乳腺癌受体改变或可预测结局

旧金山——在美国临床肿瘤学会(ASCO)等多家学会主办的乳腺癌研讨会上公布的一项多因素分析显示，新辅助治疗后任何乳腺癌肿瘤生物标志物的改变与5年复发风险降低37%独立相关。


Napa Parinyanitikul医生

德克萨斯大学MD安德森癌症中心的Napa Parinyanitikul医生及其同事分析了1992~2012年在该中心接受治疗的患者的治疗前活检样本和新辅助化疗后残留疾病样本的肿瘤生物标志物结果。大部分受试者为白人，临床疾病分期为Ⅱ期或Ⅲ期。在这些肿瘤中，49%为激素受体阳性和人表皮生长因子受体2(HER2)阴性；18%为HER2阳性，33%为所有3种受体阴性(三阴性乳腺癌)。

新辅助化疗包括含紫杉烷类方案(10%)、含蒽环类方案(19%)、含蒽环类/紫杉烷类方案(71%)和含曲妥珠单抗化疗(49%)。88%的激素受体阳性疾病患者接受他莫昔芬或芳香化酶抑制剂辅助内分泌治疗。在中位随访40个月后，32%的女性死亡，42%复发乳腺癌。

依据乳腺癌亚型的不同，受体状态改变的可能性存在显著差异。在激素受体阳性癌症中，51%发生受体状态改变，而在HER2阳性癌症中，27%发生受体状态改变，在三阴性乳腺癌中，22%发生受体状态改变。

其他因素不显著影响受体状态改变的可能性，包括患者年龄或种族、组织学、肿瘤分期或分级、存在淋巴血管侵犯、或新辅助化疗药物的类别。

在ER阳性肿瘤中，11%在新辅助化疗后改变为雌激素受体(ER)阴性；在ER阴性肿瘤中，21%改变为ER阳性。在孕激素受体(PR)阳性肿瘤中，35%改变为PR阴性；在PR阴性肿瘤中，12%改变为PR阳性。在HER2阳性肿瘤中，40%改变为HER2阴性；在HER2阴性肿瘤中，3%改变为HER2阳性。在35例接受曲妥珠单抗治疗的患者中，16例(46%)的HER2状态改变。

ER阴性状态未改变的肿瘤患者的5年总生存率(47%)和无复发生存率(40%)差于ER阳性状态未改变的肿瘤患者(总生存率81%，无复发生存率63%)、ER状态从阳性改变为阴性的患者(总生存率67%，无复发生存率66%)和ER状态从阴性改变为阳性的患者(总生存率75%，无复发生存率59%)。

同样，PR阴性肿瘤状态未改变的患者的总生存率(51%)和无复发生存率(41%)显著低于PR阳性肿瘤状态未改变的患者(总生存率87%，无复发生存率67%)、PR状态从阳性改变为阴性的患者(总生存率78%，无复发生存率73%)和PR状态从阴性改变为阳性的患者(总生存率69%，无复发生存率55%)。

HER2状态改变或缺乏改变与各种转归无显著关联。

研究者还以10%增量为临界在10%至50%范围内探讨ER或PR状态的绝对百分改变率。ER状态改变20%以上的ER阳性患者的5年总生存率显著高于ER状态改变低于20%的患者(87% vs. 73%)。ER状态改变20%以上的患者的5年无复发生存率也显著高于ER状态改变低于20%的患者(71% vs. 59%)。

在新辅助化疗前激素受体阳性和HER2阴性的肿瘤中，20%在治疗后改变为HER2阳性或三阴性乳腺癌，12%的HER2阳性肿瘤在治疗后改变为三阴性肿瘤，2%的三阴性乳腺癌在治疗后改变为HER2阳性。这些改变对转归产生的唯一显著影响是：从HER2阳性改变为三阴性乳腺癌的患者的5年总生存率(23%)显著低于HER2阳性乳腺癌未改变为三阴性乳腺癌的患者(71%)。

