalence and dynamics of circulating tumor DNA (ctDNA) among patients (pts) with HER2+ breast cancer (BC) receiving neoadjuvant paclitaxel/trastuzumab/pertuzumab (THP) in the DAPHNe trial. J Clin Oncol. 2024;42(Suppl 16):558. Doi:10.1182/blood-2024-202676Will Phase 3 Results Prompt A Shift In Neoadjuvant Treatment For HER2+ Early Breast Cancer?
The combination of nab-paclitaxel, trastuzumab, and pertuzumab may provide advantages over standard neoadjuvant therapy and become a new standard of care for patients with HER2-positive early breast cancer, according to researchers.
The team found that nab-paclitaxel plus trastuzumab and pertuzumab improved the pathologic complete response (pCR) rate when compared to docetaxel plus carboplatin, trastuzumab, and pertuzumab. In addition, patients in the nab-paclitaxel arm generally had fewer severe adverse events (AEs). The researchers reported these findings, from the phase 3 HELEN-006 trial, in The Lancet Oncology.
The trial (NCT04547907) enrolled adults with previously untreated, stage II-III, HER2-positive breast cancer who were treated at 6 hospitals in China. The patients were randomly assigned to receive nab-paclitaxel (125 mg/m² on days 1, 8, and 15) for six 3-week cycles or docetaxel (75 mg/m² on day 1) plus carboplatin (area under the curve, 6 mg/mL per min on day 1) for six 3-week cycles. All patients received trastuzumab (loading dose of 8 mg/kg, maintenance dose of 6 mg/kg on day 1) and pertuzumab (loading dose of 840 mg, maintenance dose of 420 mg on day 1).
A total of 669 patients received at least 1 dose of study treatment and were included in the full analysis set — 332 in the nab-paclitaxel arm and 337 in the docetaxel-carboplatin arm. Baseline characteristics were considered well balanced between the treatment arms. All patients were Asian women, and their median age at baseline was 50 years.
The median follow-up was 26 months. The pCR rate was significantly higher in the nab-paclitaxel arm overall and among patients with hormone receptor (HR)-negative disease but not among patients with HR-positive disease.
In the full analysis set, the pCR rate was 66.3% in the nab-paclitaxel arm and 57.6% in the docetaxel-carboplatin arm (odds ratio, 1.54; 95% CI, 1.10-2.14; P =.011). Among patients with HR-negative disease, the pCR rate was 86.0% in the nab-paclitaxel arm and 70.1% in the docetaxel-carboplatin arm (P =.0010). Among patients with HR-positive disease, the pCR rate was 52.6% and 48.2%, respectively (P =.39).
The rate of grade 3-4 AEs was 30% in the nab-paclitaxel arm and 38% in the docetaxel-carboplatin arm. The most common grade 3-4 AEs (in the nab-paclitaxel and docetaxel-carboplatin arms, respectively) were nausea (7% and 23%), diarrhea (8% and 16%), and neuropathy (13% and 2%).
The researchers noted that the nab-paclitaxel arm had "substantially fewer" cases of grade 3-4 anemia, leukopenia, neutropenia, thrombocytopenia, nausea, vomiting, and diarrhea. However, patients in the nab-paclitaxel arm had higher rates of grade 3-4 neuropathy, increased alanine aminotransferase, and increased aspartate aminotransferase. There were no treatment-related deaths in either arm.
"Findings from the HELEN-006 trial suggest a potential shift in neoadjuvant treatment practices for patients with HER2-positive early breast cancer, specifically using nab-paclitaxel to reduce treatment-related toxicity without compromising efficacy," the researchers wrote. "This approach seems especially beneficial for hormone receptor-negative patients, who showed significant improvements in pathological complete response rates. Future research should focus on long-term outcomes, such as event-free survival and overall survival, to further validate the clinical benefits of this regimen."
Disclosures: This research was funded by the National Natural Science Foundation of China and the Science and Technology Research Projects of Henan Province, China. The study authors said they have no conflicts of interest. Please see the original reference for complete disclosures.
This article originally appeared on Cancer Therapy Advisor
Evaluating The Impact Of Neoadjuvant Therapy In Localized Breast Cancer
Neoadjuvant chemotherapy's effect on local disease management of breast cancer has a number of clinical implications, including tumor downsizing, potentially improved overall survival, and more.
