Kate Johnson

Disclosures

August 26, 2016

"Precision medicine" has been championed in oncology as a means of focusing on the genomic target of an individual's cancer. The aim is to personalize therapy so that only the necessary surgery, radiation, and chemotherapy are delivered. Clinicians who embrace the "less is more" approach to treatment can minimize toxicity and maximize therapeutic benefit for their patients, a panel of experts noted at the annual American Society of Clinical Oncology (ASCO) meeting.

In breast cancer, the addition of genomic tests to clinicopathologic information can assist clinicians in identifying patients who can safely avoid chemotherapy, noted Fatima Cardoso, MD, of the Champalimaud Cancer Centre in Lisbon, Portugal.

Genomic Tools Indicate Who Needs Chemo...

As reported by Medscape, MINDACT (Microarray for Node-Negative Disease May Avoid Chemotherapy Trial), for which Dr Cardoso was one of the principal investigators, demonstrated how the 70-gene MammaPrint assay can combine a patient's clinicopathologic and genomic information and come up with a risk score predicting need for adjuvant chemotherapy.[1]

This risk assessment can reduce the delivery of chemotherapy to 46% of patients who might otherwise receive it on the basis of clinical assessment alone, said Dr Cardoso.

"It's a substantial reduction in chemotherapy with no negative impact on outcome. The MINDACT results provide level 1A evidence of the clinical utility of MammaPrint for assessing the lack of a clinically relevant chemo benefit in the clinically high-risk population," she said. "This is very important because almost 50% of this population have node-positive disease, and in the majority of cases when a patient has node-positive disease, they immediately go for chemotherapy."

Oncotype DX is another genetic assessment tool that is currently being evaluated in TAILORx (Trial Assigning IndividuaLized Options for Treatment). By measuring the expression of 21 genes, the test generates a recurrence score to predict a patient's 10-year risk for relapse, which can guide clinicians on the appropriateness of prescribing chemotherapy.

Initial results in the low-risk arm of the trial were published in late 2015[2] and showed that the test could identify patients for whom endocrine therapy alone "does extremely well," said Dr Cardoso. The 5-year invasive disease-free survival rate was 93.8%, and "also for the other endpoints there an excellent outcome without chemotherapy. We still need to see what happens in the intermediate-risk group, which is the most difficult to treat."

Overall, all of these genomic tools are predictive of response to chemotherapy in general "in the sense that those who are classified as high risk derive a substantial benefit from chemotherapy," said Dr Cardoso. But she emphasized that they should not replace, but rather complement, classic prognostic factors.

"Even when you put the genomic test into the multivariate analysis, node positivity and tumor size come out independently prognostic," she stressed.

First-generation genomic signature tests such as Oncotype DX and MammaPrint have time-dependent hazard ratios, so they are better at predicting early relapses.

Second-generation signatures such as PAM50 (Prosigna) and ENDOPREDICT are helpful in predicting later relapse, therefore guiding clinicians in the 5- to 10-year follow-up, "maybe one day to help distinguish those who need extended adjuvant therapy from those who don't," said Dr Cardoso.

...And Who Doesn't Need Chemo

The MammaPrint test has also been used to identify women with ultra-low-risk, "indolent" tumors, noted Laura Esserman, MD, of the University of California, San Francisco.

With increased focus on breast cancer screening, "we've surfaced an indolent reservoir": tumors for which aggressive therapies produce "financial toxicity, toxicity from therapy, and also from anxiety," she said.

Using an ultralow MammaPrint risk score of 0.7, which they call the "indolent threshold," her team identified a group of breast cancer patients with zero 15-year breast cancer–specific mortality after surgical treatment and a short (2-5 years) course of tamoxifen, said Dr Esserman, who presented the findings at the 2015 San Antonio Breast Cancer Symposium.[3]

In DCIS, Less Works for Margins but Not Radiation

Another "victim" of aggressive breast cancer screening is ductal carcinoma in situ (DCIS), for which overtreatment is common, said Eun-Sil Shelley Hwang, MD, of Duke University in Durham, North Carolina.

"Even with the very-low-risk lesions, we are still treating patients with a heck of a lot of surgery," said Dr Hwang, citing a recent Surveillance, Epidemiology, and End Results (SEER) registry analysis by her group[4]showing that 46% of patients with DCIS were treated with lumpectomy and radiation, 21% with radiation alone, 19% with unilateral mastectomy, and—"very concerningly"—8% with bilateral mastectomy.

The analysis showed no difference in disease-specific survival whether patients were treated with mastectomy or lumpectomy (with or without radiation). "Regardless of what treatment patients get, they have somewhere between a 98% and 99% 10-year breast cancer–specific survival after treatment for DCIS, which really begs the question of whether we're doing a bang-up job of treating everyone with DCIS or whether some proportion could have done just fine if we hadn't treated or diagnosed their DCIS," said Dr Hwang.

As reported by Medscape recent recommendations from the Society of Surgical Oncology and American Society for Radiation Oncology (SSO-ASTRO)[5] on surgical margins for DCIS "will guide some of our immediate concerns about how large the margin width needs to be in women who are undergoing lumpectomy," she added.

The new guidelines concluded that 2 mm should be the standard for an "adequate" margin because it is associated with a reduced risk for ipsilateral breast tumor recurrence (IBTR) compared with narrower cancer-free margins. Of note, wider margins conveyed no benefit. However, the differences in outcomes (ie, IBTR) between smaller, narrower negative margins are "relatively small."

One area where the less-is-more philosophy does not seem to apply is radiation therapy for DCIS.

"There have now been several large randomized trials on which we can base some of our recommendations, and in aggregate, there's a substantial reduction in new breast cancers in the ipsilateral breast with the addition of radiotherapy on top of lumpectomy," noted Dr Hwang.

In RTOG 9804, the most recent trial[6]involving very-low-grade DCIS, the 7-year local failure rate was 0.9% in patients who received lumpectomy plus radiotherapy compared with 6.7% in those receiving lumpectomy alone.

In disease treated less aggressively, the Oncotype DX DCIS Score "appears to have some prognostic efficacy in terms of risk after lumpectomy such that radiation may be considered," said Dr Hwang, citing the most recent validation of this test.[7]

"In my practice, if I have a patient whose clinical parameters would dictate that she would be very reasonably managed without any radiation, I don't choose to have the patient undergo testing with this score. On the other hand, if the patient is extremely high risk, I also wouldn't test her because then we would recommend radiation. It's really in the intermediate group that you might consider this test," she said.

And finally, there is growing interest in investigating an active surveillance approach for low-risk DCIS. Usual care (ie, surgery and/or radiation) is being compared with active surveillance in two European trials already underway (LORD and LORIS and the soon-to-be-launched US COMET (Comparison of Operative vs Medical Therapy) trial, for which Dr Hwang is the principal investigator.

Dr Cardoso disclosed consulting or advisory roles with: Astellas Pharma; AstraZeneca; Celgene; Daiichi Sankyo; Eisai; GE Healthcare; Genentech; GlaxoSmithKline; Merck Sharp & Dohme; Merus; Novartis; Pfizer; Pierre Fabre Medicament; Roche; Sanofi; Teva.

Dr Esserman disclosed consulting or advisory roles with Genentech (Inst); and travel, accommodations, expenses paid by Genentech.

Dr Hwang disclosed employment with Genomic Health; a consulting or advisory role with GHI Pharma; and travel, accommodations, and expenses paid by GHI Pharma.

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