研究者表示，需开展样本量更大的前瞻性研究，以确认上述研究结果并确定生物标志物的改变对远期生存的任何影响。

Parinyanitikul医生声明无经济利益冲突。

专家点评：技术上的不精确影响受体状态的改变


Lajos Pusztai医生

耶鲁大学乳腺肿瘤内科主任Lajos Pusztai医生表示，即使实际的标志物状态并未发生任何改变，如果重复对相同样本进行检测，也可能观察到ER和PR状态改变。一项“经典”研究显示，在通过飞机将样本从一个中心转移至另一个中心后，有23%的样本发生HER2或ER状态改变。你不能因此得出飞机运输引起受体状态改变的结论。同样，在上述研究中，你无法得出化疗导致受体状态改变的结论，因为这种不一致性部分是由检测技术的不精确引起。例如，如果检测的准确性为90%，则10%的首次检测结果将为“噪音”，20%的重复检测结果将不一致。另外，在现实临床环境中，常有这种情况，即患者第一次的受体状态检测是在某个实验室进行，而第二次检测是在不同的实验室进行。上述研究未报告此类患者比例，这也是独立于治疗以外的导致受体不一致的显著原因。Pusztai医生与BiPar Sciences/赛诺菲等多家药企存在利益关系。

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By: SHERRY BOSCHERT, Internal Medicine News Digital Network

SAN FRANCISCO – A change in the status of any breast cancer tumor biomarker after neoadjuvant therapy was independently associated with a 37% decreased likelihood of recurrence in 5 years, a multivariate analysis showed.

The subtyping of breast cancer by receptor status changed in 41% of 398 samples between the initial tumor and residual disease after neoadjuvant chemotherapy.

In patients with any change in the status of estrogen receptor (ER), progesterone receptor (PR), or human epidermal growth factor receptor 2 (HER2), after neoadjuvant chemotherapy, 63% were relapse free 5 years later as compared with 48% of patients with no receptor change, a significant difference.

Overall survival at 5 years, however, did not differ significantly based on receptor status change, Dr. Napa Parinyanitikul and her associates reported at a breast cancer symposium sponsored by the American Society of Clinical Oncology. At 5 years, 73% of patients with a receptor status change and 63% with no change were alive.

The study analyzed data on patients treated at her institution in 1992-2012 who had tumor biomarker results from pretreatment biopsies and from samples of residual disease after neoadjuvant chemotherapy. Most patients in the study were white, with clinical stage II or III disease.

Of the tumors, 49% were hormone receptor–positive and HER2 negative; 18% were HER2 positive, and 33% were negative for all three receptors (triple-negative breast cancer). Neoadjuvant chemotherapy consisted of a taxane-based regimen in 10%, an anthracycline-based regimen in 19%, an anthracycline/taxane-based regimen in 71%, and trastuzumab-based chemotherapy in 49%. The 88% of patients with hormone receptor-positive disease received adjuvant endocrine therapy with tamoxifen or an aromatase inhibitor.

After a median of 40 months of follow-up, 32% of women had died and 42% had a recurrence of breast cancer, reported Dr. Parinyanitikul, a fellow at the University of Texas MD Anderson Cancer Center, Houston.

The likelihood of receptor status changes differed significantly by the subtype of breast cancer. Of hormone receptor–positive cancers, 51% had a change in receptor status, compared with 27% of HER2-positive cancers and 22% of triple-negative breast cancers.

Other factors did not significantly affect the likelihood of receptor status change, including patient age or race, histology, tumor stage or grade, the presence of lymphovascular invasion, or the class of neoadjuvant chemotherapeutic agents.