The effect of neoadjuvant chemotherapy (NAC) on local disease management of breast cancer has a number of clinical implications. First, it can lead to tumor downsizing, reducing the size of the tumor to allow for breast-conserving surgery. Second, it boosts the potential for improved overall survival by achieving pathologic complete response (pCR), and third, it can guide future treatment decisions, such as the use of adjuvant therapy after surgery. These implications were explored by Anna Weiss, MD, during the 42nd Annual CFS, an event sponsored by Physicians' Education Resource®, LLC (PER®).1
Several landmark NAC trials were influential in establishing the role of neoadjuvant therapy in breast cancer.2,3 The National Surgical Adjuvant Breast and Bowel Project (NSABP) Protocol B-18 was initiated in 1988 to determine whether 4 cycles of doxorubicin/cyclophosphamide given preoperatively improved survival and disease-free survival (DFS) compared with the same chemotherapy given postoperatively.2 Perioperative chemotherapy was shown to be safe for patients with breast cancer in the phase 3 European Organization for Research and Treatment of Cancer (EORTC) 10994/ BIG1-00 trial.3
"These landmark neoadjuvant clinical trials helped us downsize breast tumors and achieve breast conservation," Weiss, an associate pro- fessor of surgery and medicine, University of Rochester Medicine, and director of the breast cancer service line at Pluta Breast Center/Wilmot Cancer Institute in Rochester, New York, said during her presentation. "Where neoadjuvant [therapy] shines for these patients is in the larger tumors," Weiss said (TABLE 14). "It's helpful when you have a big tumor that you need to get a little bit smaller in order to try for breast conservation," Weiss added.
The benefit of NAC in locoregional recurrence (LRR) has also been demonstrated, according to Weiss. A meta-analysis by Mieog et al,5 evaluated 14 studies that randomly assigned 5500 women to receive neoadjuvant vs adjuvant chemotherapy for early breast cancer. The investigators reported that mastectomy rates had decreased by 16% (95% CI, 15.1%-18.1%) for patients who received NAC, with no differences observed in LRR in patients treated with NAC vs adjuvant chemotherapy; additionally, no differences in LRR were observed between those receiving planned breast-conserving therapy and those downstaged to breast-conserving therapy.5
Breast Conservation EligibilityWhat tools are used to determine breast conservation eligibility? "I would say that my most useful tool is MRI," Weiss said. "In this particular scenario, we know that MRI is 71% accurate when assessing neoadjuvant therapy response, the size of the tumor in the breast according to MRI, and the correlation of that with pathology is the most accurate for MRI."
Yeh et al6 carried out a prospective comparison of mammography, sonography, and MRI in patients undergoing neoadjuvant chemotherapy. The investigators evaluated 41 patients with stage IIB to III palpable breast cancer; 31 patients completed the protocol of doxorubicin followed by paclitaxel or vice versa. All patients underwent physical examination, mammography, sonography, and MRI before and after receiving each neoadjuvant drug.
Agreement with the rate of response as measured by clinical examination, mammography, sonography, and MRI was 19%, 26%, 35%, and 71%, respectively, compared with pathology, the gold standard. MRI was determined to agree with the gold standard significantly more often (P < .002 for all 3 paired comparisons with MRI).6
Margin ConcernsWeiss noted that, ideally, tumor shrinkage occurs evenly in a unifocal fashion. However, that's not always the case because the tumor often has a "buckshot pattern of response, as opposed to nice concentric shrinkage," Weiss said. "This has caused some investigators to ask [whether] pathologic response patterns can explain this radiologic response that we see as surgeons."
Pastorello et al gave a detailed review of histologic sections of the posttreatment surgical specimens for 665 patients with stage I to III breast cancer treated with NAC followed by surgery.7 Among 389 patients with residual invasive cancer in whom the pattern of residual disease could be assessed, 287 (73.8%) had a scattered pattern and 102 (26.2%) had a circumscribed pattern. There was a significant association between tumor subtype and pattern of response. Among patients with hormone receptor–positive, HER2-negative tumors, 89.4% had a scattered pattern and only 10.6% had a circumscribed pattern. In contrast, among those with triple-negative breast cancer, 52.8% had a circumscribed pattern and 47.2% had a scattered pattern (P < .001).7
What does this mean to the surgeon?"If you resect this area and you have clear margins, you may think you've gotten all the cancer, and you actually have not," Weiss said. "And this is something we worry about at tumor board."
Investigators in a study that sought to determine the impact of margin width on local recurrence and survival after NAC and breast-conserving therapy evaluated 382 patients with stage I to III breast cancer.8
Choi J et al8 noted that breast pCR was achieved in 105 (27.5%) of patients. Final margin status was positive in 8 (2.1%) patients, 1 mm or less in 65 (17.0%), 1.1 to 2.0 mm in 30 (7.9%), and greater than 2.0 mm in 174 (45.5%). The 5-year locoregional recurrence-free survival (LRFS) rate was 96.3% (95% CI, 94.0-98.6), DFS was 85.5% (95% CI, 81.8-90.7), and OS was 90.8% (95% CI, 87.4-94.2). There was no difference in LRFS, disease-free survival (DFS), or OS for margins of 2 mm or less vs greater than 2 mm. In addition, no differences in DFS or OS for margins 1 mm or less vs greater than 1 mm were reported.
Another study found similar results. Of 582 patients, 88% of patients had margins greater than 2 mm, and 12% had margins of 2 mm or less.9 The majority of tumors were HER2-positive (38%) or triple negative (31%). Investigators reported that pCR was observed in 29% of patients.
NAC and Lymph Node DiseaseThe benefits of using NAC to eradicate nodal disease have been documented by a number of investigators.10
Mamtani A et al10 showed that of 288 node-positive patients, 70% were candidates for sentinel lymph node biopsy (SLNB) after receiving NAC. For 48%, axillary lymph node dissection was avoided, which sup- ports the role of NAC.
In the study, 534 patients with stage II and III cancer receiving NAC were identified.10
Among the patients with node-positive disease (n = 288), 132 (68%) were eligible for SLNB. Of those, 73 (55%) had estrogen receptor (ER)–positive disease; 21 (16%) had ER-negative, HER2-positive disease; and 38 (29%) had triple-negative disease. In 4 cases, SLNB was deferred intraoperatively.
"Patients who are ER-positive, HER2-negative have a lower pCR in the nodes, in a similar fashion as in the breast," Weiss said (TABLE 210).
What Effect Does NAC Have on SLNB?Results of several studies have suggested identification rates that range from 80.1% to 92.9%, with a corresponding false negative rate that ranges from 9.6% to 15.0%.11-13
"Even the study NSABP B-27,11 conducted in 2005, had a group of surgeons that each performed at least 1 sentinel node followed by axillary dissection in a patient, and they had an 85% sentinel node identification rate and a false-negative rate of 10.7%," Weiss said.
Further prospective studies evaluated patients who had received NAC followed by SLNB and axillary dissection. In those studies, false-negative rates were higher than 10%. "At that point, we asked, 'Could a surgeon reduce the false-negative rate?'" Weiss said. There were a number of technical factors, including the mapping agent, number of lymph nodes obtained, pathologic evaluation, and localization/ identification of the clipped node. "All of these are technical factors that could reduce the false-negative rate," Weiss said.
Notably, the trials looking at clipping the lymph node garnered further attention. Clipping and ensuring the lymph node is removed with SLNB provides the lowest false-negative rate, results showed.14-16
Future for Patients With cN0 and cN1 DiseaseNodal pCR rates can be very high. One of the biggest predictors of nodal pCR rate, aside from clinical nodal status, is breast pathologic response. Weiss et al17 showed that 96% or more of patients with cN0 disease and who experienced breast pCR had nodal pCR as well.
Two studies explored this further. The EUBreast-01 study evaluated 267 patients who had a radiologic CR and underwent a lumpectomy.18
If the patient had a breast pCR, they were followed, but if residual disease was found, they underwent an SLNB.
The ASICS trial (NL-OMON48085) in the Netherlands evaluated 340 patients. If the patient has a breast MRI that shows radio- logic CR, they undergo a lumpectomy, and not doing SLNB.19
"That's going a little bit further, but it's interesting, nonetheless," Weiss said.
In patients with cN1 disease, the challenges with NAC and residual disease are the volume of nodes that are positive and the patient's response or lack of response to therapy. "I think the concern is that there is probably a high volume of disease present," Weiss said. "These are higher-stage, aggressive tumors. Usually, we give patients NAC, and if there is residual disease, it means that the disease has not responded to therapy. It also indicates that there might be a lot more nodes that are positive. I think we need to do an axillary dissection for cN1 node-positive patients after NAC."
Weiss concluded, "Surgical de-escalation is made possible by neoadjuvant therapy. Breast conservation does not rely on a breast pCR, but [you should] consider the pattern of response [when reviewing margins]. Axillary nodal PCR rates are high, and many patients can avoid an axillary dissection, and even more will be able to avoid it in the future, but for now, these [patients] should have a dissection.
REFERENCES
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