Of ER-positive tumors, 11% changed to ER negative after neoadjuvant chemotherapy; of ER-negative tumors, 21% changed to ER positive. Of the PR-positive tumors, 35% changed to PR-negative; of PR-negative tumors, 12% changed to PR positive. Of HER2-positive tumors, 40% changed to HER2 negative; of HER2-negative tumors, 3% changed to HER2 positive. Among 35 patients treated with trastuzumab, the HER2 status changed in 16 (46%).

Patients who had tumors with an ER-negative status that did not change had the worst 5-year rates for overall survival (47%) and relapse-free survival (40%), compared with patients whose tumors had an ER-positive status did not change (81% overall survival and 63% relapse-free survival), patients whose ER status changed from positive to negative (67% and 66% survival rates, respectively), and patients whose ER status changed from negative to positive (75% and 59%, respectively).

Similarly, patients who had PR-negative tumors whose status did not change had significantly lower rates of overall survival (51%) and relapse-free survival (41%), compared with patients whose PR-positive tumor status did not change (87% and 67%, respectively), those who changed from PR positive to PR negative (78% and 73%, respectively), and patients whose PR-negative status changed to PR positive (69% and 55%, respectively).

Changes or lack of change in HER2 subgroups were not significantly associated with varying outcomes.

The investigators also looked at the absolute percent changes in ER or PR status using cutoffs in 10% increments from 10% to 50%. The 5-year overall survival rate was significantly greater in ER-positive patients who had at least a 20% change in ER status, compared with those with less than a 20% change (87% vs. 73%, respectively). The 5-year relapse-free survival rate also was significantly greater if the ER status changed by at least 20% (71%), compared with smaller ER changes (59%).

Of cancers that were hormone receptor–positive and HER2 negative before neoadjuvant chemotherapy, 20% changed to HER2-positive or triple-negative breast cancer after treatment, 12% of tumors that had been HER2 positive changed to triple negative tumors, and 2% of triple negative breast cancers changed to HER2-positive after treatment. These changes produced only one significant effect on outcomes: 5-year overall survival rates were significantly lower in patients who changed from HER2-positive to triple-negative breast cancer (23%), compared with those whose HER2-positive cancer did not change to triple negative (71%).

Larger prospective studies are needed to confirm the findings and to determine any impact of biomarker changes on long-term survival, she said.

Previous studies have reported discordance in hormone receptor status in up to 51% of breast cancers between the primary tumor and residual disease and changes in HER2 status in up to 43% of cases. Conclusions about associations between changes in receptor status and clinical outcomes have been inconsistent.

The symposium was cosponsored by the American Society of Breast Disease, the American Society of Breast Surgeons, the National Consortium of Breast Centers, the Society of Surgical Oncology, and the American Society for Radiation Oncology.

Dr. Parinyanitikul reported having no financial disclosures.

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Technical imprecision affects status changes

Technical artifacts when testing receptor status in breast cancer complicate assessments of their potential ramifications on outcomes.

ER and PR status can change if you repeat the testing on the same specimen without any change in the actual marker status. In one "classic" study, the HER2 or ER status changed in 23% of samples after they were air-mailed from one center to another. You can’t conclude that it was the airplane flight that changed receptor status.

Similarly, in the current study, you can’t conclude that it was the chemotherapy that changed the receptor status, because part of this discordance is from the technical imprecision of the test. If a test is 90% accurate, for example, 10% of results on first testing will be "noise" and approximately 20% of results on repeat testing will be discordant.

The study also did not report the proportion of cases in which initial receptor status tests were conducted in one laboratory and the second test was conducted at a different center, as is often the case in the real world. That also introduces a very large, obvious cause for receptor discordance independent of therapy.

Dr. Lajos Pusztai is a professor of medicine and director of the Breast Medical Oncology Section at Yale University, New Haven, Conn. He made his remarks during a question-and-answer session at the meeting. Dr. Pusztai reported financial associations with BiPar Sciences/Sanofi, Bristol-Myers Squibb, Pfizer, AstraZeneca, Roche/Genentech, and Foundation Medicine.